The fallopian tube as the origin of non-uterine pelvic high-grade serous carcinoma

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1 DOI: /tog The Obstetrician & Gynaecologist ;18: Education The fallopian tube as the origin of non-uterine pelvic high-grade serous carcinoma Ieera Madan Aggarwal MBBS MD MRCOG, a, * Yu Hui Lim MBBS, b Timothy Yong Kuei Lim MBBS MRCOG FAMS c a Consultant Gynaecologist, Department of Gynaecological oncology, KK Women s and Children Hospital, Bukit Timah Road, Singapore b Resident, Department of Obstetrics and Gynaecology, KK Women s and Children Hospital, Bukit Timah Road, Singapore c Head of Department and Senior Consultant, Department of Gynaecological Oncology, KK Women s and Children Hospital, Bukit Timah Road, Singapore *Correspondence: Ieera Aggarwal. imaggar@hotmail.com Accepted on 16 September 2015 Key content Advances in histopathology, immunohistochemistry and molecular genetics have led to evidence that the fimbrial end of the fallopian tube may be the source of origin of non-uterine highgrade pelvic serous carcinoma (HGPSC). Most of the evidence comes from studies in risk-reducing salpingo-oophorectomy in BRCA carriers. A proportion of these high-grade tumours have been proven to develop from specific precursor lesions, such as serous tubal intraepithelial carcinoma (STIC), before transformation into invasive high-grade pelvic serous carcinoma. Detailed sectioning of the fallopian tube is suggested using the SEE-FIM protocol (Sectioning and Extensively Examining the Fimbriated end of the fallopian tube). Clinical management of STIC in the absence of malignancy is not yet clearly defined. Learning objectives To review the various theories of pathogenesis of nonuterine HGPSC. To discuss the clinical management of STIC. Preventative strategies for HGPSC. Ethical issues Role for salpingectomy as a mode of sterilisation in women with completed family and salpingectomy during hysterectomy for benign cases. Could risk-reducing salpingectomy be recommended instead of risk-reducing salpingo-oophorectomy in young women, to avoid menopausal side effects? Keywords: fallopian tube cancers / high-grade serous cancers / riskreducing salpingo-oophorectomy Please cite this paper as: Aggarwal IM, Lim YH, Lim TYK. The fallopian tube as the origin of non-uterine pelvic high-grade serous carcinoma. The Obstetrician & Gynaecologist 2016;18: DOI: /tog Introduction Fallopian tube cancers are rare and account for 0.3% of all cancers of the female genital tract. 1 They appear most frequently in the fifth and sixth decades of women s lives. Advances in histopathology, immunohistochemistry and molecular genetics have led to evidence that the fimbrial end of the fallopian tube may more commonly be the source of origin of non-uterine high-grade pelvic serous carcinoma (HGPSC) of tubal, ovarian or peritoneal sites than previously thought. This article aims to review the theories of pathogenesis of HGPSC and their implications in clinical management and prevention. Most ovarian cancers are epithelial carcinomas (around 90%) with a small proportion being germ cell tumours and sex cord stromal tumours. Epithelial ovarian cancers are divided into different subtypes, including serous, clear cell, endometrioid and mucinous. Serous carcinomas are the most common and lethal subtype, comprising up to 68%. 2 The dualistic model proposed by Kurman et al. 3 divides epithelial tumours into Type 1 and Type 2 based on the morphology, biological behaviour and molecular genetics. Table 1 4 and Figure 1 outline the differences between Type 1 and Type 2 tumours. Traditional view on the pathogenesis of ovarian cancers Fathalla 5 proposed his theory of incessant ovulation in The ovarian surface is lined by coelomic epithelium, which consists of flattened cuboidal cells. Repetitive and chronic trauma to the ovarian surface epithelium (OSE) during ovulation and the subsequent repair process predisposes it to malignant transformation. During this reparative process the OSE invaginates to form cortical inclusion cysts (CIC). These undergo metaplasia to a m ullerian type of epithelium. ª 2016 Royal College of Obstetricians and Gynaecologists 143

2 Fallopian tube origin of pelvic high-grade serous carcinoma Table 1. Differences between Type 1 and Type 2 tumours 4 Type 1 Type 2 Gene mutations KRAS BRAF ERBB2 PTEN beta-catenin PIK3CA CTNNB1 ARID1A TP53, BRCA Early lesion Cystadenoma, borderline cystadenoma, endometriosis Serous tubal intraepithelial carcinoma (STIC) Histological type Presentation and transition to malignancy Spread pattern Endometrioid, clear cell, mucinous, low-grade serous carcinoma, Brenner Early stage, slow, gradual Multifocal distribution, distant recurrence, systemic spread High-grade serous carcinoma, carcinosarcoma, undifferentiated Advanced stage, abrupt Mesothelial lined surfaces of the ovary, fallopian tube and peritoneum Figure 1. Type 1 and Type 2 ovarian tumours. Reproduced with permission from Jones PM, Drapkin R. Modeling high-grade serous carcinoma: how converging