The tumour-derived extracellular vesicle proteome varies by endometrial cancer histology and is confounded by an obesogenic environment.

Endometrial cancer, the most common gynaecological cancer worldwide, is closely linked to obesity and metabolic diseases, particularly in younger women. New circulating biomarkers have the potential to improve diagnosis and treatment selections, which could significantly improve outcomes. Our approach focuses on extracellular vesicle (EV) biomarker discovery by directly profiling the proteome of EVs enriched from frozen biobanked endometrial tumours. We analysed nine tissue samples to compare three clinical subgroups-low BMI (Body Mass Index) Endometrioid, high BMI Endometrioid, and Serous (any BMI)-identifying proteins related to histological subtype, BMI, and shared secreted proteins. Using collagenase digestion and size exclusion chromatography, we successfully enriched generous quantities of EVs (range 204.8-1291.0 µg protein: 1.38 × 1011-1.10 × 1012 particles), characterised by their size (∼150 nm), expression of EV markers (CD63/81), and proposed endometrial cancer markers (L1CAM, ANXA2). Mass spectrometry-based proteomic profiling identified 2075 proteins present in at least one of the 18 samples. Compared to cell lysates, EVs were successfully depleted for mitochondrial and blood proteins and enriched for common EV markers and large secreted proteins. Further analysis highlighted significant differences in EV protein profiles between the high BMI subgroup and others, underlining the impact of comorbidities on the EV secretome. Interestingly, proteins differentially abundant in tissue subgroups were largely not also differential in matched EVs. This research identified secreted proteins known to be involved in endometrial cancer pathophysiology and proposed novel diagnostic biomarkers (EIF6, MUC16, PROM1, SLC26A2).

Prevaccine Human Papillomavirus Status in Invasive and Intraepithelial Lesions of the Vulva in New Zealand Women.

OBJECTIVE: The human papillomavirus (HPV) vaccine, introduced in New Zealand (NZ) in 2008, is predicted to substantially lower the incidence of HPV-associated precancers and cancers. The aim of this study is to estimate the proportion of vulvar intraepithelial neoplasia (VIN) lesions and invasive vulvar squamous cell carcinomas (SCCV) attributable to HPV in NZ women treated by the Auckland Regional Gynecological Oncology Service, covering an estimated 50% of the NZ population. MATERIALS AND METHODS: Polymerase chain reaction and reverse hybridization were used to analyze retrospective histologically proven SCCV from 1990 to 2007 and VIN lesions from 2000 to 2007 for HPV content and genotype in a collaborative study with the Catalan Institute of Oncology. Immunohistochemistry for p16INK4a was performed on SCCV, which were attributed to HPV if both tested positive. RESULTS: Polymerase chain reaction testing for HPV content and genotype was performed on 66 VIN lesions (all high-grade squamous intraepithelial lesions) and 189 SCCV. In addition, p16 immunohistochemistry was performed on 168 of the 189 SCCV (88.9%) tested for HPV-DNA. Overall, 61 SCCV cases (36.3%) were attributed to HPV (HPV+/p16+), and 89 SCCV cases (53%) were considered to have developed independently of HPV (HPV-/p16-). Known high-risk HPV genotypes were present in 96.8% of HPV-DNA-positive vulvar high-grade squamous intraepithelial lesions and 98.4% of HPV-attributable SCCV. Human papillomavirus 16 represented the most common genotype in both. CONCLUSIONS: Overall, the HPV vaccine is likely to substantially alter the profile of SCCV in our region. The results provide a baseline assessment of the HPV status of vulvar neoplasia before the introduction of the HPV vaccine.

HPV-independent and HPV-associated vulvar squamous cell carcinoma: two different cancers.

