Tubal Intraepithelial Carcinoma Research Articles

Serous tubal intraepithelial carcinoma: Emerging trend in ovarian neoplasm: A must know for a pathologist

Among all gynecological malignancies, ovarian cancer is associated with the highest rate of mortality. Most ovarian carcinomas have been suggested to originate from the ovarian surface epithelium or postovulatory inclusion cysts formed after follicular rupture and repair. Over the past decade, a new model has emerged to explain the origin of epithelial tumors of the ovary and the fallopian tube now appears to play a central role; however, there is now compelling evidence that many epithelial pelvic cancers, especially high-grade serous carcinomas of the ovary/peritoneum, begin in the mucosa of the fallopian tube as serous tubal intraepithelial carcinoma.

Exploring the clinical significance of serous tubal intraepithelial carcinoma associated with advanced high-grade serous ovarian cancer: A Memorial Sloan Kettering Team Ovary Study

ObjectiveTo evaluate the clinical significance and genomic associations of concurrent serous tubal intraepithelial carcinoma (STIC) with high-grade serous carcinoma (HGSC) of the ovary in women undergoing primary debulking surgery (PDS). MethodsAll patients who underwent PDS for HGSC between 01/2015 and 12/2018 were captured in a prospectively maintained institutional database. Patients were categorized based on the presence or absence of concurrent STIC noted on final pathology. Demographic, perioperative, and outcomes data were collected, and groups were compared using standard statistical tests. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. For comparison of differences in somatic alterations between the two cohorts, specimens were sequenced using MSK-IMPACT. ResultsOf 306 eligible patients, 87 (28%) had a concurrent STIC lesion (+STIC) and 219 (72%) did not (no-STIC). Demographics and clinicopathological factors were similar between the two cohorts, except for a significantly higher median preoperative CA-125 level in the no-STIC group (423 U/mL vs. 321 U/mL; p=0.029). There were no significant differences in median PFS (22.7 months [95%CI: 18.9-28.4] vs. 27.7 months [95%CI: 25.5-30.5]; p=0.126) and 3- year OS rate (81% [95%CI: 70-88%] vs. 85% [95%CI: 78-90%]; p=0.392) between +STIC and no-STIC patients, respectively. Targeted DNA-sequencing via MSK-IMPACT showed a similar distribution of driver mutations or structural genetic alterations, and affected genetic signaling pathways were similar between the cohorts. ConclusionsThere were no identifiable clinical and genetic differences in patients with HGSC and concurrent STIC. These data suggest a comparable, if not identical, disease process.

Proteomic Analysis of Pre-Invasive Serous Lesions of the Endometrium and Fallopian Tube Reveals Their Metastatic Potential.

Serous endometrial cancer (SEC) and high grade serous ovarian cancer (HGSOC) are aggressive gynecological malignancies with high rates of metastasis and poor prognosis. Endometrial intraepithelial carcinoma (EIC), the precursor for SEC, and serous tubal intraepithelial carcinoma (STIC), believed to be the precursor lesion for HGSOC, can also be associated with intraabdominal spread. To provide insight into the etiology of these precancerous lesions and to explore the potential molecular mechanisms underlying their metastatic behavior, we performed a proteomic mass spectrometry analysis in a patient with synchronous EIC and STIC. Through histological and molecular identification of precancerous lesions followed by laser capture microdissection, we were able to identify over 450 proteins within the precancerous lesions and adjacent healthy tissue. The proteomic analysis of STIC and EIC showed remarkable overlap in the proteomic patterns, reflecting early neoplastic changes in proliferation, loss of polarity and attachment. Our proteomic analysis showed that both EIC and STIC, despite being regarded as premalignant lesions, have metastatic potential, which correlates with the common presentation of invasive serous gynecological malignancies at advanced stage.

DNA Methylation Profiling of Premalignant Lesions as a Path to Ovarian Cancer Early Detection

Genome-wide DNA methylation profiles of serous tubal intraepithelial carcinomas (STIC) resemble methylation profiles of high-grade serous ovarian carcinomas (HGSOC) more closely than normal fallopian tube epithelium. While STICs and HGSOCs share subsets of common hypermethylated regions, DNA methylation can distinguish STICs from HGSOCs to provide proof-of-principle that DNA methylation can identify HGSOC initiation.See related article by Pisanic et al., p. 6310.

