Serous Tubal Intraepithelial Carcinoma Research Articles

Uterine washing biomarkers as a novel screening tool for high-grade serous carcinoma

Objective: High-grade serous carcinoma (HGSC) of the pelvis is an aggressive gynecologic malignancy often detected at advanced stage. Clinically proven screening tests are lacking. Recent data suggest that a precursor lesion – serous tubal intraepithelial carcinoma – arises from the distal fallopian tube. We hypothesize that given HGSC’s tubal origin, biomarkers previously studied in the serum may also be elevated in washings from the uterine cavity, representing a novel approach to early detection.

Serous tubal intraepithelial carcinoma frequency in endometriosis-associated epithelial ovarian cancer

Objective: With the discovery of serous tubal intraepithelial carcinoma (STIC), the fallopian tube has been identified as the site of origin for many serous ovarian cancers. We hypothesized that endometriosis-associated ovarian cancer would have the equivalent or lower frequency of STICs as epithelial ovarian cancer alone because its site of origin is outside the fallopian tube.

Early Telomere Shortening and Genomic Instability in Tubo-Ovarian Preneoplastic Lesions

Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD). Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX. TOD showed marked telomere shortening compared with noncancerous controls (P < 10(-7)). STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P < 10(-7)). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers. These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia.

Abstract 4791: Serous cancer progenitor cells in the oviduct.

Abstract Background: A spectrum of precursors has been identified in the distal fallopian tube with a relationship to pelvic serous cancer ("ovarian cancer") and linked to p53 mutations, absence of PAX2 expression (PAX2-) or both. Because a wide range of precursors are PAX2-, we hypothesized that the PAX2- immunophenotype was a property of a serous cancer progenitor cell rather than acquired during neoplastic transformation. This study explored this concept. Methods: Oviductal epithelia were immunostained concurrently with PAX2 (a non-ciliated cell marker), FOXJ1 (a ciliated cell marker) and CD3 (lymphocyte marker) to identify PAX2- secretory cells. Genes over-expressed in PAX2- precursors based on expression arrays were selected (ALDH1, LEF1, EZH2). Derived antibodies were used to co-localize expression with the PAX2- cells candidate progenitor cells, precursor lesions and serous carcinomas. Results: Immunostaining of human and murine oviducts revealed discrete PAX2- cells in the epithelium. In the mouse, PAX2- cells were confined to the distal tube. PAX2- cells were seen individually and in non-stratified epithelium and accounted for less than 10% of the non-ciliated cell population. However, PAX2- cell clusters were discovered and larger populations of PAX2- cells were identified, both in the middle of the epithelium and adjacent to the basement membrane. Discrete expansions (termed secretory cell outgrowths or SCOUTs) were common, particularly in fallopian tubes of women with pelvic serous cancer, and coincided with an ALDH1-, LEF1+, EZH2+ immunophenotype. This same immunophenotype characterized serous cancer precursors associated with over-accumulation of p53 (p53 signatures, serous tubal intraepithelial carcinomas) and invasive serous carcinomas. Conclusion: This report proposes a candidate cell of origin for both benign proliferations and high grade serous carcinoma in the oviduct that is a PAX2- secretory cell. The distribution of the PAX2- cells is emblematic of their role in both physiologic cell proliferation and clonal expansion, the latter including altered expression of ALDH1, LEF1 and EZH2, among others. The phenotypic range of PAX2- cell expansions is consistent with the imposition of multiple stimuli on this cell, including both preservation and loss of p53 function. This population of PAX2- cells provides a unique substrate for studying cell-specific vulnerabilties in serous carcinogenesis and the molecular underpinnings of the varied differentiation paths that seem to ensue during clonal expansion of this unique cell type. Citation Format: Gang Ning, Michael Herfs, Jonathan G. Bijron, Yasuke Yamamoto, Daniela Dinulescu, Frank D. McKeon, Christopher P. Crum, Wa Xian. Serous cancer progenitor cells in the oviduct. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4791. doi:10.1158/1538-7445.AM2013-4791