OBJECTIVES: We report the disease-specific survival of patients with human papillomavirus (HPV)-associated and HPV-independent vulvar squamous cell carcinomas and determine whether differences exist and are independent of stage and age at diagnosis. METHODS: This was a retrospective cohort study with case note and pathology slide review of 265 consecutive women with vulvar squamous cell carcinoma. These patients were treated over a 15 year period (2001-2016) at a centralized cancer center covering half the population of New Zealand. The women's cancers were categorized dependent on their adjacent pathology, immunohistochemistry and HPV status following expert slide review. Disease-specific survival was calculated using Kaplan-Meier univariable and Cox proportional hazard (adjusting for stage, age, and HPV dependence) multivariable methods. RESULTS: The survival analysis included 236 women with follow-up to 96 months; 124 of them were HPV-associated, 95 HPV-independent, and 17 were unclassifiable. Of the 236 women, 146 were stage 1 (92 HPV-associated, 49 HPV-independent, 5 unclassifiable), 13 stage II (7 HPV-associated, 6 HPV-independent), 62 stage III (20 HPV-associated, 34 HPV-independent, 8 unclassifiable) and 15 stage IV (5 HPV-associated, 6 HPV-independent, 4 unclassifiable). HPV-independent vulvar squamous cell carcinomas had significantly worse survival than HPV-associated vulvar squamous cell carcinomas independent of stage and age at diagnosis (HR 3.6 (95% confidence interval (CI): 1.6 to 8.2)). Tumors that were unclassifiable by HPV type also had significantly worse survival than HPV-associated tumors independent of stage and age at diagnosis (HR 6.2 (95% CI: 2.4 to 16.0)). CONCLUSIONS: HPV-independent vulvar squamous cell carcinomas present more frequently in older women than HPV-associated tumors. However, the poorer prognosis is independent of age and stage, with worse outcomes even in early stage disease.

Predicting regression of cervical intraepithelial neoplasia grade 2 in women under 25 years.

BACKGROUND: A number of retrospective and prospective studies have documented substantial rates of regression in cervical intraepithelial neoplasia grade 2 lesions in young women. Initial observational management of cervical intraepithelial neoplasia grade 2 is increasingly accepted as appropriate for women under 25 years of age with screen-detected abnormalities and is included in a number of clinical guidelines. However, there has been a paucity of large prospective studies on observational management with strict inclusion criteria. A number of important questions remain, specifically regarding the clinical variables that are associated with the risk of progression or persistence of disease. To investigate these factors and to ensure that young women with cervical intraepithelial neoplasia grade 2 undergoing observational management were being managed in a well-monitored and an appropriately informed fashion, we conducted a large, multicenter prospective study on observational management of cervical intraepithelial neoplasia grade 2 in women under 25 years. OBJECTIVE: This study aimed to determine the regression rates and clinical, cytologic, and pathologic predictors of regression of cervical intraepithelial neoplasia grade 2 in women under 25 years undergoing observational management over 24 months. STUDY DESIGN: This study was a multicenter prospective study on observational management of cervical intraepithelial neoplasia grade 2 (ie, repeat colposcopy, cytology, and cervical biopsy every 6 months) for up to 24 months. A total of 615 consenting women under 25 years with newly-diagnosed, biopsy-proven cervical intraepithelial neoplasia grade 2 were recruited (from 2010 to 2016) through 16 hospital-based colposcopy units in New Zealand and Australia. RESULTS: At completion, 326 women had confirmed regression, 156 had persistent high-grade cervical intraepithelial neoplasia grade 2 or 3 or adenocarcinoma in situ, and 24 had unconfirmed regression (ie, first regression at the 24-month follow-up). A total of 109 women did not complete the protocol (41 because of delayed follow-up, 41 lost to follow-up, 22 elected treatment, 4 refused a biopsy, and 1 died of an unrelated cause). Confirmed regression was observed in 53% (326 of 615) of all women enrolled in the study and, when missing data were imputed, it was estimated that 64% of women (95% confidence interval, 60%-68%) would have experienced regression. Similarly, lesions regressed in 64% (326 of 506) of women who completed the observational protocol. Based on a multivariable analysis, detection of human papillomavirus 16 in a liquid-based cytology sample at the time of initial colposcopy decreased the chance of regression by 31% (risk ratio, 0.69; 95% confidence interval, 0.56-0.86; P<.001). In addition, at initial colposcopy, low-grade or normal colposcopic impression, later year of diagnosis, low-grade or normal cytology, and being a nonsmoker were all independently associated with an increased chance of regression. CONCLUSION: More than half of women under 25 years with cervical intraepithelial neoplasia grade 2 will regress to cervical intraepithelial neoplasia grade 1 or normal within 24 months without destructive treatment. The absence of human papillomavirus 16 is the most important predictor of regression.

Vulval squamous cell carcinoma arising from hidradenitis suppurrativa.

