Origin Of High-grade Serous Carcinoma Research Articles

Beyond Sterilization: A Comprehensive Review on the Safety and Efficacy of Opportunistic Salpingectomy as a Preventative Strategy for Ovarian Cancer.

Ovarian cancer (OC) is Canada's third most common gynecological cancer, with an estimated 3000 new cases and 1950 deaths projected in 2022. No effective screening has been found to identify OC, especially the most common subtype, high-grade serous carcinoma (HGSC), at an earlier, curable stage. In patients with hereditary predispositions such as BRCA mutations, the rates of HGSC are significantly elevated, leading to the use of risk-reducing salpingo-oophorectomy as the key preventative intervention. Although surgery has been shown to prevent HGSC in high-risk women, the associated premature menopause has adverse long-term sequelae and mortality due to non-cancer causes. The fact that 75% of HGSCs are sporadic means that most women diagnosed with HGSC will not have had the option to avail of either screening or prevention. Recent research suggests that the fimbrial distal fallopian tube is the most likely origin of HGSC. This has led to the development of a prevention plan for the general population: opportunistic salpingectomy, the removal of both fallopian tubes. This article aims to compile and review the studies evaluating the effect of opportunistic salpingectomy on surgical-related complications, ovarian reserve, cost, and OC incidence when performed along with hysterectomy or instead of tubal ligation in the general population.

Abstract A63: Estrogen receptor signaling in fallopian tube epithelia of BRCA mutation carriers

Abstract Background: The most common and aggressive type of epithelial ovarian cancers (EOC) is high-grade serous carcinoma (HGSC), which accounts for 90% of ovarian cancer deaths. HGSC is the predominant histotype associated with BRCA1 and BRCA2 mutations. Prophylactic surgery in BRCA mutation carriers has implicated the fallopian tube epithelium (FTE), a hormonal responsive tissue, as the etiologic site of origin for HGSC. Estrogen and its receptors are major regulators of growth and differentiation in normal ovaries and fallopian tubes, and its mutagenic properties have been linked to ovarian carcinogenesis. Estrogen receptors (ER) are rarely mutated, amplified, or deleted in HGSC, yet only 10% of patients respond to antiestrogen treatment. TP53 mutations in the form of the p53 signature have been found in serous tubal intraepithelial carcinomas (STIC) and are ubiquitously present in patients with HGSC. We hypothesized that in the presence of dysfunctional p53, subsequent promiscuous binding of ER will yield aberrant signaling, contributing to cellular transformation. Methods: We used our previously published gene expression profiles to generate a candidate gene list, which was chosen based on the presence of known estrogen-responsive elements. We analyzed expression of 6 ER responsive genes using data collected from laser capture microdissection in normal FTE tissues. Tissue microarray analysis (TMA) was also performed on a subset of HGSC tumor samples from this cohort, staining for PR, ER, and p53, and expression was analyzed alongside their respective outcome and overall survival Finally, to mimic the in vivo environment of early carcinogenesis, FTE-normal and FTE-p53 mutant cell lines were established and treated with 100nM estradiol, an estrogen analog, to observe changes in response. Results: Preliminary data showed that FTE-BRCA and FTE-nonBRCA seemingly look and express ER and PR proteins similarly. Underlying these morphologic similarities is a potential haploinsufficiency predisposing FTE-BRCA to cytotoxic stresses. Microarray gene expression of laser captured FTE-BRCA and FTE-nonBRCA showed varied levels of ER mRNA expression across samples (n=25) while PR transcript levels change dynamically. The data generated have facilitated the development of gene signatures and biomarkers that will predict response to antiestrogen therapy and identify patients who will benefit from hormonal therapies. Citation Format: Leah V. Dodds, Omar Nelson, Patricia Shaw, Anca Milea, Ramlogan Sowamber, Sophia HL George. Estrogen receptor signaling in fallopian tube epithelia of BRCA mutation carriers. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A63.

Estudio macro y microscópico de salpingectomías profilácticas en mujeres BRCA positivo