insights into pathogenesis and genetics are driving better experimental platforms. Front Oncol 2013;3:217. Hormonal influences or genotoxic stress could transform these CICs into serous carcinomas. Clinico-epidemiological studies lend credence to this theory whereby nulliparity and oral contraceptive pills are associated with a reduction in the risk of ovarian carcinoma, whereas those with early menarche and/or late menopause are associated with a higher risk. However, the lack of a well-defined precursor lesion in or on the ovarian surface has raised doubts and questions about this mechanism. The gonadotrophin theory described by Cramer and Welch 6 in 1983 attempted to overcome some of the weaknesses in the incessant ovulation theory. Overstimulation of the OSE by the gonadotrophin (follicle-stimulating hormone, luteinising hormone) receptors was believed to cause its proliferation and malignant transformation. This explained the increased risk in perimenopausal women and in those with polycystic ovarian syndrome and infertility. The levels of gonadotrophins increase with advancing age and after menopause, consistent 144 ª 2016 Royal College of Obstetricians and Gynaecologists

3 Aggarwal et al. with the age-specific rates of epithelial ovarian cancers. However, animal studies have not been able to confirm this hypothesis. Risk-reducing salpingo-oophorectomy in BRCA carriers and emergence of new evidence in histogenesis It has been well demonstrated that inherited mutations in BRCA1 and BRCA2 genes increase the risk of ovarian, tubal and peritoneal cancers. Approximately 10% of women with ovarian cancer have a positive family history and a heterozygous mutation in BRCA1 or BRCA2 genes has been found in most cases. With BRCA1, the lifetime risk of developing ovarian cancer is as high as 25 50% whereas with BRCA2, it is 10 20%. These cancers tend to present at an earlier age in women with a BRCA1 mutation; the median age is mid-40s. 4 Risk-reducing bilateral salpingooophorectomy (RRSO) at the completion of childbearing is recommended in women with documented germline mutations or in those with a very strong family history. Finch et al. 7 have carried out extensive research on this topic and recently published findings that preventative oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube or peritoneal cancer in BRCA1 and BRCA2 carriers, and a 77% reduction in all-cause mortality. The specimens obtained from these prophylactic procedures provided an opportunity to identify early precursor lesions. The finding that many of these early lesions were evolving in the tube rather than the ovary has caused a paradigm shift in our understanding of the pathogenesis of HGPSC. In 2001, Piek et al. 8 studied the fallopian tubes from 12 women who underwent prophylactic adnexectomy because of a high-risk genetic predisposition to developing ovarian cancer. They noted the presence of dysplasia in 6 out of 12 cases. These dysplastic areas consisted of secretory cells suggestive of a shift towards the secretory type with dysplastic progression. Five of these 12 cases had tubal hyperplasia that could also be a feature in salpingitis. Subsequently, in 2003, Piek et al. 9 proposed the hypothesis that most hereditary serous cancers arise from the fallopian tube epithelium and then spread to the ovarian surface. A few other studies noted that patients undergoing RRSO had either an occult tubal carcinoma or an intraepithelial carcinoma in the tubal fimbriae. This raised the possibility that the origin of high-grade serous carcinomas is the fimbriae rather than the ovary. The frequency and location of malignancies in BRCA-positive women undergoing prophylactic surgery were analysed by Callahan et al After extensive histological examination they found that seven out of 122 women (6%) harboured cancers originating from the fimbrial end of the fallopian tube. Similarly, in a study involving 159 women with BRCA1 or BRCA2 mutations, Finch et al. 13 identified 4.4% of occult fallopian tube cancers. A fundamental step in the evolution and propagation of the tubal origin hypothesis was the development of the SEE-FIM protocol (Sectioning and Extensively Examining the FIMbriated end of the fallopian tube) at Brigham and Women s Hospital (Figure 2). 14 Steps of the SEE-FIM protocol are as follows: 1. Fix the entire tube in formalin for 4 hours to minimise loss of epithelium. 2. Transect the distal 2 cm of the fimbriated end and section longitudinally into four pieces. 3. Transversely section the remaining tube into 2 3 mm pieces. 4. Submit the entire tube for histology. Using this technique increased the surface area examined by 60% 10 and improved the detection rate of occult tubal carcinoma by at least 17%. 15 Immunostaining with p53 and Ki-67 supplements the information gained morphologically. This process further established that the fimbriae were the most common site of serous adenocarcinoma in BRCApositive women. 