A 47- year-old woman developed a rapidly enlarging vulvar mass. Although the clinical appearance suggested malignancy, its lack of atypia and invasion on initial superficial biopsy delayed the pathological diagnosis. It was not until a large incisional biopsy was performed that showed the diagnosis of verrucous squamous cell carcinoma (VSCC) involving pre-existing sinuses of hidradenitis suppurativa (HS). VSCC arising in HS is very rare and often leads to death in published cases. This case demonstrates the challenge in pathological diagnosis of this condition which impacted time to treatment.

Vulval lichen sclerosus: An Australasian management consensus.

BACKGROUND/OBJECTIVES: Vulval lichen sclerosus (VLS) is a chronic inflammatory skin condition predominantly affecting the anogenital region in women and children. To date, there is lack of agreement amongst experts on a severity scale to aid assessment, research and treatment stratification on VLS. Furthermore, literature on best practice for long-term management of VLS is lacking. The aim of this consensus is to provide broad guidelines on the short and long-term management of VLS. METHODS: An initial focus group of Australasian experts in vulval dermatology developed a draft consensus statement for the management of VLS. Based on the results of the draft statement, a consensus panel of 22 Australasian experts, comprised of the initial and additional members, participated in an anonymous four-stage eDelphi process. Round 1 involved generation and voting on statements from the draft consensus statement developed by the focus group. In Rounds 2, 3 & 4, panel members were presented formal feedback from previous rounds and asked to indicate their level of agreement. Consensus was reached if there was ≥70% agreement on the importance of an item in the 4 (agree) to 5 (strongly agree) range. RESULTS: The expert panel, with a total of 504 collective years of experience in the field of VLS, reached consensus on a core set of 51 management statements related to diagnosis, severity, initial and long-term management, follow-up, and complications of VLS. CONCLUSIONS: This study has identified a set of management statements for VLS that may be useful in clinical practice in the Australasian population.

Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

Trends in the diagnosis of high-grade cervical abnormalities in young women in the post-vaccination era.

BACKGROUND: Most cervical cancers are associated with human papillomavirus (HPV) types 16 and 18. In 2008, New Zealand commenced a quadrivalent HPV (virus-like particles of types 6, 11, 16 and 18) vaccination programme. AIM: Document trends in number of colposcopy referrals and number and grade of cervical abnormalities diagnosed in women (20-24 years) referred to three large colposcopy clinics over time. METHOD: Retrospective analysis of colposcopy clinic data. RESULTS: The dataset included 5,012 episodes from 4,682 women. In Auckland (2013-2017), there was a 38% decrease in colposcopy referrals and 55% decrease in cervical intraepithelial neoplasia grade 2 (CIN2) or worse diagnoses. In Waikato (2011-2017), there was an 8% decrease in referrals and 22% reduction in CIN2 or worse diagnoses. In Canterbury (2011-2017), there was a 24% decrease in referrals and 49% reduction in CIN2 or worse diagnoses. Across all centres, the decrease in cervical intraepithelial neoplasia grade 3 (CIN3) or worse diagnoses was marked and more consistent than in CIN2 diagnoses. However, while the proportion of biopsies reported as CIN3 or worse decreased in non-Maori (24% in 2013 vs 16% in 2017, nptrend z=-4.24, p>|z| <.001), there was no change in Maori women (31% in 2013 vs 29% in 2017, nptrend z=-0.12, p>|z| =.90). CONCLUSIONS: We observed a decreased number of CIN diagnoses in young women over time, with a particularly large drop in the number of CIN3/AIS/CGIN diagnoses. However, compared to non-Maori, Maori women having biopsies are more likely to have CIN3 or worse and there was a smaller reduction in the total number of Maori women diagnosed with CIN2 or worse.

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.

Demographics of New Zealand women with vulval lichen sclerosus: is specialist care equitable?