Methylomic Landscapes of Ovarian Cancer Precursor Lesions.

The current paradigm in the development of high-grade serous ovarian carcinoma (HGSC) proposes that the majority of HGSCs arise from precursor serous tubal intraepithelial carcinoma (STIC) lesions of the fallopian tube. Here we survey genome-wide methylation in HGSC precursor lesions to identify genomic regions that exhibit high-specificity differential hypermethylation for potential use as biomarkers for detecting STIC and HGSC at stages when curative intervention likely remains feasible. We first identified quality control criteria for performing reliable methylomic analysis of DNA-limited tubal precursor lesions with the Illumina Infinium MethylationEPIC array. We then used this platform to compare genome-wide methylation among 12 STICs with paired adjacent-normal epithelia, one p53 signature lesion and two samples of concurrent HGSC. The resulting methylomic data were analyzed by unsupervised hierarchical clustering and multidimensional analysis. Regions of high-confidence STIC-specific differential hypermethylation were identified using selective bioinformatic criteria and compared with published MethylationEPIC data from 23 HGSC tumors and 11 healthy fallopian tube mucosae. Unsupervised analysis showed that STICs largely clustered with HGSCs, but were clearly distinct from adjacent-normal fallopian tube epithelia. Forty-two genomic regions exhibited high-confidence STIC-specific differential hypermethylation, of which 17 (40.5%) directly overlapped with HGSC-specific differentially methylated regions. Methylation at these shared loci was able to completely distinguish STIC and HGSC samples from normal and adjacent-normal specimens. Our results suggest that most STICs are epigenetically similar to HGSCs and share regions of differential hypermethylation that warrant further evaluation for potential use as biomarkers for early detection of ovarian HGSC.See related commentary by Ishak and De Carvalho, p. 6083.

Secretory Cell OUT growth (SCOUT), Serous Tubal Intraepithelial Carcinoma (STIC) and P53 expression in fallopian fimbriae of ovarian serous tumors- A tertiary care center study

The proposed histopathological precursor lesions of high grade ovarian serous tumors are Secretory Cell OUT growth (SCOUT) and Serous Tubal Intraepithelial Carcinoma (STIC) in fallopian fimbriae. P53 signature in fimbriae is considered as immunohistochemical precursor lesion. This study compared the p53 expression pattern of serous tumors and their fallopian tubes to explore their relationships.To study the histopathological changes in fallopian fimbriae of ovarian serous tumors with p53 expression pattern.A cross-sectional study of 90 cases of serous ovarian tumors were done. (61 benign, 6 borderline and 23 malignant). Their fallopian tubes were examined as per SEE-FIM PROTOCOL. P53 expression pattern of serous tumors and fimbriae were analyzed using SPSS software version 20.Among the 90 cases, SCOUTs were distributed in all categories of serous tumors and 59% of them were in nonmalignant tumors. Only 22.4% of SCOUTs showed p53 signature. STIC were distributed more in high grade tumors (66.6%) and were absent in benign tumors. All the STICs showed aberrant p53 expression pointing mutant p53 gene. Aberrant p53 pattern was high in high grade tumors (91.6%) compared to benign, borderline, low grade tumors (0%, 16.7%,18.2%).STIC and p53 signatures were common in high grade serous carcinoma and their fallopian tubes. SCOUT was present both in benign and malignant tumors but p53 signature was low. Hence it can be presumed that SCOUT is an initial event, later progressing through p53 positive STICs leading to high grade serous carcinoma in ovaries.

Specialist oncological surgery for removal of the ovaries and fallopian tubes in BRCA1 and BRCA2 pathogenic variant carriers may reduce primary peritoneal cancer risk to very low levels.