Serous ovarian cancer is a type of ovarian carcinoma. Two subtypes of serous carcinoma can be distinguished: Type 1 (frequent mutation of PTEN, KRAS and BRAF), corresponding to low-grade serous carcinoma, and Type 2 (frequent mutation of p53), corresponding to high-grade serous carcinoma. Its origin is not clear; classically causative factors included continuous ovulation, damage to the ovarian surface during ovulation and subsequent metaplasia. However, recently it has been proposed that the fallopian tube may be the origin of high-grade serous carcinoma. In order to test this hypothesis, we analyzed samples from 20 patients with known mutations in BRCA1-2 who had undergone bilateral salpingo-oophorectomy. The fallopian tube was studied macroscopically following the SEE-FIM protocol and Kurman's algorithm for the diagnosis of serous tubal intraepithelial carcinoma. All the sections were tested immunohistochemically with Ki-67 and p53 and the fallopian tubes were classified into 4 categories: normal, STIC (intraepithelial carcinoma), STIL (intraepithelial tubal lesion in transition) and p53 signature. In the series studied, 7 cases (35%) were diagnosed as abnormal: 2 STIL (10%) and 5 p53 signature (25%). The rest of the fallopian tubes showed no cytological atypia or immunostaining with the antibodies used. A study of the ovaries found no lesions in any of the cases. These findings agree with the results of other authors, and point to an initial lesion in the tube, reflecting a mutation of a tumour-suppressing gene (p53), which might play an important role in the development of high grade ovarian serous carcinoma.

Abstract POSTER-CTRL-1208: A dualistic model for the origin of high-grade serous carcinoma: BRCA mutation status, histology and tubal intraepithelial carcinoma

Abstract 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.

Serous tubal intraepithelial carcinoma localizes to the tubal-peritoneal junction: a pivotal clue to the site of origin of extrauterine high-grade serous carcinoma (ovarian cancer).

Recent data suggest that intraepithelial carcinoma of the fallopian tube [serous tubal intraepithelial carcinoma (STIC)] is the precursor of high-grade extrauterine serous carcinoma. A more specific location for the origin of this lesion is suggested by the recently described junction between the fallopian tubal epithelium and the peritoneum [tubal-peritoneal junction (TPJ)]. Fallopian tubes from 202 patients with advanced-stage high-grade extrauterine serous carcinoma or carcinosarcoma were evaluated histologically as were 124 prophylactic salpingo-oophorectomy specimens. These included 54 patients with BRCA or other high-risk mutation or a family history of BRCA mutation and 70 with a personal or family history of breast carcinoma. STIC was found in 81 of 202 patients with serous carcinoma (40.1%). STIC was present in 73 of 141 (52%) cases in which the fimbriae were present and in 62 of 100 (62%) cases in which the TPJ was present (P not significant). In comparison with these groups, when fimbriae and TPJ were absent, STIC was found in 8 of 61 (13%) cases (P<0.0001). None of the prophylactic specimens contained STIC. The mean size of STIC was 1.7 mm. In 32 cases (39.5%), the lesion was flat and in 49 (60.5%), papillary. The mean size of flat STICs was 0.8 mm as compared with 2.3 mm for papillary STICs (P=0.00005). STIC was identified in the same tissue fragment as the junction in 48 cases. The mean distance of STIC to the junction was 1.8 mm. In 11 cases, STIC was flanked by peritoneal mesothelium on one side and tubal epithelium on the opposite side. In 51 patients, the mean distance of invasive carcinoma from the TPJ was 1.8 mm. This distance was 1.9 mm when STIC was present (37 cases) in comparison with 1.5 mm when STIC was absent (14 cases) (P not significant). In 27 of 42 cases (64%), STIC was contiguous with invasive carcinoma. Lamina propria invasion was present in 71% of cases in which STIC was present as compared with 26% of cases in which STIC was absent (P<0.0001). Myosalpingeal invasion was present in 40% of cases in which STIC was present as compared with 26% of cases in which STIC was absent (P not significant). It is concluded that serous tubal intraepithelial carcinoma occurs at and in the immediate vicinity of the TPJ. In combination with the findings that STICs are present in a majority of cases when the TPJ is present, that flat STICs are smaller than papillary STICs, and that lamina propria invasion is more frequent in the presence of STIC, these data support STIC as the precursor of extrauterine high-grade serous carcinoma, they provide important clues to the site of origin of high-grade serous carcinoma (ovarian cancer), and can guide further research.

Are All Pelvic (Nonuterine) Serous Carcinomas of Tubal Origin?