AIM: Vulval lichen sclerosus is an inflammatory genital skin condition associated with poor quality of life, sexual dysfunction and risk of squamous cell carcinoma. The aim of this study was to document the demographics of women with lichen sclerosus seen at specialist vulval clinics. METHOD: We performed a retrospective review of women with lichen sclerosus seen at a tertiary combined gynaecology/dermatology vulval clinic over 12 months and Auckland Regional sexual health vulval clinics over five years. Data were collected for age, ethnicity, skin biopsy, treatment, referral source and time from symptom onset to diagnosis. Ethnicity was compared with Census data for the Auckland region. DISCUSSION: Three hundred and thirty-five women were included; 273 from the gynaecology/dermatology clinic and 62 from sexual health. Women seen at sexual health were younger than those seen by gynaecology/dermatology (mean age 45 and 64, respectively; p<0.0001). Most referrals were from general practitioners (54%), although self-referrals made up 42% of sexual health consultations. The most common ethnicity was European (82%) followed by Asian (10%), Maori (4%) and Pacific Peoples (3%). Compared with Census data, European women were over-represented and Maori, Pacific and Asian women were under-represented. CONCLUSION: We found inequitable ethnic representation of women with vulval lichen sclerosus seen at our institution. Causes may include sociocultural beliefs, variations in access to care or ethnic differences in the prevalence of lichen sclerosus. A deeper understanding of underlying issues would enable planning of initiatives to ensure equitable access to specialist care for all New Zealand women with vulval conditions.

Evaluation of guidelines for observational management of cervical intraepithelial neoplasia 2 in young women.

BACKGROUND: A high rate of regression in young women with cervical intraepithelial neoplasia grade 2 has been recorded. However, there are few prospective data by which to evaluate management guidelines. OBJECTIVE: This study evaluates the American Society for Colposcopy and Cervical Pathology recommendations for follow-up of young women with cervical intraepithelial neoplasia 2 using data created by a large prospective multicenter study of observational management. MATERIALS AND METHODS: Participants were 616 women under 25 years with biopsy-diagnosed cervical intraepithelial neoplasia 2 following a referral to colposcopy for an abnormal smear with no previous high-grade abnormality. The protocol included colposcopy, cytology, and colposcopically directed biopsy at the initial visit and at 6- and 12-month follow-ups visits, and these data were analyzed. Histology from the corresponding cervical biopsy was treated as the reference diagnostic test. For young women with cervical intraepithelial neoplasia 2, we aimed to determine the following: (1) the ability of colposcopy to identify women with cervical intraepithelial neoplasia 3 or worse at 6 months; and (2) the ability of colposcopy, cytology, and a combination of cytology and colposcopy to identify residual high-grade abnormalities at 12 months. In addition, although not specified in the guidelines, we investigated the ability of high-risk human papillomavirus positivity alone or with cytology as a co-test to identify residual high-grade abnormalities at 12 months. RESULTS: At 6 months, cervical intraepithelial neoplasia 3+ colposcopic appearance identified only 28% (95% confidence interval, 18-40%) of women diagnosed with cervical intraepithelial neoplasia 3. At 12 months, a high-grade colposcopic appearance identified only 58% (95% confidence interval, 48-68%) of women with residual histological cervical intraepithelial neoplasia 2 or 3. At 12 months, high-grade cytology identified only 58% (95% confidence interval, 48-68%) of women with cervical intraepithelial neoplasia 2 or 3. However, the combination of either high-grade cytology or colposcopic appearance proved substantially more sensitive (81%; 95% confidence interval, 72-88%). High-risk human papillomavirus positivity at 12 months was a sensitive (96%; 95% confidence interval, 89-99%) indicator of persisting high-grade histology. However, this sensitivity came at the expense of specificity (52%; 95% confidence interval, 45-58%). A co-test of high-risk human papillomavirus positivity or high-grade cytology at 12 months provided a high sensitivity (97%; 95% confidence interval, 90-99%) but low specificity (51%; 95% confidence interval, 45%-58%). CONCLUSION: Colposcopy and cytology are limited in their ability to exclude persistent high-grade abnormality for young women undergoing observational management for cervical intraepithelial neoplasia 2. We recommend biopsy for all women at 12 months. High-risk human papillomavirus positivity is a sensitive indicator of persistent abnormality and should be considered in those not having a biopsy.

Trends in HPV-dependent and HPV-independent vulvar cancers: The changing face of vulvar squamous cell carcinoma.