Precursors and pathogenesis of ovarian carcinoma

The ultimate goal of defining cancer specific precursors is to facilitate early detection and intervention before the development of invasive malignancy. Unlike other malignancies involving the female genital tract such as cervical or endometrial carcinomas, precursor lesions of ovarian carcinomas have not been well characterised, resulting in a failure to develop effective screening programs. Recent clinicopathological and molecular studies have provided new insight into the origin and pathogenesis of ovarian carcinomas. It has been shown that ovarian cancer is comprised of different tumour types differing not only in morphology, but also in pathogenesis, molecular alterations and clinical progression. A dualistic model of ovarian carcinogenesis has been proposed. Type I tumours which include low grade serous, low grade endometrioid, clear cell, mucinous carcinomas and Brenner tumours, are generally indolent and tend to be genetically stable, although clear cell carcinoma would probably belong to an intermediate category. They demonstrate a step-wise progression from a benign precursor such as a benign to borderline tumour or endometriosis and are characterised by genetic aberrations targeting specific cell signalling pathways. Type II tumours comprise high grade serous, high grade endometrioid, and undifferentiated carcinomas as well as malignant mixed mesodermal tumours. They are clinically aggressive and exhibit high genetic instability with frequent p53 mutations. Mounting evidence suggests that many high grade serous carcinomas originate from the epithelium of the distal fallopian tube, and that serous tubal intraepithelial carcinoma (STIC) represents the putative precursor of these neoplasms. Low grade serous carcinomas arise via transformation of benign and borderline serous tumours, thought to be derived from inclusion cysts originating from the ovarian surface or tubal epithelium. Recently it has been suggested that papillary tubal hyperplasia may be a putative precursor lesion for serous borderline tumours. Both endometrioid and clear cell carcinomas develop from endometriosis, via alterations affecting different genetic pathways. The origin of mucinous and transitional cell neoplasms is not well characterised, although new data suggest a possible origin from transitional cell nests present at the tubal-mesothelial junction. Likewise, the pathogenesis of carcinosarcomas is also not well established because of their rarity but there is accumulating evidence that the carcinomatous component determines the course of the disease and gives rise to the malignant mesenchymal component. This review discusses recent developments in the pathogenesis of ovarian carcinoma, with particular emphasis on the putative precursor lesions that give rise to the major histological subtypes. Recognition of these lesions is not only important in improving the understanding of ovarian carcinogenesis, but it will also influence our approach to prevent, detect and treat these tumours.

Clinicopathologic study of serous tubal intraepithelial carcinoma with invasive carcinoma: is serous tubal intraepithelial carcinoma a reliable feature for determining the organ of origin?

In the past several decades, the concept of serous ovarian carcinoma has been revised repeatedly. However, the exact pathogenesis remains controversial. The most popular current concept is origin from the epithelium of the fimbriated ends of the fallopian tubes. The objective of our study was to evaluate the characteristic clinical and morphologic features of serous tubal intraepithelial carcinoma (STIC) and associated invasive carcinomas. One hundred sixteen consecutive cases of STIC seen from 2007 to 2011 were included in this study. High-grade serous carcinoma (HGSC) with or without a mixed component was identified in 107 cases (92.2%), non-HGSC in 5 cases, and STICs without invasive carcinoma in 4 cases. Using conventional criteria, HGSCs were classified as fallopian tube in origin in 65 cases (60.7%), as ovarian in 30 (28.0%), as peritoneal in 9 (8.4%), and as endometrial in 3 (2.8%). Among the 107 cases with HGSCs, most STICs (86; 80%) were present unilaterally, whereas invasive tumors more commonly involved the ovaries bilaterally (79%; 84 cases). These findings support the hypothesis that STIC acts as a precursor lesion for most fallopian tube, ovarian, and peritoneal HGSCs, but not for endometrial HGSC.

High-Grade serous carcinoma of the fallopian tube: two cases presenting as inguinal lymph node metastasis

Primary fallopian tube high-grade serous carcinoma (HGSCa) has historically been considered an uncommon neoplasm. Recent evidence, however, suggests that most extrauterine HGSCa arise within the fimbriae of the fallopian tube, via an intraepithelial precursor lesion known as serous tubal intraepithelial carcinoma (STIC), which is thought to metastasise to the ovary and pelvic peritoneum. HGSCa typically present with advanced disease and the prognosis is notoriously poor. Presentation of HGSCa as lymph node metastasis is distinctly unusual, even more so in the absence of detectable pelvic disease. We describe two cases of HGSCa of fallopian tube origin presenting as inguinal lymph node metastasis, both with clinically silent pelvic disease at presentation. Although an uncommon mode of presentation, these cases reinforce the need to maintain a high index of suspicion for HGSCa, even in the absence of gynaecological symptoms. Accurate diagnosis is achievable with careful morphological assessment teamed with an immunoperoxidase panel which includes Wilms’ tumour 1 (WT1) and may provide an opportunity for definitive surgery before bulky pelvic disease supervenes. This new model of tumourigenesis of HGSCa may have significant implications for the management of BRCA mutation carriers and potentially all women undergoing pelvic surgery.