Risk‐reducing bilateral salpingo‐oophorectomy (RRBSO) is highly effective for the prevention of high‐grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic variant carriers (PVCs), but does not completely eliminate future risk of primary peritoneal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC) lesions may not have been appreciated historically. We calculated rates of HGSOC and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥ 35 years and 0.5% for BRCA2 ≥ 45 years. Follow‐up before 35/45 years was “risk free” and lead time excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively. Women were followed from personal mutation report (controls) or RRBSO (cases) to death, ovarian/peritoneal cancer or last follow‐up, whichever was sooner. In total, 891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow‐up ≥35 years (BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk eligible years (mean = 8.15 years). Twenty‐one occult ovarian cancers were found at RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were expected but only 3 were observed (HR = 0.053; 95% CI = 0.013‐0.14), with combined Kaplan‐Meier analysis HR = 0.029 (95% CI = 0.009‐0.100, P < .001). Risk reduction was greater in specialist (HR = 0.03; 95% CI = 0.001‐0.13) compared to non‐specialist centres (HR = 0.11; 95% CI = 0.02‐0.37) (P = .07). In controls, 23.35 ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95% CI = 0.95‐1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer by 95% in BRCA1/2 PVCs and may be greater in specialist centres.

High grade mucosal serous carcinoma of fallopian tube and serous tubal intraepithelial carcinoma (STIC) coexistent with ectopic tubal gestation

High-grade serous tubal intraepithelial carcinomas (STICs) are noninvasive carcinomas of the fallopian tube that have been found with varying frequency in tubectomy specimens. Serous tubal intraepithelial carcinoma is a precursor lesion for high-grade serous ovarian and peritoneal carcinoma. The incidence of STIC is estimated to occur in 0.6% to 6% of women who are BRCA positive or have a strong family history of breast or ovarian carcinoma. Immunohistochemical staining demonstrates aberrant p53 protein [removed]either diffuse nuclear over expression or complete absence of staining) and an increased Ki-67 proliferation index. We are describing rare incidental occurrence of high grade mucosal serous carcinoma of the fallopian tube with STIC in a patient undergoing tubectomy for ectopic tubal gestation and relevant immunohistochemical study of the lesion. Much attention has been directed to the fallopian tubes as the origin of malignant epithelial ovarian tumors, and STIC is now considered to be the origin of high-grade serous ovarian cancer. To avoid overlooking early-stage fallopian tube cancer, surgery for benign disease should also be accompanied by a detailed histopathological examination of the fallopian tubes. Possible management options include observation with annual physical examination and CA-125 estimation, surgical staging, or empiric chemotherapy. However, due to the lack of consensus regarding management options, referral to a gynecologic oncologist recommended. Associated ectopic gestation is probably due to partial obstruction caused by mucosal serous carcinoma of fallopian tube. Close spatial relationship of two such lesions suggests that, in all probability intraluminal mucosal carcinoma was responsible for interference in free transportation of the fertilized ovum through the tube , possibly, by impaired contractile activity of myosalpinx and consequently caused the ectopic tubal pregnancy. Keywords: Serous tubal intraepithelial c

Genomic analysis of serous tubal intraepithelial carcinoma-like lesions and concurrent endometrial serous carcinoma: Related entities?

Objective: In women with endometrial serous carcinoma (ESC) confined to the uterine corpus, concurrent isolated serous tubal intraepithelial carcinomas (STIC)-like lesions in the fallopian tube(s) may be found. We sought to define whether these ESCs and STICs are synchronous unrelated lesions or whether they are genetically related (potentially implying that one is a metastasis from the other).

Serous tubal intraepithelial carcinoma (STIC) at the time of primary debulking surgery (PDS) of high-grade serous ovarian cancer (HGSOC): Does it matter?

Objective: The aim of this study was to evaluate the clinical significance and genomic associations of concurrent serous tubal intraepithelial carcinoma (STIC) fallopian tube lesions identified in women with high-grade serous carcinoma (HGSC) undergoing primary debulking surgery (PDS).

Ovarian serous carcinoma: A retrospective study of clinicopathological findings and postchemotherapy changes

Abstract Background: Ovarian carcinoma represents 30% of all cancers of the female genital tract, of which high-grade serous carcinomas (HGSCs) are predominant, accounting for 70%. Aims and Objectives: To study the clinicopathological findings and to analyze the postchemotherapy changes in tumors treated with neoadjuvant chemotherapy (NACT). Materials and Methods: All cases diagnosed as ovarian serous carcinoma between 2015 and 2017 at our institute were retrospectively reviewed. Clinical and gross findings were collected, microscopic findings were reviewed, and tumor grade was reassessed as per the World Health Organization 2014 criteria. Chemotherapy response score (CRS) was assessed in cases which received prior chemotherapy. Results: Among malignant ovarian tumors, serous carcinoma was the most common, accounting to 38 cases (44.7%). Of these, six were low-grade serous carcinoma and 32 were HGSC. Among HGSC, six (18.75%) cases showed serous tubal intraepithelial carcinoma. Among 18 (47.4%) cases with prior NACT, CRS-1 was seen in six cases, CRS-2 in seven cases, and CRS-3 in five cases. Cancer antigen (CA)-125 levels were markedly raised in all cases. In six cases postchemotherapy, CA-125 levels were below normal with a CRS-2–3. Omental deposits were seen in 15 (39.47%) cases and showed lesser response to prior NACT compared to tumor in the ovary. Conclusion: HGSC is the most common ovarian serous carcinoma. There is correlation between the biochemical and morphological response to chemotherapy in our study. Pathologists should be well aware of postchemotherapy morphological changes in ovarian serous carcinoma.

