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Most early adnexal carcinomas detected in asymptomatic women with germline BRCA mutations (BRCA) present as serous tubal intraepithelial carcinomas (STIC). However, STICs are found in only ∼40% of symptomatic high-grade serous carcinomas (HGSCs) and less frequently in pseudoendometrioid variants of HGSC. Consecutive cases of untreated HGSC from BRCA and BRCA women with detailed fallopian tube examination (SEE-FIM protocol) were compared. STIC status (+/-) was determined, and tumors were classified morphologically as SET ("SET",50% solid, pseudoendometrioid, or transitional) or classic predominate ("Classic"). SET tumors trended toward a higher frequency in BRCA versus BRCA women (50% vs. 28%, P=0.11), had a significantly younger mean age than those with classic HGSC in BRCA women (mean 56.2 vs. 64.8 y, P=0.04), and displayed a better clinical outcome in both groups combined (P=0.024). STIC was significantly more frequent in tumors from the BRCA cohort (66% vs. 31%, P=0.017) and specifically the BRCA tumors with classic morphology (83%) versus those with SET morphology (22%, P=0.003). Overall, several covariables-histology, BRCA status, age, coexisting STIC, and response to therapy-define 2 categories of HGSC with differences in precursor (STIC) frequency, morphology, and outcome. We introduce a dualistic HGSC model that could shed light on the differences in frequency of STIC between symptomatic and asymptomatic women with HGSC. This model emphasizes the need for further study of HGSC precursors to determine their relevance to the prevention of this lethal malignancy.

Extra-uterine high-grade serous carcinoma (HGSC) is linked to the fimbria via serous tubal intraepithelial carcinoma or STIC. Women with deleterious BRCA1/2 germ-line mutations (BRCA+) are at high risk for HGSC and ~5% of risk reducing salpingo-oophorectomies harbor a STIC. However, STIC is found in only~40% of the HGSC population and less frequently in endometrioid variants of HGSC (Roh 2009). Consecutively tested women with untreated HGSC, with detailed fallopian tube examination (SEE-FIM protocol), who had germ-line BRCA testing were studied. STIC status was determined by histologic exam, and tumors were classified as predominately SET (> 50% solid, endometrioid-like, or transitional, Soslow 2012) or classic histology. SET features trended towards a higher frequency in BRCA+ vs BRCA- women (50 vs 28%, p = .11). BRCA- subjects with SET morphology were significantly younger than those with classic HGSC (mean 56.2 vs 64.8 years; p=0.04), with a generally better clinical outcome. STIC was significantly more frequent in BRCA- tumors (66 vs 31%, p = 0.017) and more frequent in classic HGSCs in BRCA- (83 vs 22%, p = 0.003) women. Overall, several co-variables – histology, BRCA status, age, coexisting STIC, response to therapy - suggest two categories of HGSC with differences in speed of development, progression, outcome, histology, and possibly, precursor type. We introduce a dualistic HGSC model with a faster evolving tumor type that is not linked to a long-standing STIC. Resolving the nature of this second pathway is germane to both resolving the precursors and expectations from both screening and prevention of HGSC. Citation Format: Brooke E Howitt MD, Suchanan Hanamornroongruang MD, Douglas Lin MD PhD, James E Conner MD PhD, Stephanie Schulte MD, Judy Garber MD, Christopher P Crum MD, Emily E Meserve MD MPH. A dualistic model for the origin of high-grade serous carcinoma: BRCA mutation status, histology and tubal intraepithelial carcinoma [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1208.