14, 16 However, as BRCA carriers constitute approximately only 10 15% of all patients with ovarian cancer, studies then began to focus on ovarian cancers outside this cohort of BRCA carriers. In 2007, in a study of 55 women, Kindelberger et al. 17 explored the possibility of a causal relationship between tubal intraepithelial carcinoma (TIC) and pelvic serous carcinoma. TIC was identified in 5 out of 5 tubal carcinoma, 4 of 6 peritoneal carcinoma, and 20 of 30 ovarian carcinoma cases. Overall, they reported TIC in 48% of the cases classified as ovarian serous carcinomas. In another study, Przybycin et al. 18 noted that the frequency of serous tubal intraepithelial carcinoma (STIC) associated with HGPSC was 61%. Studies analysing TP53 mutations support a clonal relationship between STIC and ovarian carcinomas due to the presence of identical p53 mutations. 19 STICs consist of noninvasive malignant tubal epithelium and exhibit multiple foci of overwhelming p53 mutations, known as p53 signatures (Figure 3). These refer to tubal epithelium consisting of benign non-ciliated cells with an overexpression of p53 and a low Ki-67 signalling index. 20 Lee et al. 21 reported that 57% of the p53 signatures contained a TP53 mutation, were commonly observed in patients with BRCA mutations and usually detected in the fimbrial end of the fallopian tube. Importantly, they also noted that the p53 signatures were equally common in women with and without known BRCA mutations, and were present in about onethird of each group. A study by Folkins et al. 22 in 2008 supported this finding by the acknowledgement that the ª 2016 Royal College of Obstetricians and Gynaecologists 145

4 Fallopian tube origin of pelvic high-grade serous carcinoma (a) (b) (c) (d) Figure 2. SEE-FIM protocol. a) Fix the entire tube in formalin for 4 hours to minimise loss of epithelium. b) Transect the distal 2 cm of the fimbriated end and section longitudinally into four pieces. c) Transversely section the remaining tube into 2 3 mm pieces. d) Submit the entire tube for histology. Reproduced with permission from Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006;30: Figure 3. Histology sections stained for p53 illustrating the transformation of normal tubal epithelium to invasive carcinoma. STIC = serous tubal intraepithelial carcinoma. Reproduced with permission from Jones PM, Drapkin R. Modeling high-grade serous carcinoma: how converging insights into pathogenesis and genetics are driving better experimental platforms. Front Oncol 2013;3:217. initial events of serous carcinogenesis were independent of any known genetic factors. STICs associated with HGPSC have shortened telomeres compared with ovarian carcinomas, which suggests that the STIC precedes the invasive carcinoma. 23 STICs have been found in 10 15% of prophylactic bilateral salpingooophorectomy specimens, suggesting a primary origin rather than a spread or lateral extension from an ovarian carcinoma. Similarly, in a retrospective analysis of 51 patients from a single institution, 56% of patients who were originally classified as having a primary peritoneal carcinoma were found to have STIC in the fallopian tubes. 24 Reports have also emerged of secretory cell outgrowths (SCOUTS), histological lesions that have been found in benign tubal epithelia as well as in areas with STIC. SCOUTS are secretory cell proliferations with at least 30 cells. 25 These 146 ª 2016 Royal College of Obstetricians and Gynaecologists

5 Aggarwal et al. outgrowths are observed in both proximal and distal segments of the tube and they do not have p53 mutations. 26 A p53 signature is essentially a p53-positive SCOUT, which could be the surrogate or latent precursor to STIC. Genetic aberrations such as the loss of BRCA function could transform these precursor p53 signatures to STIC and malignant tumours. However, more research is needed to clarify whether SCOUTS are reactive or precancerous. Table 2 outlines the pathological and immunohistochemical differences among these lesions. Despite extensive histological examination of the fallopian tubes, 40% of HGPSC are not associated with STIC, raising the question of whether the ovary is still the site of origin in these cases. These could be explained by possible implantation of fimbrial tubal epithelium on to the ovarian surface during ovulation or as a result of inflammatory adhesions. This m ullerian-type epithelium then forms the CIC, and the ovarian microenvironment and genetic aberrations may subsequently cause malignant transformation of these CICs. This theory eliminates the step of m ullerian metaplasia. However, the OSE has not been shown to have a mix of serous and coelomic epithelium and primary peritoneal carcinomas are also not accounted for by this argument. A few high-grade tumours have also been thought to develop from dedifferentiation of a borderline or a low-grade serous tumour, but the incidence is low. 3,27 29 Role of the secondary m ullerian system Various hypotheses regarding the development of HGPSC have been proposed and investigated. The traditional coelomic hypothesis has failed to fully convince everyone, as ovarian epithelial tumours are composed of cell types not present in normal ovaries, and precursor lesions could not be identified on OSE despite extensive histopathological examination. 