Colposcopy performance in the new primary HPV screening in Australia: How to determine colposcopy competency?

AIMS: To assess colposcopic performance and determine indicators for competency within the new Australian primary human papillomavirus (HPV) cervical screening program. MATERIALS AND METHODS: A retrospective observational study of 4542 women seen at The Royal Women's Hospital Colposcopy Clinic in Melbourne, from 1 December 2017 to 31 July 2020 after a higher-risk cervical screening test (CST) result. RESULTS: Histological CIN2+ was detected in 25.1% up to two years from first colposcopy visit (FCV). The majority (86.7%) of CIN2+ was detected early within the first six months of presentation. Biopsy rate overall was 96.1% with abnormal colposcopic impression. Of four colposcopists with a lower biopsy rate, only one was able to achieve this early detection rate. Biopsy was also taken in over 30% of cases with negative reflex cytology and normal colposcopy, with CIN2+ detected in 5.0% among positive HPV16/18 and 3.8% with non-16/18 HPV. Positive predictive value of high-grade colposcopic impression at FCV averaged 66.4% (range: 54.9-81.6% among our colposcopists) and is poorly correlated with early detection rate of CIN2+. Overall accuracy of colposcopy is 84.5% (range: 78.7-90.3%), buoyed by high true negative colposcopic predictions secondary to high rates of negative reflex cytology referral with the new screening algorithm and is also unlikely to be a useful colposcopy indicator. CONCLUSIONS: Early detection rate of CIN2+ within the first six months of presentation is a useful measure of colposcopy competency and we would encourage our National Cancer Screening Register to explore this with the participating colposcopists.

Diagnostic outcomes after colposcopy at a tertiary clinic for women aged 50-74 referred after detection of oncogenic human papillomavirus at primary screening.

AIMS: To examine outcomes in women aged 50-74 years after detection of oncogenic human papillomavirus (HPV) at cervical screening. MATERIALS AND METHODS: A retrospective observational study of 464 women seen in the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020, 292 (62.9%) were positive for HPV16/18 and 172 (37.1%) for HPV (not 16/18). RESULTS: Fifty-four women (11.6%) had histologically proven CIN2+ including seven cancers, up to two years after first colposcopy visit (FCV): 48 (88.9%) detected at FCV or at excisional treatment (Excision) arranged after no CIN2+ detected at FCV. There was no significant difference (P = 0.14) in proportion of CIN2+ detected between the two groups, 'HPV16/18' (9.9%) or 'HPV (not 16/18)' (14.5%), nor with reflex cytology types. The positive predictive value (PPV) of high-grade impression at colposcopy was 63.6%. There were 243 (52.4%) who had Type 3 transformation zone (TZ3) with 20 CIN2+ detected, 13 at FCV including all three cancers and five at Excision. There were 214 (73.3%) with positive HPV16/18 who had reflex negative cytology, of which seven had CIN2+ including one cancer but only two (1.4%) CIN2+ when their repeat cytology at colposcopy was negative. CONCLUSIONS: Most CIN2+ were detected at first colposcopy or at subsequent excision. We would encourage high biopsy rates at colposcopy and vigilance in selection for excisional treatment in TZ3 cases if there is no significant suspicion of high-grade abnormality. There is a need to refine the algorithm for management of persistent HPV16/18 infections with reflex negative cytology to reduce colposcopy referrals in women aged 50 and above.

Outcomes of women with positive oncogenic HPV and reflex cytology showing possible high-grade squamous intraepithelial lesion.