Papillary Syncytial Metaplasia of Fallopian Tube Endometriosis: A Potential Pitfall in the Diagnosis of Serous Tubal Intraepithelial Carcinoma

Histopathologic diagnosis of tubal intraepithelial carcinoma (TIC) has emerged as a significant challenge in the last few years. The avoidance of pitfalls in the diagnosis of TIC is crucial if a better understanding of its natural history and outcome is to be achieved. Herein, we present a case of a 52-year-old woman who underwent a risk-reducing salpingo-oophorectomy procedure. Histologic examination of a fallopian tube demonstrated a focus of atypical epithelial proliferation, which was initially considered to be a TIC. Complete study of the case indicated that the focus was, in fact, papillary syncytial metaplasia of tubal mucosal endometriosis. Papillary syncytial metaplasia may resemble TIC and should be considered in cases of proliferative lesions of the tubal epithelium.

Fallopian tube precursors of ovarian low‐ and high‐grade serous neoplasms

Traditionally, it was thought that ovarian high-grade serous carcinoma arises from the ovarian surface epithelium and epithelial inclusion glands and that the pathogenesis is de novo; nonetheless, a convincing precursor in the ovary or peritoneum has not been identified to date. During the last few years, however, there has been a dramatic shift in thinking, and a candidate precursor is now recognized in the fallopian tube, especially within the fimbriated end - serous tubal intra-epithelial carcinoma (STIC). Accordingly, STIC is probably the earliest histologically recognizable lesion in the pathogenesis of high-grade serous carcinoma, but steps in this pathway which precede STIC have also been proposed. With subsequent progression, STIC implants onto the ovary and then develops into an invasive high-grade serous carcinoma with rapid tumour growth. For invasive low-grade serous carcinoma, it is well-established that its pathogenesis begins with serous cystadenoma/adenofibroma, which develops sequentially into atypical proliferative serous tumour (typical serous borderline tumour), non-invasive micropapillary (low-grade) serous carcinoma (micropapillary serous borderline tumour) and then invasive low-grade serous carcinoma in a relatively slow stepwise process. It is presumed that cystadenoma/adenofibroma arises from epithelial inclusion glands in the ovary, but recent evidence suggests that epithelial inclusion glands originate in the fallopian tube. Alternatively, it has been proposed that the other early precursors in the low-grade pathway, including serous borderline tumours, non-invasive implants and endosalpingiosis, may also arise directly from tubal mucosa. Therefore, the precursor of most ovarian high-grade serous carcinomas originates in the fallopian tube, and that for low-grade serous tumours may also be derived from the tube. This review paper provides an overview of the fallopian tube's potential role in the pathogenesis of both types of serous neoplasms of the ovary.

The Diagnostic and Biological Implications of Laminin Expression in Serous Tubal Intraepithelial Carcinoma

There is compelling evidence to suggest that serous tubal intraepithelial carcinoma (STIC) is the likely primary site for the development of many pelvic high-grade serous carcinomas (HGSCs). Identifying molecules that are upregulated in STIC is important not only to provide biomarkers to assist in the diagnosis of STIC but also to elucidate our understanding of the pathogenesis of HGSC. In this study, we performed RNA sequencing to compare transcriptomes between HGSC and normal fallopian tube epithelium (FTE), and we identified LAMC1 encoding laminin γ1 as one of the preferentially upregulated genes associated with HGSC. Reverse transcription polymerase chain reaction further validated LAMC1 upregulation in HGSC as compared with normal FTE. Immunohistochemical analysis was performed on 32 cases of concurrent HGSC and STIC. The latter was diagnosed on the basis of morphology, TP53 mutations, and p53 and Ki-67 immunohistochemical patterns. Laminin γ1 immunostaining intensity was found to be significantly higher in STIC and HGSC compared with adjacent FTE in all cases (P<0.001). In normal FTE, laminin γ1 immunoreactivity was predominantly localized in the basement membrane or on the apical surface of ciliated cells, whereas in STIC and HGSC cells, laminin γ1 staining was diffuse and intense throughout the cytoplasm. More importantly, strong laminin γ1 staining was detected in all 13 STICs, which lacked p53 immunoreactivity because of null mutations. These findings suggest that the overexpression of laminin γ1 immunoreactivity and alteration of its staining pattern in STICs can serve as a useful tissue biomarker, especially for those STICs that are negative for p53 and have a low Ki-67 labeling index.

