Improved Risk Prediction in Human Papillomavirus-Associated Endocervical Adenocarcinoma Through Assessment of Binary Silva Pattern-based Classification: An International Multicenter Retrospective Observational Study Led by the International Society of Gynecological Pathologists (ISGyP).

Endocervical adenocarcinomas (EACs) are a group of malignant neoplasms associated with diverse pathogenesis, morphology, and clinical behavior. As a component of the International Society of Gynecological Pathologists International Endocervical Adenocarcinoma Project, a large international retrospective cohort of EACs was generated in an effort to study potential clinicopathological features with prognostic significance that may guide treatment in these patients. In this study, we endeavored to develop a robust human papillomavirus (HPV)-associated EAC prognostic model for surgically treated International Federation of Gynecology and Obstetrics (FIGO) stage IA2 to IB3 adenocarcinomas incorporating patient age, lymphovascular space invasion (LVSI) status, FIGO stage, and pattern of invasion according to the Silva system (traditionally a 3-tier system). Recently, a 2-tier/binary Silva pattern of invasion system has been proposed whereby adenocarcinomas are classified into low-risk (pattern A/pattern B without LVSI) and high-risk (pattern B with LVSI/pattern C) categories. Our cohort comprised 792 patients with HPV-associated EAC. Multivariate analysis showed that a binary Silva pattern of invasion classification was associated with recurrence-free and disease-specific survival (P < 0.05) whereas FIGO 2018 stage I substages were not. Evaluation of the current 3-tiered system showed that disease-specific survival for those patients with pattern B tumors did not significantly differ from that for those patients with pattern C tumors, in contrast to that for those patients with pattern A tumors. These findings underscore the need for prospective studies to further investigate the prognostic significance of stage I HPV-associated EAC substaging and the inclusion of the binary Silva pattern of invasion classification (which includes LVSI status) as a component of treatment recommendations.

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.

Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data.

OBJECTIVE: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. METHODS: We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). RESULTS: 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66; P < 0·001) and 0·65 (95% CI 0·50-0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027). CONCLUSIONS: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.

RANZCOG Fellows' adherence to guidelines following cytological prediction of cervical adenocarcinoma-in-situ: Cause for concern?

BACKGROUND: For Australian women with screen-detected adenocarcinoma-in-situ (AIS), an excisional biopsy is mandatory for further assessment, treatment, and to exclude the presence of cervical adenocarcinoma. The only exclusion to this rule is if the woman has a clinically evident invasive cervical malignancy. Excisional treatments should be tailored according to a patient's age and future obstetric needs. To date, practitioner compliance with this recommendation has not been investigated. AIMS: To investigate clinical management for patients with a cytological test result predicting AIS. Secondary aims were to report the most severe histological findings of excisional biopsy specimens following cytological prediction of AIS and investigate treatment outcomes for conservatively managed patients with biopsy-confirmed AIS. MATERIALS AND METHODS: A retrospective, population-based cohort study was conducted. Cases were ascertained from the Tasmanian and Western Australia Cervical Screening Registries. Cytology and histology results for women with an index cervical smear reporting AIS from 2001 to 2012 were reviewed. RESULTS: Three hundred and twenty-one women (age range 18-69 years) had an index smear reporting AIS. Cervical cancer was diagnosed in 62 (19.3%) patients within the study cohort. Twenty-one of 321 patients (6.7%) were not initially managed according to the 2005 NHMRC Guidelines for the management of asymptomatic women with screen-detected abnormalities, including two women diagnosed with an occult cancer following a total hysterectomy. CONCLUSIONS: A minority of women were not managed in accordance with guidelines. This is of concern given that nearly one in five women with a smear predicting AIS had a final diagnosis of cervical cancer.

Morbidity after surgical management of cervical cancer in low and middle income countries: A systematic review and meta-analysis.

OBJECTIVE: To investigate morbidity for patients after the primary surgical management of cervical cancer in low and middle-income countries (LMIC). METHODS: The Pubmed, Cochrane, the Cochrane Central Register of Controlled Trials, Embase, LILACS and CINAHL were searched for published studies from 1st Jan 2000 to 30th June 2017 reporting outcomes of surgical management of cervical cancer in LMIC. Random-effects meta-analytical models were used to calculate pooled estimates of surgical complications including blood transfusions, ureteric, bladder, bowel, vascular and nerve injury, fistulae and thromboembolic events. Secondary outcomes included five-year progression free (PFS) and overall survival (OS). FINDINGS: Data were available for 46 studies, including 10,847 patients from 11 middle income countries. Pooled estimates were: blood transfusion 29% (95%CI 0.19-0.41, P = 0.00, I2 = 97.81), nerve injury 1% (95%CI 0.00-0.03, I2 77.80, P = 0.00), bowel injury, 0.5% (95%CI 0.01-0.01, I2 = 0.00, P = 0.77), bladder injury 1% (95%CI 0.01-0.02, P = 0.10, I2 = 32.2), ureteric injury 1% (95%CI 0.01-0.01, I2 0.00, P = 0.64), vascular injury 2% (95% CI 0.01-0.03, I2 60.22, P = 0.00), fistula 2% (95%CI 0.01-0.03, I2 = 77.32, P = 0.00,), pulmonary embolism 0.4% (95%CI 0.00-0.01, I2 26.69, P = 0.25), and infection 8% (95%CI 0.04-0.12, I2 95.72, P = 0.00). 5-year PFS was 83% for laparotomy, 84% for laparoscopy and OS was 85% for laparotomy cases and 80% for laparoscopy. CONCLUSION: This is the first systematic review and meta-analysis of surgical morbidity in cervical cancer in LMIC, which highlights the limitations of the current data and provides a benchmark for future health services research and policy implementation.

Risk of high-grade serous ovarian cancer associated with pelvic inflammatory disease, parity and breast cancer.

BACKGROUND: Ovarian carcinoma is not a single disease, but rather a collection of subtypes with differing molecular properties and risk profiles. The most common of these, and the subject of this work, is high-grade serous ovarian carcinoma (HGSC). METHODS: In this population-based study we identified a cohort of 441,382 women resident in Western Australia who had ever been admitted to hospital in the State. Of these, 454 were diagnosed with HGSC. We used Cox regression to derive hazard ratios (HRs) comparing the risk of disease in women who had each of a range of medical diagnoses and surgical procedures with women who did not. RESULTS: We found an increased risk of HGSC associated with a diagnosis of pelvic inflammatory disease (PID) (HR 1.47, 95% CI 1.04-2.07) but not with a diagnosis of infertility or endometriosis with HRs of 1.12 (95% CI 0.73-1.71) and 0.82 (95% CI 0.55-1.22) respectively. A personal history of breast cancer was associated with a three-fold increase in the rate of HGSC. Increased parity was associated with a reduced risk of HGSC in women without a personal history of breast cancer (HR 0.57; 95% CI 0.44-0.73), but not in women with a personal history of breast cancer (HR 1.48; 95% CI 0.74-2.95). CONCLUSIONS: Our finding of an increased risk of HGSC associated with PID lends support to the hypothesis that inflammatory processes may be involved in the etiology of HGSC.

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.