AIM: To examine outcomes in women following cervical screening detection of oncogenic human papillomavirus (HPV), with reflex cytology showing possible high-grade squamous intraepithelial lesion (pHSIL). MATERIALS AND METHODS: A retrospective observational study of 523 women seen in the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020. RESULTS: Two hundred eighty-two (53.9%) women had histology-confirmed HSIL, encompassing CIN2 or worse (CIN2+), including seven cancers (1.3%) and two adenocarcinoma in situ (AIS) (0.4%). In 81.2% (229/282) of women with CIN2+, this was detected on cervical biopsy at initial colposcopy, with another 8.9% (25/282) of CIN2+ detected at cervical excision following initial colposcopy and the remaining 9.9% (28/282) at follow-up colposcopy thereafter. When discordant cervical biopsy results were discussed at multidisciplinary meeting (MDM), 66.7% of women with pHSIL cytology upgraded to definite HSIL were found to have CIN2+, but only 20.8% when pHSIL cytology was retained and none when downgraded to low-grade (LSIL) or normal. No significant difference was found in the proportion of CIN2+ based on patient age above or below 40, HPV16 and/or 18 versus non 16/18, or whether discordant findings were reviewed at MDM. CONCLUSIONS: We propose a pathway for management of women with positive oncogenic HPV and reflex pHSIL cytology. MDM review is recommended when CIN2+ is not identified on cervical biopsy at initial colposcopy. Conservative management is safe with low risk of CIN2+ when LBC prediction of pHSIL is confirmed or downgraded at MDM with no high-grade change on colposcopy or repeat cytology.

Primary HPV cervical screening: Clinical audit of outcomes of women seen at a tertiary referral centre for colposcopy in Australia.

BACKGROUND: Primary human papillomavirus (HPV) screening was introduced in Australia in December 2017. AIMS: Outcomes for women after positive HPV in their cervical screening test (CST). MATERIALS AND METHODS: A retrospective observational study of 4458 women seen at the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020. RESULTS: HPV16/18 was positive (considered higher-risk CST) in 42.2% of women in the study, 16.6% with reflex possible with high-grade squamous intraepithelial lesions (pHSIL) or worse and 54.9% with normal cytology. There were 24.8% of women with positive HPV16/18 who had histological confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+), 10.3% CIN2+ (including six cancers) among women with reflex negative cytology and 87.7% CIN2+ among women with reflex HSIL cytology. In women with positive HPV (not 16/18), CIN2+ was found in 60.2% with reflex pHSIL or worse cytology (higher risk) and 10.2% with reflex low-grade SIL (LSIL) or normal cytology (intermediate risk). Median waiting time to colposcopy with the intermediate-risk group went up to 181 days. Our colposcopists were able to achieve a positive predictive value (PPV) for CIN2+ of 69.9%, higher than 57.8% PPV in the National Cervical Screening Program (NCSP) 2020 monitoring report. Women with type 3 transformation zone on colposcopy could be followed up with CST if no HSIL was suspected on screening or at colposcopy as their risk of CIN2+ was only 2.5%. CONCLUSIONS: Our findings support direct referral to colposcopy for women with higher-risk CST, with all cancers confined to this group. The NCSP recommendation to refer for colposcopy only after three intermediate-risk CST will need monitoring with the LSIL triage group.

Excisional treatment comparison for in situ endocervical adenocarcinoma (EXCISE): A phase 2 pilot randomized controlled trial to compare histopathological margin status, specimen size and fragmentation after loop electrosurgical excision procedure and cold knife cone biopsy.

OBJECTIVE: Adenocarcinoma in situ (AIS) of the cervix is a precursor to cervical adenocarcinoma. When AIS is detected by cervical screening an excision biopsy is mandatory to exclude invasion. We aimed to compare margins status, specimen size and fragmentation after loop electrosurgical excision procedure (LEEP) and 'cold knife cone biopsy' (CKC). METHODS: The EXCISE Trial was an investigator-initiated, multicenter, open-label, parallel-group, phase 2, randomized study. Patients were enrolled at seven hospitals in Australia and New Zealand. We randomly assigned women aged ≥18 to ≤45 years with screen detected AIS to LEEP or CKC. Co-primary endpoints were margin status, specimen size and fragmentation. Analysis was by intention-to-treat. RESULTS: Between August 2, 2017 and September 6, 2019, 40 patients were randomly assigned 2:1 to LEEP or CKC. Margin status was evaluable in 36 cases. The proportion of patients with involved margins did not differ between groups. 25 of 26 LEEP and all 14 CKC biopsies were excised as single specimens (p = 1·00). There were no differences in specimen dimensions. Patients in the CKC group had more post-operative complications (64.3% compared to 15.4% for LEEP p = ·00). There were no differences in grade three complications (p = ·65). CONCLUSIONS: LEEP was not associated with a greater likelihood of positive margins, specimen fragmentation or smaller excision compared to CKC when performed according to a standardized protocol. However, the study was not powered to establish non-inferiority of LEEP and a definitive phase 3 trial to compare margin status and rates of treatment failure after LEEP and CKC is warranted.