Proliferation in the Normal FTE Is a Hallmark of the Follicular Phase, Not BRCA Mutation Status

Women who have inherited germline mutations of BRCA1/BRCA2 are at increased risk of developing high-grade serous carcinoma, and many of these cancers arise in the distal fimbriated end of the fallopian tube. We have previously shown that the fallopian tube epithelia of BRCA1 mutation carriers (FTE-BRCA) have altered signaling pathways compared to nonmutation carriers. In this study, we sought to determine whether these differences result in a proliferative advantage to the epithelia in this high-risk patient population and to investigate whether the postovulation environment of the FTE-BRCA compared to FTE from nonmutation carriers experiences a differential abundance of immune cells. Immunohistochemistry for Ki67, CD3, CD8, CD20, and CD68 was performed on histologically normal tubal epithelium (ampulla, n = 83), fimbria (n = 18) with known ovarian cycle status and germline mutation status and for Ki67 on fimbrial epithelium from women (n = 144) with and without BRCA1 or BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO). Serous tubal intraepithelial carcinomas (STIC) with concomitant cancer (n = 15) were also analyzed for presence of immune infiltrates. All slides were digitized and analyzed using automated image analysis software. There was no significant difference in the proliferative index in histologically normal FTE between BRCA1/BRCA2 and non-BRCA, in 144 fimbriae and 83 ampullae. The FTE-BRCA1 epithelia did not exhibit a differential presence of lymphocytes or macrophages, however more macrophages were present in the luteal phase compared to the follicular phase epithelia. In STICs macrophages were more abundant than lymphocytes with an incremental increase noted with disease progression. BRCA1/2 mutation carriers exhibited no significant increase in proliferation in the fallopian tube epithelial cells either in the ampulla or fimbriated ends of the tube. Rather, a significant proliferative increase was defined in the cases determined to be in the follicular, or proliferative, preovulatory phase of the ovarian cycle. Finally, we also show an incremental increase in leukocytes invading the STICs and HGSC, implicating a possible role of the leukocytes early in the progression or inhibition of tumor formation, which is independent of ovarian cycle status.

Ki-67 Labeling Index as an Adjunct in the Diagnosis of Serous Tubal Intraepithelial Carcinoma

There is mounting evidence that serous tubal intraepithelial carcinoma (STIC) may be the immediate precursor of ovarian high-grade serous carcinoma (HGSC) but the criteria for its diagnosis are not well established as highlighted in a recent study showing that interobserver reproducibility, even among expert gynecologic pathologists, was moderate at best. Given the clinical significance of a diagnosis of STIC in a patient who has no other evidence of ovarian carcinoma, this is a serious issue that we felt needed to be addressed. Although it is not clear, at this time, whether such a patient should or should not be treated, the importance of an accurate and reproducible diagnosis of precursors of ovarian carcinoma cannot be underestimated. We hypothesized that an elevated Ki-67 labeling index may aid the diagnosis of STIC. Accordingly, we compared the Ki-67 index of STIC and HGSC to normal fallopian tube epithelium (FTE) in the same patients and to a control group of patients without carcinoma, matched for age. A total of 41 STICs were analyzed, of which 35 were associated with a concurrent HGSC. In FTE, immunoreactivity for Ki-67 was restricted to a few scattered cells (mean 2.0%). No statistically significant difference was found between patients with and without HGSC (P>0.05). However, both STICs and HGSC had significantly higher Ki-67 indices than normal FTE (P<0.0001). STICs uniformly had an elevated Ki-67 labeling index that ranged from 11.7% to 71.1% (average 35.6%). There was no correlation of the Ki-67 labeling index in the STICs and the associated HGSC, as the labeling index was lower in STIC in 18/35 (51.4%) whereas it was higher in 17/35 (48.6%) (P=0.86). In conclusion, the findings in this study indicate that compared with FTE, STICs have a significantly higher Ki-67 index similar to HGSC. Accordingly, the Ki-67 index can aid the diagnosis of intraepithelial tubal proliferations suspicious for STIC. Therefore, we propose that a Ki-67 index of 10% is a useful diagnostic tool to distinguish STICs from normal FTE.