Prophylactic Salpingectomy for Prevention of Ovarian Cancer at the Time of Elective Laparoscopic Cholecystectomy

(Abstracted from BJS 2020;107:519–524) The majority of ovarian cancers are now believed to originate in the fimbriae of the fallopian tubes as serous tubal intraepithelial carcinomas (STICs). Removal of the fallopian tubes (salpingectomy) has been associated with a reduced risk of developing ovarian cancer, leading to gynecologic societies recommending prophylactic salpingectomy at the time of pelvic surgery in appropriate women.

Characterization of TP53-wildtype tubo-ovarian high-grade serous carcinomas: rare exceptions to the binary classification of ovarian serous carcinoma.

While TP53 mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rare TP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25 TP53-wildtype tubo-ovarian HGSCs, constituting 2.5% of 987 HGSCs profiled by the MSK-IMPACT sequencing platform. Consistent with serous differentiation, positive staining for Pax8 and WT1 was present in virtually all TP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations of CCNE1 and BRCA1/2 were identified in these tumors, furthering supporting their classification as bona fide HGSC, despite lacking TP53 mutations. Overall, the level of chromosomal instability of TP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) and TP53-mutated HGSC. Morphologic assessment by observers blinded to mutation status revealed a significant subset of tumors with Grade 2 nuclear atypia (which exceeds the degree of atypia allowed for LGSC, but less than typically encountered for HGSC) combined with micropapillary features (6/19, 32%, chemotherapy-naive TP53-wildtype HGSCs compared to 0/21, 0%, TP53-mutated HGSCs; p = 0.007). Some TP53-wildtype HGSCs harbored driver mutations in KRAS (n = 3), BRAF (n = 1) or NRAS (n = 2). Overall, 10 (40%) cases had "LGSC-like" morphology (i.e., Grade 2 nuclear atypia and micropapillary features) and/or RAS/RAF mutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remaining TP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventional TP53-mutated HGSC. Despite lacking genetic alterations of TP53, these "usual HGSC-like" tumors often showed evidence of p53 dysfunction, including downregulation of expression ('null' or equivocal p53 staining in 9/14, 64%) or MDM2 amplification (n = 2). Our results support the existence of TP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms.

Abstract B26: The natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions

Abstract High-grade serous carcinoma (HGSC) is the most common and devastating type of ovarian cancer; its etiology, mechanism of malignant transformation, and origin remain controversial. Recent studies have identified secretory cells at the fimbria of the fallopian tube as the cell of origin of HGSC, initiating TP53 mutation, evolving to tubal precursor lesions, including “p53 signature” and serous tubal intraepithelial carcinoma (STIC), and metastasizing to the ovary as clinically evident ovarian cancer. The etiologic mechanisms associated with the known epidemiologic risk factors, i.e., ovulation and retrograde menstruation, have also been unveiled. Mutagens and transforming growth factors, such as reactive oxygen species and IGF axis proteins, as well as the apoptosis-rescuing protein hemoglobin are abundantly present in the ovulatory follicular fluid and peritoneum fluid, which bathes the fimbrial epithelium, and induces malignant transformation after repeated exposure. Meanwhile, in accordance with the proposed therapeutic effect of progesterone from studies on oral contraceptive (OC) use or term pregnancy, our recent study indicated that the p53-null tubal epithelial cells are selectively cleared by progesterone depending on its progesterone receptor (PR). In this report, by analyzing different time-effects of OC use or pregnancy in the prevention of ovarian cancer and by aligning them with the carcinogenic and therapeutic clearance concepts of ovulation and P4, as well as the fact of progressive loss of PR during tubal transformation, we deduced the natural history of ovarian HGSC. The natural history begins at the first ovulation and spans more than 30 years, taking 10 years from the normal tubal epithelium to the “p53 signature” status, another 15 years to PR(-) STIC, and a final 5+ years to HGSC. The estimated natural history may help understand the pathogenesis of HGSC and defines the window for early detection and chemoprevention. Citation Format: Tang-Yuan Chu, Na-Yi Yuan Wu, Jing Wang. The natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B26.