OBJECTIVE: To investigate the incidence and survival of Vulvar Squamous Cell Carcinoma (VSCC) by etiology over a 27 year period. METHOD: Retrospective case-note and pathology slide review of 390 consecutive VSCC, treated at a Centralized Cancer Centre covering half New Zealand's population, 1990-2016. Incidence was calculated in 5-6 year cohorts and correlated with precursor of the VSCC, age and stage. RESULTS: Age-standardized incidence of all VSCC did not change significantly, however age standardized incidence of HPV-dependent VSCC increased significantly, from 0.55/100,000 (95% CI 0.38-0.72) in 1991-2000 to 0.83/100,000 (95% CI 0.68-0.97) in 2001-2016, with a significant decrease in the incidence of HPV-independent VSCC, from 0.76/100,000 (95% CI 0.58-0.95) to 0.54/100,000 (95%CI 0.43-0.65). HPV-dependent VSCC in women ≥50 years increased significantly from 0.75/100,000 (95% CI 0.45-1.17) to 1.43/100,000 (95% CI 1.14-1.77), with no significant change seen in younger women. HPV-independent VSCC in women ≥50 years has decreased significantly from 2.53/100,000 (95% CI 1.95-3.23) to 1.62/100,000 (95% CI 1.31-1.98) with no change in younger women. The proportion of HPV-dependent VSCC has increased from 25% to 50%. Age standardized death rate from VSCC has not changed significantly from 0.22/100,000 (95% CI 0.10-0.34) in 2001-5 to 0.27/100,000 (95% CI 0.15-0.40) in 2011-16. Five year survival for HPV-dependent VSCC was 93% and 68% for HPV-independent VSCC (p < .0001). CONCLUSIONS: HPV-dependent VSCC incidence has increased significantly and now accounts for half of VSCC, with a significant rise in women over 50. HPV-dependent and independent VSCC have different prognoses and should be registered and investigated separately.

Increasing incidence of endometrial carcinoma in a high-risk New Zealand community.

BACKGROUND: Endometrial carcinoma (EC) is increasing in incidence, attributed largely to the obesity epidemic. Ethnic differences in New Zealand have long been recognised, with Pacific women bearing the greater burden of disease. We hypothesise that the pooled national incidence rates underestimate the true burden of EC in our high-risk community. AIMS: We aimed to: (1) determine the incidence, trends and outcome of EC in the high-risk community served by our hospital, relative to national data; and (2) examine associated demographic, and clinicopathological features with reference to risk factors, to identify potential clinical and population intervention points. MATERIALS AND METHODS: All area-resident women treated for EC at Middlemore Hospital from 2000 to 2014 were identified from records, and clinicopathological data obtained. Incidence and time trend analyses were performed with reference to tumour type, age and ethnicity. RESULTS: The study included 588 women. Pacific, followed by Maori, women had the highest incidence of EC (relative risk = 5.11 and 2.47, respectively, relative to 'Other' women). The incidence increased for all ethnicities (annual percentage change (APC) of 7.3; 95% CI 3.6-11.1), most marked in women aged below 50 years (APC of 12.2; 95% CI 5.2-19.7). This occurred predominantly in Pacific women, who had a high prevalence of potentially reversible risk factors. Disease-specific survival was worse in Pacific, and to a lesser extent, Maori women. CONCLUSIONS: Prompt investigation of symptomatic, high-risk women regardless of age may detect endometrial abnormalities at an early, potentially reversible stage. The prevention and management of identifiable high-risk factors would help mitigate the risk of EC and associated diseases.

Using animated visualization to improve postoperative mobilization: A randomized controlled trial.

OBJECTIVE: Enhanced recovery after surgery (ERAS) programs fast-track recovery for surgical procedures, including colorectal and gynecological oncology surgery. Early mobilization is a postoperative ERAS module that can be self-managed by patients, but poor adherence is common. Visualization is increasingly being used to improve patient understanding and adherence to health behaviors. This study tested whether an animated visualization intervention could improve adherence to postoperative mobilization. METHOD: Ninety six colorectal and gynecological oncology surgery patients were randomized to intervention, active control, or standard care groups. Intervention participants saw an animated intervention on a computer tablet at Day 1 postsurgery. All participants wore fitness trackers from day of discharge to 7 days postdischarge, and completed psychological measures at baseline, Day 1 postsurgery, and 7 days postdischarge. RESULTS: Step count data was available for 57 colorectal surgery participants. A main effect of group demonstrated that intervention participants had a significantly higher average daily step count from discharge across the week following discharge (Madj = 2,294.60, 95% confidence interval [CI] [1,746.11, 2,744.89]) compared with control participants (Madj = 1,347.25, 95% CI [826.51, 1,871.20]; p = .05). At postsurgery, intervention participants reported significantly greater perceived quality of recovery and less difficulty in being mobile compared with control participants. There were no between-group differences in self-reported exercise or perceptions of surgery and recovery. CONCLUSION: This brief intervention appears effective in improving perceptions of early mobilization, and initial evidence suggests improvements in adherence to postsurgical mobilization. This intervention has high clinical applicability and could be incorporated into postoperative standard care. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Referral patterns for genetic counselling of women diagnosed with tubo-ovarian or peritoneal high-grade serous carcinoma (HGSC) within the Auckland Gynaecological Oncology Centre.