Biomarker expression in normal fimbriae: Comparison of high- and low-grade serous ovarian carcinoma

The objective of this study was to assess the difference in fimbriae of high- and low-grade ovarian serous carcinoma (OSC). The fimbriae of normal appearance [without serous tubal intraepithelial carcinoma (STIC)] from 28 patients with high-grade OSCs and 24 patients with low-grade OSCs were assessed for the expression of 6 markers [E-cadherin, matrix metalloproteinase-2 (MMP-2), phospho-AKT (pAKT), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and p53] using immunohistochemistry. Sectioning and extensively examining the fimbria (SEE-FIM) was performed to exclude fimbrial involvement for all the cases. The immunostaining levels of pAKT and COX-2 were significantly higher in the fimbriae of normal appearance from high-grade OSCs compared with low-grade OSCs (61 vs. 8% and 71 vs. 21%; P=0.005 and 0.007, respectively). The immunostaining of E-cadherin was significantly higher in the fimbriae of low-grade OSCs compared with high-grade OSCs (83 vs. 21%; P= 0.003). The remaining 3 markers (MMP-2, VEGF and p53) had similar expression in low- and high-grade OSCs (21 vs. 13%; 25 vs. 21%; and 14 vs. 8%; P=0.78, 0.86 and 0.82, respectively). Our results suggest marked biological differences in the behavior of the fimbriae in high- and low-grade OSCs and indicate that proliferation, cell adhesion and the inflammatory microenvironment of fimbriae in high-grade OSCs without STIC had changed prior to p53 mutation.

Morphologic changes of fallopian tubal epithelium in ovarian serous tumors

To study the morphologic changes of fallopian tubal epithelium in patients with ovarian serous epithelial tumors and to explore the relationship between the tubal epithelial changes and tumorigenesis of serous ovarian carcinoma. The fallopian tubes in 79 cases of high-grade serous ovarian carcinoma, 12 cases of low-grade serous ovarian carcinoma, 16 cases of serous borderline ovarian tumor and 11 cases of non-ovarian benign tumors were serially examined under light microscope. Immunohistochemical study with EnVision method was used to detect the expression of p53 and bcl-2 protein in the fallopian tubal epithelium in all cases. The occurrences of secretory cell outgrowth (SCOUT), p53 signature, serous tubal intraepithelial carcinoma (STIC) and serous invasive carcinoma were analyzed. SCOUT in tubal epithelium was observed in 60.8% (48/79) of the high-grade serous carcinoma group, 4/12 of the low-grade serous carcinoma group, 3/16 of the serous borderline tumor group and 2/11 of the non-ovarian benign tumor group (P = 0.001). P53 signature, STIC and serous invasive carcinoma occurred only in the fallopian tubal epithelium of patients with high-grade serous ovarian carcinoma, with the positive rates being 29.1% (23/79), 15.2% (12/79) and 44.3% (35/79), respectively. Of the 23 cases with p53 signature, 17 cases had solitary lesion and 6 cases involved more than two sites. A total of 33 p53 signature positive foci were found, with 22 foci located at fimbria and 11 at ampulla. Bcl-2 expression was demonstrated in 90.9% of those foci (30/33). Of the 12 patients with STIC, 7 cases were solitary and 5 cases involved more than two sites. A total of 18 STIC foci were found, with 16 foci located at fimbria and 2 at ampulla. All of them were positive for bcl-2. SCOUT is found in fallopian tubal epithelium in patients with serous ovarian epithelial tumors, especially high-grade serious carcinoma. On the other hand, p53 signature, STIC and invasive serous carcinoma of tubal epithelium are observed only in patients with high-grade serous ovarian carcinoma, with a predilection of fimbrial involvement. Correlation exists between SCOUT, p53 signature, STIC and high-grade serous ovarian carcinomas. Bcl-2 and p53 immunostaining is helpful for demonstrating such lesions.