Recurrent post-coital bleeding: Should colposcopy still be mandatory?

BACKGROUND: Colposcopy has been recommended for all women with recurrent post-coital bleeding (PCB) even if their cervical cytology or co-test (involving oncogenic human papillomavirus (HPV) DNA testing and cytology) are negative. AIMS: To determine the risk of cervical cancer and its precursors among women with recurrent PCB with negative cytology or co-test. MATERIALS AND METHODS: A retrospective analysis of two cohorts of women with PCB referred to a tertiary colposcopy clinic. Cohort (1) (n = 1846) between 1 January 2000 and 31 December 2016 (cytology-based screening) and Cohort (2) (n = 215) from 1 January 2018 to 31 December 2019 after introduction of primary HPV screening. RESULTS: In 1217 (65.9%) women in Cohort (1) referred with negative cytology, there was one cancer (0.08%) and 22 high-grade squamous intraepithelial lesions (HSIL (cervical intraepithelial neoplasia 2/3)) on histopathology. In Cohort (2), there was no cancer or HSIL in 83 women with negative co-tests (negative for oncogenic HPV and cytology). False-negative cytology after a negative referral cytology or co-test was low with 2% of repeat cytology at initial colposcopy showing possible HSIL or worse. CONCLUSIONS: Women presenting with PCB and negative cytology alone have a low risk of cancer and could have HPV testing before being triaged to colposcopy. We showed that with the assurance of a negative co-test and the low likelihood of false-negative cytology, these women could avoid colposcopy unless cervical cancer is clinically suspected. There is a need for a larger cohort study to substantiate our findings with more precision.

Increased risk of cervical dysplasia in females with autoimmune conditions-Results from an Australia database linkage study.

BACKGROUND: Autoimmune conditions (AICs) and/or their treatment may alter risk of human papilloma virus (HPV) infection and females with AICs are therefore at an increased risk of cervical dysplasia. However, inclusion of these at-risk populations in cervical cancer screening and HPV-vaccination guidelines, are mostly lacking. This study aimed to determine the prevalence of cervical dysplasia in a wide range of AICs and compare that to HIV and immunocompetent controls to support the optimisation of cervical cancer preventive health measures. METHODS: Data linkage was used to match cervical screening episodes to emergency department records of females with AICs or HIV to immunocompetent controls over a 14-year period. The primary outcome was histologically confirmed high-grade cervical disease. Results, measured as rates by cytology and histology classification per 1,000 females screened, were analysed per disease group, and intergroup comparisons were performed. RESULTS: Females with inflammatory bowel disease (2,683), psoriatic and enteropathic arthropathies (1,848), multiple sclerosis (MS) (1,426), rheumatoid arthritis (1,246), systemic lupus erythematosus and/or mixed connective tissue disease (SLE/MCTD) (702), HIV (44), and 985,383 immunocompetent controls were included. SLE/MCTD and HIV groups had greater rates of high-grade histological and cytological abnormalities compared to controls. Increased rates of low-grade cytological abnormalities were detected in all females with AICs, with the exception of the MS group. CONCLUSIONS: Females with SLE/MCTD or HIV have increased rates of high-grade cervical abnormalities. The increased low-grade dysplasia rate seen in most females with AICs is consistent with increased HPV infection. These findings support expansion of cervical cancer preventative programs to include these at-risk females.