BACKGROUND: Germline BRCA1/2 mutations account for approximately 15% of invasive ovarian carcinomas. Referral of all women with non-mucinous epithelial tubo-ovarian and peritoneal cancer, especially high-grade serous carcinoma (HGSC) to genetic services for genetic counselling and subsequent BRCA testing, has become standard of care in many countries. Publicly funded BRCA testing was restricted to women ≤70 years old with HGSC in New Zealand for most of our study period. Referral rates of women with HGSC for BRCA mutation testing in New Zealand have not previously been reported. AIMS: To determine the proportion of eligible patients with tubo-ovarian or peritoneal HGSC referred to Auckland Gynaecologic Oncology Centre who were referred for genetic counselling. To determine the number of patients who underwent BRCA1/2 genetic testing and the rate of germline BRCA mutations. METHODS: Eligible cases were identified from Auckland Gynaecologic Oncology multidisciplinary meetings database from 1 January 2012 to 31 December 2014. Genetic referrals sent were checked against the genetic services database to ensure that referrals were received. Genetic counselling clinic attendance, uptake and results of genetic testing were also collected. RESULTS: One hundred and four eligible patients were identified with 58 patients referred. Referral rates increased from 37.5% in 2012 to 64.3% in 2014. Of the 58 patients referred, 53 attended genetic counselling, and 49 underwent BRCA mutation testing, of whom 10 (20.4%) tested positive for a germline BRCA mutation. CONCLUSION: Overall, 55.8% of eligible patients were referred for genetic testing; however, referral rates increased with time. This BRCA mutation-positive rate is comparable with current international data.

Pathological process has a crucial role in sentinel node biopsy for vulvar cancer.

OBJECTIVES: To report the interim findings of an audit of the outcomes of sentinel node (SN) biopsy performed as a replacement for groin node dissection in women with early stage vulvar cancer in routine clinical practice in Australia and New Zealand. METHODS: A prospective multi-center study in 8 participating centers. Eligible patients had squamous cell carcinomas clinically restricted to the vulva <4 cm in diameter. SN procedures and pathological assessment were to be performed in accordance with the methods published by the GROINSS-V collaboration [1]. RESULTS: 130 women with apparent early stage vulvar cancer were enrolled. Seventeen women subsequently did not meet the eligibility criteria and were excluded. SNs were identified in 111/113 of the remaining women. Twenty-two women had positive nodes. Sixteen of these women had at least 12 months follow up and 7 (44%) had recurrent disease. Eighty-nine women had only negative nodes. Seventy-four of these women had at least 12 months follow up and 6 (8%) had recurrent disease (including 2 [2.7%] with recurrence in the groin). On subsequent review of the two women with negative SNs who had groin recurrences, it was found that the recommended pathology protocol had not been followed. In both cases, SN metastases were identified following serial sectioning of the nodes. CONCLUSIONS: SN biopsy is feasible in routine clinical practice. However, undetected metastases in a removed SN may be associated with groin recurrence. To ensure patient safety, strict adherence to the pathology protocol is an essential component in the utilization of the sentinel lymph node technique in vulvar cancer.

Clinical and molecular classification of vulvar squamous pre-cancers.