Validation of an Algorithm for the Diagnosis of Serous Tubal Intraepithelial Carcinoma

It has been reported that the diagnosis of serous tubal intraepithelial carcinoma (STIC) is not optimally reproducible on the basis of only histologic assessment. Recently, we reported that the use of a diagnostic algorithm that combines histologic features and coordinate immunohistochemical expression of p53 and Ki-67 substantially improves reproducibility of the diagnosis. The goal of the current study was to validate this algorithm by testing a group of 6 gynecologic pathologists who had not participated in the development of the algorithm (3 faculty and 3 fellows) but who were trained in its use by referring to a website designed for the purpose. They then reviewed a set of microscopic slides, which contained 41 mucosal lesions of the fallopian tube. Overall consensus (≥4 of 6 pathologists) for the 4 categories of STIC, serous tubal intraepithelial lesion (our atypical intermediate category), p53 signature, and normal/reactive was achieved in 76% of the lesions, with no consensus in 24%. Combining diagnoses into 2 categories (STIC versus non-STIC) resulted in an overall consensus of 93% and no consensus in 7%. The κ value for STIC versus non-STIC among all 6 observers was also high at 0.67 and did not significantly differ, whether for faculty (κ=0.66) or fellows (κ=0.60). These findings confirm the reproducibility of this algorithm by a group of gynecologic pathologists who were trained on a website for that purpose. Accordingly, we recommend its use in research studies. Before applying it to routine clinical practice, the algorithm should be evaluated by general surgical pathologists in a community setting.

BRCA, the Oviduct, and the Space and Time Continuum of Pelvic Serous Carcinogenesis

In recent years, the distal oviduct has emerged as a critical organ in the pathogenesis of pelvic ("ovarian") serous cancer. Studies have uncovered early serous tubal intraepithelial carcinomas in approximately 8% of asymptomatic women with germline BRCA1 or BRCA2 mutations, linked serous tubal intraepithelial carcinomas to one half of serous cancers irrespective of genetic risk, and described a precursor lesion in the distal tube with early alterations in p53 function (the p53 signature). This work has established a linear serous carcinogenic sequence in a single focus within the fimbria. In addition, a more broadly distributed array of gene alterations has been discovered in the oviduct, manifested as secretory (or stem) cell outgrowths that are increased in frequency as a function of older age and serous cancer status. These "surrogate precursors" expand the existing model beyond the fimbria, implying that the molecular events leading to serous cancer are distributed over space and time. The potential promise of these discoveries is "targeted prevention" by discovering of multiple pathways integral to carcinogenesis and successfully preventing malignancy by interrupting one or a few of these pathways.

MiR‐182 overexpression in tumourigenesis of high‐grade serous ovarian carcinoma

Molecular pathogenesis of high-grade serous ovarian carcinoma (HG-SOC) is poorly understood. Recent recognition of HG-SOC precursor lesions, defined as serous tubal intraepithelial carcinoma (STIC) in fimbria, provides a new venue for the study of early genetic changes in HG-SOC. Using microRNA profiling analysis, we found that miR-182 expression was significantly higher in STIC than in matched normal Fallopian tube. Further study revealed that miR-182 was significantly overexpressed in most HG-SOC cases. To test whether miR-182 plays a major role in early tumourigenesis of HG-SOC, we overexpressed miR-182 in immortalized ovarian surface, Fallopian tube secretory cells and malignant ovarian cell lines, and found that miR-182 overexpression resulted in increased tumour transformation in vitro, and enhanced tumour invasiveness in vitro and metastasis in vivo. Mechanistically, we demonstrated that the oncogenic properties of miR-182 in ovarian cancer were mediated in part by its impaired repair of DNA double-strand breaks and negative regulation of breast cancer 1 (BRCA1) and metastasis suppressor 1 (MTSS1) expression as well as its positive regulation of the oncogene high-mobility group AT-hook 2 (HMGA2). Our findings suggest that miR-182 dysregulation confers powerful oncogenic potential in the tumourigenesis of HG-SOC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Abstract 114: Study of the high-grade ovarian cancer precursors in the oviduct