Findings and Outcomes in a Prevaccination Cohort of Women Younger Than 25 Years Attending a Tertiary Colposcopy Service.

OBJECTIVE: To describe clinical presentation and treatment in women younger than 25 years referred to the Royal Women's Hospital colposcopy clinic, before implementation of the National Human Papillomavirus Vaccination Program. METHODS: Retrospective cohort analysis of women younger than 25 years referred to a tertiary hospital colposcopy clinic between 1998 and 2007. Clinical presentation and correlation between cervical cytology, biopsy, and histology at treatment was examined. RESULTS: Approximately 14,635 colposcopies were undertaken in 4104 women (median age, 22 years); 3051 had abnormal referral cytology, of whom, 23.8% had high-grade disease on punch biopsy. High-grade disease was found in 15.1% of those with possible low-grade or low-grade cytology (293/1932), 42.4% of those with possible high-grade or high-grade cytology (474/1119). Sensitivity and specificity of colposcopy for high-grade disease (high-grade epithelial abnormality, adenocarcinoma in situ, cervical cancer up to 2 years follow-up) was 60.0% and 82.3%, respectively. Thirty-nine percent (n = 1180) with abnormal cytology had treatment, of which, 66.6% was ablative. Histological CIN3+ was found in 53.8% of those with a previous high-grade punch biopsy (126/234) at excisional treatment, and 23.0% of those with a previous low-grade punch biopsy (20/87) (relative risk, 2.3 [CI, 1.6-3.5]). Four cancers were detected (0.1% of the total cohort, 0.5% of those with a high-grade biopsy, and 1.7% of those with a high-grade biopsy who underwent excisional treatment.) CONCLUSIONS: Before vaccination, young women experienced a high real-time burden of high-grade disease and high rates of intervention. These baseline data contribute to monitoring of HPV vaccination and revised cervical screening strategies.

Clinicians' attitude towards changes in Australian National Cervical Screening Program.

BACKGROUND: Australian guidelines for cervical cancer screening are being revised under the "renewal program". Physicians' willingness to accept these changes will play a pivotal role in its success. OBJECTIVE: To understand the willingness and acceptance of, as well as barriers and facilitators for Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) affiliates to screening using human papillomavirus (HPV) testing, starting at 25 years of age, every 5 years. STUDY DESIGN: An electronic survey of RANZCOG affiliates was undertaken April-June 2014, while renew was announced April 28th 2014. Responses used a 7 point Likert scale, which was dichotomized as ≤4, indicating 'unwilling' and >4, indicating 'willing' to adopt revised practices. RESULTS: Response rate was 22% (n=956): 60% were obstetricians and gynaecologists (OG); 27% general practitioner diplomates; 13% OG trainees. Overall, 60% (n=526/874) were willing to revise their screening practice. This correlated with awareness of new guidelines (p=<0.001). Fifty percent (n=438/869) of respondents were concerned about delaying to 25 years, and 48% (n=421/869) concerned cervical cancers would be missed. Reasons respondents gave for wishing to continue screening from 18 years contrary to guidelines included: women not being vaccinated (65.6%), immunosuppressed women (92.2%) and women who had been victims of childhood sexual assault (73.9%). CONCLUSIONS: The majority of RANZCOG affiliates were willing to change screening practice however, a number of barriers to delaying onset of screening age to age 25 years were reported. Effective change management strategies will need to be implemented to address the concerns raised to ensure best practice for cervical screening.

New technologies and advances in colposcopic assessment.