Vulvar intraepithelial neoplasia (VIN) is a precursor to vulvar squamous cell carcinoma and is defined histopathologically by the presence of atypia. VIN has been classified into two types: usual vulvar intraepithelial neoplasia (uVIN), which is also referred to as a vulvar high-grade squamous intra-epithelial lesion (HSIL), and differentiated VIN (dVIN). The former is associated with chronic infection by sub-types of the human papilloma virus (HPV), whereas dVIN is HPV-independent and frequently associated with lichen sclerosus. The distinction is important because dVIN has a greater risk of, and more rapid transit to, vulvar squamous cell carcinoma. Furthermore, dVIN-associated vulvar cancers have an increased risk of recurrence and higher mortality than those arising from HSIL. Molecular characterization of vulvar squamous cell carcinoma precursors using next-generation sequencing is a relatively novel, but rapidly advancing field. This review appraises recent studies that have investigated the risks of progression to vulvar malignancy associated with HSIL and dVIN, the prognosis of HPV-dependent and HPV-independent vulvar squamous cell carcinomas, and conducted next generation sequencing mutation analyses to elucidate the genomic profiles underlying VIN. These studies suggest that HSIL and dVIN are characterized by different underlying molecular alterations that may have important implications for treatment and follow-up of women diagnosed with vulvar squamous cell cancer.

Changes in human papillomavirus genotypes associated with cervical intraepithelial neoplasia grade 2 lesions in a cohort of young women (2013-2016).

In 2008, a quadrivalent human papillomavirus (HPV) vaccine (genotypes 6, 11, 16, 18) became available in New Zealand. This study investigated whether the proportion of cervical intraepithelial neoplasia grade 2 (CIN2) lesions associated with HPV genotypes 16 and 18 changed over time in young women recruited to a prospective CIN2 observational management trial (PRINCess) between 2013 and 2016. Partial HPV genotyping (16, 18, or other high risk HPV) was undertaken on n = 392 women under 25 years (mean age 21.8, range 17-24) with biopsy-diagnosed CIN2. High risk HPV genotypes were detected in 96% of women with CIN2 lesions. Between 2013 and 2016, the proportion of women whose liquid-based cytology samples were HPV 16 or 18 positive decreased from 43% to 13%. HPV vaccination status was known for 78% of women. Between 2013 and 2016, the proportion of HPV 16/18 positivity did not significantly change in HPV-vaccinated women, but decreased from 66% to 17% in unvaccinated women. The reducing proportion of HPV 16/18-related CIN2 in our cohort of young New Zealand women may be attributable to the introduction of a national HPV vaccination program. The substantial decrease in HPV 16/18 positivity observed in unvaccinated women is likely to be due to a herd effect.

Excisional treatment in women with cervical adenocarcinoma in situ (AIS): a prospective randomised controlled non-inferiority trial to compare AIS persistence/recurrence after loop electrosurgical excision procedure with cold knife cone biopsy: protocol for a pilot study.

INTRODUCTION: Adenocarcinoma in situ (AIS) of the uterine cervix is the precursor to invasive endocervical adenocarcinoma. An excisional biopsy such as a cold knife cone biopsy (CKC) should be performed to exclude invasive adenocarcinoma. Loop electrosurgical excision procedure (LEEP) is an alternative modality to CKC but is controversial in AIS. There is a perception that there is a greater likelihood of incomplete excision of AIS with LEEP because the depth of excised tissue tends to be smaller and the tissue margins may show thermal artefact which can interfere with pathology assessment. In the USA, guidelines recommend that any treatment modality can be used to excise AIS, provided that the specimen remains intact with interpretable margins. However, there are no high-quality studies comparing LEEP with CKC and well-designed prospective studies are needed. If such a study were to show that LEEP was non-inferior to CKC for the outcomes of post-treatment persistence, recurrence and adenocarcinoma, LEEP could be recommended as an appropriate treatment option for AIS in selected patients. This would benefit women because, unlike CKC, LEEP does not require general anaesthesia and may be associated with reduced morbidity. METHODS AND ANALYSIS: The proposed exploratory study is a parallel group trial with an allocation ratio of 2:1 in favour of the intervention (LEEP: CKC). Participants are women aged ≥18 to ≤45 years diagnosed with AIS on cervical screening and/or colposcopically directed biopsy in Australia and New Zealand, who are to receive excisional treatment in a tertiary level centre. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the St John of God Healthcare Human Research Ethics Committee (reference number #1137). Results from the study will be presented at conferences and published in a peer-reviewed scientific journal. REGISTRATION: ANZCTR registration number ACTRN12617000132347 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372173&isReview=true.