Consensus based recommendations for the diagnosis of serous tubal intraepithelial carcinoma: an international Delphi study.

AIM: Reliably diagnosing or safely excluding serous tubal intraepithelial carcinoma (STIC), a precursor lesion of tubo-ovarian high-grade serous carcinoma (HGSC), is crucial for individual patient care, for better understanding the oncogenesis of HGSC, and for safely investigating novel strategies to prevent tubo-ovarian carcinoma. To optimize STIC diagnosis and increase its reproducibility, we set up a three-round Delphi study. METHODS AND RESULTS: In round 1, an international expert panel of 34 gynecologic pathologists, from 11 countries, was assembled to provide input regarding STIC diagnosis, which was used to develop a set of statements. In round 2, the panel rated their level of agreement with those statements on a 9-point Likert scale. In round 3, statements without previous consensus were rated again by the panel while anonymously disclosing the responses of the other panel members. Finally, each expert was asked to approve or disapprove the complete set of consensus statements. The panel indicated their level of agreement with 64 statements. A total of 27 statements (42%) reached consensus after three rounds. These statements reflect the entire diagnostic work-up for pathologists, regarding processing and macroscopy (three statements); microscopy (eight statements); immunohistochemistry (nine statements); interpretation and reporting (four statements); and miscellaneous (three statements). The final set of consensus statements was approved by 85%. CONCLUSION: This study provides an overview of current clinical practice regarding STIC diagnosis amongst expert gynecopathologists. The experts' consensus statements form the basis for a set of recommendations, which may help towards more consistent STIC diagnosis.

Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis.

PURPOSE: After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO. METHODS: Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study. RESULTS: From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO. CONCLUSION: BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.

Recommendations for diagnosing STIC: a systematic review and meta-analysis.

Our understanding of the oncogenesis of high-grade serous cancer of the ovary and its precursor lesions, such as serous tubal intraepithelial carcinoma (STIC), has significantly increased over the last decades. Adequate and reproducible diagnosis of these precursor lesions is important. Diagnosing STIC can have prognostic consequences and is an absolute requirement for safely offering alternative risk reducing strategies, such as risk reducing salpingectomy with delayed oophorectomy. However, diagnosing STIC is a challenging task, possessing only moderate reproducibility. In this review and meta-analysis, we look at how pathologists come to a diagnosis of STIC. We performed a literature search identifying 39 studies on risk reducing salpingo-oophorectomy in women with a known BRCA1/2 PV, collectively reporting on 6833 patients. We found a pooled estimated proportion of STIC of 2.8% (95% CI, 2.0-3.7). We focused on reported grossing protocols, morphological criteria, level of pathologist training, and the use of immunohistochemistry. The most commonly mentioned morphological characteristics of STIC are (1) loss of cell polarity, (2) nuclear pleomorphism, (3) high nuclear to cytoplasmic ratio, (4) mitotic activity, (5) pseudostratification, and (6) prominent nucleoli. The difference in reported incidence of STIC between studies who totally embedded all specimens and those who did not was 3.2% (95% CI, 2.3-4.2) versus 1.7% (95% CI, 0.0-6.2) (p 0.24). We provide an overview of diagnostic features and present a framework for arriving at an adequate diagnosis, consisting of the use of the SEE-FIM grossing protocol, evaluation by a subspecialized gynecopathologist, rational use of immunohistochemical staining, and obtaining a second opinion from a colleague.