It has been proposed that the presence of tubal intraepithelial carcinoma (TIC), in association with one-third to nearly half of pelvic serous carcinomas, is evidence of fallopian tube origin for high-grade serous carcinomas that would have been otherwise classified as primary ovarian or peritoneal. To address this hypothesis, we evaluated a series of 114 consecutive pelvic (nonuterine) gynecologic carcinomas at our institution (2006 to 2008) to determine the frequency of TIC in 52 cases in which all the resected fallopian tube tissue was examined microscopically. These 52 cases were classified as ovarian (n=37), peritoneal (n=8), or fallopian tube (n=7) in origin as per conventional criteria based on disease distribution. The presence of TIC and its location and relationship to invasive carcinoma in the fallopian tubes and ovaries were assessed. Among the 45 cases of ovarian/peritoneal origin, carcinoma subtypes included 41 high-grade serous, 1 endometrioid, 1 mucinous, 1 high-grade, not otherwise specified, and 1 malignant mesodermal mixed tumor. TIC was identified in 24 cases (59%) of high-grade serous carcinoma but not among any of the other subtypes; therefore, the term serous TIC (STIC) is a more specific appellation. STICs were located in the fimbriated end of the tube in 22 cases (92%) and in the ampulla in 2 (8%); they were unilateral in 21 (88%) and bilateral in 3 (13%). STICs in the absence of an associated invasive carcinoma in the same tube were detected in 7 cases (30%) and with invasive carcinoma in the same tube in 17 (71%). Unilateral STICs were associated with bilateral ovarian involvement in 15 cases and unilateral (ipsilateral) ovarian involvement in 5 (the remaining case with a unilateral STIC had a primary peritoneal tumor with no ovarian involvement); the bilateral STICs were all associated with bilateral ovarian involvement. Six of the 7 primary tubal tumors were high-grade serous carcinomas, and 4 of these 6 (67%) had STICs. Based on conventional criteria, 70%, 17%, and 13% of high-grade serous carcinomas qualified for classification as ovarian, peritoneal, and tubal in origin, respectively; however, using STIC as a supplemental criterion to define a case as tubal in origin, the distribution was modified to 28%, 8%, and 64%, respectively. Features of tumors in the ovary that generally suggest metastatic disease (bilaterality, small size, nodular growth pattern, and surface plaques) were identified with similar frequency in cases with and without STIC and were, therefore, not predictive of tubal origin. The findings, showing that nearly 60% of high-grade pelvic (nonuterine) serous carcinomas are associated with STICs, are consistent with the proposal that the fallopian tube is the source of a majority of these tumors. If these findings can be validated by molecular studies that definitively establish that STIC is the earliest form of carcinoma rather than intraepithelial spread from adjacent invasive serous carcinoma of ovarian or peritoneal origin, they will have important clinical implications for screening, treatment, and prevention.

New Insights Into the Pathogenesis of Serous Ovarian Cancer and Its Clinical Impact

There are only a handful of concepts concerning cancer and carcinogenesis that are currently beyond dispute. One such dogma is the adenoma-carcinoma sequence and that a multistep accumulation of genetic alterations is required for transformation from a benign to a neoplastic tissue. The inevitable derivative of this dogma is that every invasive carcinoma is in fact a missed intraepithelial tumor, and furthermore, a late evolutionary stage in the sequence of development from a precursor lesion. Until fairly recently, high-grade serous ovarian carcinoma seemed to be one of the only known deviants of these concepts. In this article, we discuss the emergence of the fallopian tube fimbria as a field of origin for high-grade serous carcinomas and present a binary model of ovarian cancer pathogenesis that takes into consideration prior epidemiologic, morphologic, and genetic data. With the rise of the fallopian tube secretory epithelial cell as a cell of origin for high-grade pelvic serous carcinomas, the need to develop tools and model systems to characterize the biology and physiology of this cell is recognized.

Is Chlamydia-infected tubal fimbria the origin of ovarian cancer?

Ovarian cancer is a highly lethal disease and its underlying biology is poorly understood. Prophylactic salpingo-oophorectomies in BRCA + women have recently implicated the fimbria as a site of origin for high-grade serous carcinoma and its intraepithelial precursors. This suggests that at least some ovarian cancers, probably the most aggressive ones, may not originate in the ovary itself, but rather may arise in the uterine tubes. Chronic inflammation is associated with carcinogenesis in several tissues, including liver, esophagogastric junction (cardia), and the uterine cervix. The mechanisms underlying the relationship between inflammation and cancer are complex and involve common pathways, in addition to DNA damage. A critical source of uterine tube inflammation is infection with Chlamydia trachomatis. We hypothesize that C.trachomatis infection may be involved in chronic tubal inflammation and subsequent fimbrial carcinogenesis. Fimbrial intraepithelial precursors can evolve into high grade serous carcinomas that spread rapidly to the ovarian surface and peritoneum; such tumors may appear to be primary ovarian neoplasia, though in reality being a secondary malignancy. This hypothesis must be further investigated to understand the intracellular signaling pathways involved in Chlamydia infection and its healing, and their relationship to carcinogenesis in order to discover potential therapeutic molecular targets. If our hypothesis were confirmed, salpingectomy instead of ovariectomy may also become the recommended surgery for high risk women.