Abstract The discovery that many high-grade ovarian cancers originate in the oviduct has generated a paradigm shift in the field of ovarian cancer. The description of new entities in the oviduct that signify early phases of ovarian carcinogenesis, including both serous tubal intraepithelial carcinomas and their precursors the p53 signatures, has provided a tangible sequence of events leading to malignancy that can be linked to DNA damage and p53 mutations. However, it has become clear that other pathway disturbances also play a critical role in the early development of ovarian cancer. We hypothesize that molecular alterations present in morphologically normal oviductal epithelium from ovarian cancer patients reflect the earliest events in ovarian carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Whole-genome transcriptome analysis of laser microdissected oviductal epithelium from histologically normal ovarian cancer patients and controls was performed. We identified a set of aberrantly expressed genes in the oviductal epithelium from women who developed high-grade ovarian cancer and demonstrated some of these genes are also abnormally expressed in the ovarian cancers due to the genomic alterations. We further examined the function of these genes using three-dimensional cell culture system and mouse models. Our work demonstrates the synergistic effects of defective p53 pathway and other newly found pathways in driving early steps of ovarian cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 114. doi:1538-7445.AM2012-114

Frequency of Serous Tubal Intraepithelial Carcinoma in Various Gynecologic Malignancies

Serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. We hypothesized that, if this is the case, the frequency of STIC should be substantially lower in endometrial serous carcinomas, in nonserous gynecologic malignancies, and in benign gynecologic neoplasms than in ovarian or peritoneal serous carcinomas. From 2007 to 2009 the fallopian tubes of 342 consecutive gynecologic cases were entirely submitted for histology using the Sectioning and Extensively Examining the FIMbriated end protocol. This study included 300 of these cases (277 TAH-BSO, 23 BSO) after exclusion. The hematoxylin and eosin-stained slides from the fallopian tubes were independently reviewed by 2 gynecologic pathologists who were blinded to all other findings; disagreements were resolved by a third pathologist. Among 46 cases of ovarian malignancies, STIC was identified in 6 (18.8%) of 32 cases of serous carcinoma, but not in any other subtype. Similarly, STIC coexisted in 4 (14.3%) of 28 cases of endometrial serous carcinoma; however, no STIC was identified in any of the 74 cases of nonserous endometrial malignancies. STIC was identified in 2 (28.6%) of 7 cases of peritoneal serous carcinoma. No STIC was identified among 15 nongynecologic malignancies, 90 cases of benign conditions, and 27 cases of other conditions including 4 cases of cervical adenocarcinoma in situ and high-grade cervical intraepithelial lesions, 8 cases of endometrial atypical complex hyperplasias, and 15 cases of ovarian borderline tumors. In conclusion, the fallopian tube may be the origin of some pelvic serous carcinomas. Other possibilities that may explain the origin of pelvic high-grade serous carcinoma are discussed. Given that STIC coexisted with 14% of endometrial serous carcinomas, a more unifying theory may be that gynecologic serous carcinomas and STIC are multifocal lesions.

TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high‐grade serous carcinoma—evidence supporting the clonal relationship of the two lesions

Serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of ovarian, tubal and 'primary peritoneal' (pelvic) high-grade serous carcinoma (HGSC). As somatic mutation of TP53 is the most common molecular genetic change of ovarian HGSC, occurring in more than 95% of cases, we undertook a mutational analysis of 29 pelvic HGSCs that had concurrent STICs to demonstrate the clonal relationship of STICs and HGSCs. In addition, we correlated the mutational data with p53 immunostaining to determine the role of p53 immunoreactivity as a surrogate for TP53 mutations in histological diagnosis. Somatic TP53 mutations were detected in all 29 HGSCs analysed and the identical mutations were detected in 27 of 29 pairs of STICs and concurrent HGSCs. Missense mutations were observed in 61% of STICs and frameshift/splicing junction/nonsense mutations in 39%. Interestingly, there were two HGSCs with two distinctly different TP53 mutations each, but only one of the mutations was detected in the concurrent STICs. Missense mutations were associated with intense and diffuse (≥ 60%) p53 nuclear immunoreactivity, while most of the null mutations were associated with complete loss of p53 staining (p < 0.0001). Overall, this p53 staining pattern yielded a sensitivity of 87% and a specificity of 100% in detecting TP53 missense mutations. In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histological diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation, whereas complete absence of staining correlates with null mutations.