To have a good grasp of clinical colposcopy, it is necessary to understand the histopathologic structure of the normal and dysplastic cervical epithelium. Previous meta-analyses had indicated high overall sensitivity of colposcopy in detecting dysplastic lesions, but recent studies have suggested that the technique has much lower sensitivity in detecting high-grade intraepithelial neoplasia. The best practice in colposcopy relies on accurately taking a biopsy from the correct (i.e. most morphological abnormal) site, and by taking more than one biopsy, the sensitivity for detection of high-grade cervical intraepithelial neoplasia can be increased. Cytological screening programmes of proven and maintained high quality will enhance the predictive colposcopic accuracy for high-grade cervical intraepithelial neoplasia after referral. With the advent of computerised colposcopy and the Internet, digital imaging can be transmitted in real-time for instant viewing, facilitating distant consultation and education. This form of 'telemedicine' will allow family practice and remote areas to have access to colposcopy expertise. Of all the currently available technological adjuncts to colposcopy, spectroscopy devices have demonstrated relatively high sensitivities, and seem to have the best potential to become the technique of choice in future routine clinical practice in developed countries following the human papillomavirus vaccination. Other alternatives may need to be used in parts of the globe with high disease incidence and without organised screening or vaccination programmes. Opportunities remain for global collaboration in research, education and training to promote more effective and affordable cervical screening, and to enhance the skills of colposcopists worldwide.

Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE): a randomised trial.

BACKGROUND: This two-stage randomised controlled trial, comparing total laparoscopic hysterectomy (TLH) with total abdominal hysterectomy (TAH) for stage I endometrial cancer (LACE), began in 2005. The primary objective of stage 1 was to assess whether TLH results in equivalent or improved quality of life (QoL) up to 6 months after surgery compared with TAH. The primary objective of stage 2 was to test the hypothesis that disease-free survival at 4.5 years is equivalent for TLH and TAH. Here, we present the results of stage 1. METHODS: Between Oct 7, 2005, and April 16, 2008, 361 participants were enrolled in the QoL substudy at 19 centres across Australia, New Zealand, and Hong Kong; 332 completed the QoL analysis. Randomisation was done centrally and independently from other study procedures via a computer-generated, web-based system (providing concealment of the next assigned treatment), using stratified permuted blocks of three and six patients. Patients with histologically confirmed stage I endometrioid adenocarcinoma and Eastern Cooperative Oncology Group performance status less than 2 were randomly assigned to TLH (n=190) or TAH (n=142), stratified by histological grade and study centre. Patients and study personnel were not masked to treatment assignment. QoL was measured at baseline, 1 and 4 weeks (early), and 3 and 6 months (late) after surgery, using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The primary endpoint was the difference between groups in QoL change from baseline at early and late timepoints (a 5% difference was considered clinically significant). Analysis was done according to the intention-to-treat principle. Patients for both stages of the trial have now been recruited and are being followed up for disease-specific outcomes. The LACE trial is registered with ClinicalTrials.gov, number NCT00096408. FINDINGS: Eight of 332 patients (2.4%) had treatment conversion-seven from TLH to TAH and one from TAH to TLH (patient preference). In the early phase of recovery, patients who had TLH reported significantly greater improvement in QoL from baseline compared with those who had TAH, in all subscales apart from emotional and social wellbeing. Improvements in QoL up to 6 months after surgery continued to favour TLH, except in the emotional and social wellbeing measures of FACT and the visual analogue scale of the EuroQoL five dimensions (EuroQoL-VAS). Operating time was significantly longer in the TLH group (138 min [SD 43]) than in the TAH group (109 min [34]; p=0.001). Although the proportion of intraoperative adverse events was similar between groups (TAH eight of 142 [5.6%] vs TLH 14 of 190 [7.4%]; p=0.53); postoperatively, twice as many patients in the TAH group experienced adverse events of grade 3 or higher (33 of 142 [23.2%] vs 22 of 190 [11.6%] in the TLH group; p=0.004). Postoperative serious adverse events occurred more in the TAH group (27 of 142 [19.0%]) than in the TLH group (16 of 190 [7.9%]; p=0.002). INTERPRETATION: QoL improvements from baseline during early and later phases of recovery, and the adverse event profile, favour TLH compared with TAH for treatment of stage I endometrial cancer. FUNDING: Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Women's Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.