Abstract B11: Collective extrusion initiates dissemination in organotypic model of high-grade serous carcinoma

Abstract Development of serous tubal intraepithelial carcinoma (STIC) from transformed fallopian tube secretory epithelial cells (FTSEC) is considered to be an initiating event for a significant proportion of high-grade serous carcinomas (HGSCs). Some regions of STIC lesions can form multicellular loosely cohesive outgrowths that apically extend out of the tubal epithelium. These outgrowths can detach and disseminate within the peritoneal cavity, causing organ obstruction. Immunohistochemical analysis of STICs suggests the possibility that molecular pathways associated with proliferation, DNA repair, cytoskeletal dynamics, and extracellular matrix adhesion contribute to outgrowth formation. Due to limited availability of transformed FTSEC in vitro culture models that faithfully capture outgrowth dynamics, the role of these pathways in STIC/HGSC outgrowth formation remains unknown. Here we present the development of an organotypic model of outgrowth formation. Long-term live-cell imaging of transformed human, and mouse FTSEC and STIC-like multicellular organotypic assemblies, have shown that outgrowths are initiated by collective apical extrusion of less-cohesive, loosely attached cell populations that can proliferate outside of the organotypic assembly. mRNA and immunofluorescence analysis of loosely attached cell populations revealed: (i) activation of Rho pathway, (ii) increased expression of several alpha integrin subunits that form heterodimers with beta 1 integrin, and (iii) nonpolarized apical and junctional localization of activated integrin beta 1. Pharmacologic or genetic inhibition of Rho-associated kinase (ROCK) blocked outgrowth formation without affecting cell proliferation. Conversely, activation of Rho significantly accelerated outgrowths, indicating that Rho-ROCK is a critical regulator of early steps of HGSC dissemination. Quantitative image-based evaluation of ROCK target phosphorylated myosin light chain expression in patient-derived xenograft cells revealed the presence of cell populations with high ROCK activation. Blocking integrin beta 1 activity resulted in the disintegration of already formed outgrowths. Our data indicate that cell populations with high Rho/ROCK activity remodel integrin beta 1-dependent adhesion to initiate apical extrusion and peritoneal dissemination. Citation Format: Sarah Alshehri, Sadaf Farsinejad, Douglas Kung, Estefan Santi, Yali Zhai, Thomas Cattabiani, Hongjun Wang, Kathleen Cho, Marcin Iwanicki. Collective extrusion initiates dissemination in organotypic model of high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B11.

Abstract IA10: Traditional and modern approaches for prevention and early detection

Abstract Conventionally, serum CA-125 measurements and ultrasonography have been used to try to detect ovarian carcinoma at early stage. These methods have not been proven to result in early-stage detection and seem to convey little survival benefit. It is now widely accepted that such methods are not justified for widespread use in cancer screening, and the US Preventative Services Task Force recommends against their use. CA-125 and human epididymis protein 4 (HE4) are involved in ovarian tumorigenesis, overexpressed by malignant epithelial cells, and found in patient serum. Increased levels of these proteins as well as others in patient ascites, and uterine fluid, as compared to serum, suggest that their detection may be enhanced by measurements taken from within the uterine cavity or other locations more proximal to the ovaries and fallopian tube where tumors most commonly originate. The knowledge that most high-grade serous carcinomas originate from the distal fallopian tube creates an opportunity for new screening and prevention approaches that were previously impractical when the site of origin was thought to be the ovarian surface epithelium. The fallopian tube can be accessed via a transvaginal/transuterine route, and the fallopian tubes are not necessary for normal biologic function once childbearing is complete. Based on the hypothesis that serous tubal intraepithelial carcinoma (STIC) is the precursor of most high-grade serous carcinomas (HGSCs), innovative studies aimed at providing a realistic clinical method for reducing the burden of ovarian cancer are under way. In this presentation we will discuss the latest knowledge regarding approaches for prevention and early detection of ovarian cancer. We will discuss the role of precursor lesions in the development and metastatic spread of invasive ovarian cancers. We will review ongoing and planned clinical trials of surgical prevention and discuss missed opportunities for chemoprevention. We will also discuss more innovative approaches to early detection through minimally invasive access to the distal fallopian tube and nanotechnology for highly sensitive protein detection. The approaches and others hold great promise to transform the paradigm of early ovarian cancer detection from one of traditional serum-based biomarkers to one that incorporates the current concepts of ovarian cancer origins, proximal measurements of tissue-based biomarkers, and novel circulating biomarkers. Citation Format: Douglas A. Levine. Traditional and modern approaches for prevention and early detection [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA10.

Abstract PR04: Analyses of Pax2 and Pax8 in maintaining oviduct epithelial homeostasis and fertility

Abstract Introduction: The female urogenital tract develops through a multistep process from the intermediate mesoderm (IM). Among several transcriptional regulators, Pax2 and Pax8 expression in the IM distinguishes all of the cells fated to become epithelia in the urogenital tract and are necessary to establish and maintain this phenotype. Fallopian tube epithelium mainly consists of two cell types, secretory and ciliated cells. In mice, Pax2 and Pax8 positive secretory cells are the oviduct epithelial progenitors and have the potential to self-renew as well as differentiate to ciliated cell progeny. Serous ovarian cancer (SOC) is the most common and the most lethal, and secretory cells are believed to be the progenitors of SOC. Patients with a predisposition for developing SOC were found to have tubal epithelial dysplastic lesions, such as serous tubal intraepithelial carcinoma (STIC). By generating double and single KO mouse modules of Pax2 and Pax8, we investigate their roles in maintaining the integrity of the oviductal cells and whether these proteins will provide new insight into epithelial homeostasis. Procedures: We used the Cre-loxP system to generate conditional KO of Pax2 and Pax8, using standard genetic and biochemical techniques to study the deletion of both proteins specifically in epithelium secretory cells. We used the OVGP1-Cre tamoxifen-inducible; also, some mice carried the combination with reporter mT/mG. Histology, immunohistochemistry, Western blot, and RNA meta-analysis data were collected and analyzed. Results: Mice carrying the single conditional KO of Pax2 f/f and Pax8f/f;OVGP1-CRE-ER or the double conditional KO of Pax2.flox-Pax8flox;OVGP1-CRE-ER appeared normal with no evidence of loss of function or other abnormalities. After tamoxifen administration and specific oviductal deletion of these proteins, the double Pax2 and Pax8 mutants showed oviduct phenotypes as early as 16 weeks. Such mice also failed to conceive even 8 weeks after tamoxifen administration. We observed progressive phenotypes at later times in the three combinations of protein deletion for up to one year after tamoxifen administration. Strikingly, cell lineage tracing revealed that surviving mutant cells could break through and migrate without losing their epithelial markers. These data demonstrate that Pax2 and Pax8 are needed for regenerating and maintaining the integrity of the fallopian tubes. Conclusions: Human ovarian cancer precursor lesions primarily consist of secretory cells. In mouse oviduct, secretory cells are the most frequently dividing cells of the oviductal epithelium. The mechanisms underlying epithelial homeostasis are still unknown. This in vivo genetic cell lineage tracing study showed that secretory cells give rise to ciliated cells that are altered upon Pax2 and Pax8 deletion. Using a conditional KO mouse model of Pax2 and Pax8 will allow us to identify future novel therapeutic targets and step further in the right direction to develop a novel of biomarkers for diagnostics and treatments. This abstract is also being presented as Poster B44. Citation Format: Abdulsalam Soofi, Yali Zahi, Kathleen Cho, Greg Dressler. Analyses of Pax2 and Pax8 in maintaining oviduct epithelial homeostasis and fertility [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR04.

Fallopian tube abnormalities in uterine serous carcinoma

ObjectiveUterine serous carcinoma (USC) is presumed to arise from endometrial intra-epithelial carcinoma (EIC), whereas tubo-ovarian high-grade serous carcinomas have similar precursor lesions in the Fallopian tube, i.e. serous tubal intra-epithelial carcinoma (STIC). The presence of Fallopian tube abnormalities and their clonal relationship to the concurrent USC was investigated. MethodsIn this multicenter study, all patients treated for USC between 1992 and 2017 were retrospectively identified. Histopathological diagnosis of USC, EIC and STIC was revised by an expert pathologist. Additionally, all Fallopian tube sections were immunohistochemically stained (p53 and Ki-67). Fallopian tube abnormalities were classified as either p53 signature, serous tubal intra-epithelial lesion (STIL) or STIC. The USCs and Fallopian tube abnormalities were analyzed by targeted next-generation sequencing. ResultsIn 168 included patients, Fallopian tube abnormalities were found in 27.4% (46/168): p53-signatures in 17.9% (30/168), STILs in 3.0% (5/168) and STICs in 6.5% (11/168). In subgroup analysis, STICs were found in 9.5% (11/115) of patients with at least one section of the fimbriated end embedded. Next-generation sequencing showed identical TP53-mutations in the STIC and corresponding USC. ConclusionsIn conclusion, the presence of Fallopian tube abnormalities was shown in a high percentage of patients with USC, representing either true precursor lesions or metastasized disease.

Prophylactic salpingectomy for prevention of ovarian cancer at the time of elective laparoscopic cholecystectomy.

BackgroundMost serous ovarian cancers are now understood to originate in the fallopian tubes. Removing the tubes (salpingectomy) likely reduces the risk of developing high‐grade serous ovarian cancer. Numerous gynaecological societies now recommend prophylactic (or opportunistic) salpingectomy at the time of gynaecological surgery in appropriate women, and this is widely done. Salpingectomy at the time of non‐gynaecological surgery has not been explored and may present an opportunity for primary prevention of ovarian cancer.MethodsThis study investigated whether prophylactic salpingectomy with the intention of reducing the risk of developing ovarian cancer would be accepted and could be accomplished at the time of elective laparoscopic cholecystectomy. Women aged at least 45 years scheduled for elective laparoscopic cholecystectomy were recruited. They were counselled and offered prophylactic bilateral salpingectomy at the time of cholecystectomy. Outcome measures were rate of accomplishment of salpingectomy, time and procedural steps needed for salpingectomy, and complications.ResultsA total of 105 patients were included in the study. The rate of acceptance of salpingectomy was approximately 60 per cent. Salpingectomy was performed in 98 of 105 laparoscopic cholecystectomies (93·3 per cent) and not accomplished because of poor visibility or adhesions in seven (6·7 per cent). Median additional operating time was 13 (range 4–45) min. There were no complications attributable to salpingectomy. One patient presented with ovarian cancer 28 months after prophylactic salpingectomy; histological re‐evaluation of the tubes showed a previously undetected, focal serous tubal intraepithelial carcinoma.ConclusionProphylactic salpingectomy can be done during elective laparoscopic cholecystectomy.

Lymphatic Invasion in the Fallopian Tube is a Late Event in the Progression of Pelvic Serous Carcinoma and Correlates With Distant Metastasis.

The majority of extrauterine high-grade serous carcinomas are believed to arise in the fallopian tube as serous tubal intraepithelial carcinomas. The primary mode of metastasis is intraperitoneal, and patients usually present with peritoneal carcinomatosis. Although the tubes have a rich lymphatic network, tubal lymphatic invasion is observed in only a minority of cases. Fallopian tube sections from 222 patients with advanced stage high-grade extrauterine serous carcinoma were reviewed and lymphatic invasion within the lamina propria and myosalpinx were assessed. Seventeen patients were FIGO stage II, 162 stage III, and 43 stage IV. Tubal lymphatic invasion was identified in 44 cases (19.7%). Among the cases with lymphatic invasion, nonfimbrial lamina propria, fimbrial lamina propria, and myosalpingeal lymphatic invasion were present in 23 (52%), 21 (48%), and 21 (48%), respectively. Among cases with lymphatic invasion, 16 (36%) were FIGO stage IV, while among cases without lymphatic invasion, 27 (15%) were stage IV (P=0.0014, χ). In summary, in women with advanced stage high-grade extrauterine serous carcinoma, lymphatic invasion in the fallopian tube is uncommon, and is more than twice as likely to be associated with distant metastases as compared with those without tubal lymphatic invasion.