30,31 As HGPSCs have a m ullerian origin, the m ullerian epithelial structures adjacent to the ovary and fallopian tube have come into the spotlight. These structures in the paraovarian and paratubal areas include endosalpingiosis, endometriosis and endocervicosis and have now been termed extrauterine m ullerian epithelium. These are thought to be able to develop into serous, endometrioid, mucinous cystadenoma and tumours of low malignant potential. Their roles are increasingly being explored as possible sites of origin for HGPSC. 31 This theory could also explain why the women who have already undergone risk-reducing surgery are still at risk of developing peritoneal carcinoma in future. Proposed pathways of origin Figure 4 illustrates the proposed pathways of origin of HGPSC: 1. Origin from tubal fimbriae: p53 signatures, STIC and high-grade serous carcinoma. 2. Invagination of exfoliated fimbrial cells into ovarian stroma (during ovulation or because of inflammation), which then forms the CIC and undergoes malignant transformation. 3. Origin from OSE incorporating the coelomic hypothesis, in which CICs undergo m ullerian metaplasia and malignant transformation to low-grade serous carcinoma, including rare transformation of low-grade tumours to high-grade. 4. Origin from extrauterine m ullerian epithelium. Table 2. Pathological and immunohistochemical characteristics of the various histological lesions 26 SCOUTS (secretory cell outgrowths) p53 signatures STIC (serous tubal intraepithelial carcinoma) HGPSC (high-grade pelvic serous carcinoma) Proliferation of secretory cells of tubal epithelium with minimal cytological atypia, preserved pseudostratification and low Ki67 or MIB1 index. Do not usually display TP53 alterations. Surrogate precursor lesions. Linear, strongly p53-positive segment of tubal cells spanning at least 12 consecutive secretory cell nuclei. Lack epithelial stratification and atypia. Lower frequency of nuclear MIB1 staining. Evidence of DNA damage in these lesions as detected by staining with gamma-h2ax. Can be present even in patients with benign disease and those without BRCA mutations. Cytologic atypia, high nucleocytoplasmic ratio, pleomorphism, hyperchromasia, lack of ciliated cells, loss of polarity with or without epithelial stratification, and occasional mitotic figures. Diffuse p53 expression or rarely a complete absence of staining secondary to a deletion mutation together with high MIB1 index (>40%). Detected in around 60% cases of sporadic HGPSC and in 10 15% of RRSO specimens. Possible precursor lesion. Invasive and metastatic high-grade serous carcinoma of the tube, ovary and peritoneum. ª 2016 Royal College of Obstetricians and Gynaecologists 147

6 Fallopian tube origin of pelvic high-grade serous carcinoma Figure 4. Proposed pathways of origin of high-grade serous carcinoma. CIC = cortical inclusion cyst, EUME = extrauterine m ullerian epithelium, HGSC = high-grade serous carcinoma, OSE = ovarian surface epithelium, STIC = serous tubal intraepithelial carcinoma. It is still not clear what determines the most favoured pathway, and whether more than one pathway can co-exist. Development of fallopian tube epithelium (FTE) based model systems as described in various mouse model studies is an interesting process, which will help in refining these theories. The revised International Federation of Gynecology and Obstetrics (FIGO) 2013 staging for carcinomas of the ovary, fallopian tube and peritoneum has unified the staging for tumours originating at these sites. 32 The designation of the site of origin was previously based on the distribution of the bulk of the tumour rather than being reflective of the true site of origin. Enhanced understanding of the pathogenesis of pelvic non-uterine serous cancers would aid more accurate assignment of the site of origin. Singh et al. 33 have proposed some guidelines for assigning the site of origin in HGPSC taking into account the emerging evidence of the role of the fallopian tube in its carcinogenesis. They suggest that all cases of high-grade serous carcinomas should have the fallopian tubes sampled by SEE-FIM or comparable protocols, and the presence of STIC should classify most of these cancers as tubal origin, in contrast to traditional classifications of ovarian or primary peritoneal carcinoma. Clinical management of STIC and early tubal cancer Identification of STIC can help us detect HGPSC before it presents at an advanced stage when the disease has spread. However, studies to elucidate a timescale of development of high-grade serous carcinoma from STIC are still lacking. The Association of Directors of Anatomic and Surgical Pathology has recommended a two-tiered approach to histological examination of the fallopian tube, in order to increase the detection rate of STIC. Fallopian tubes removed for benign conditions are to be sectioned at 2 3 mm intervals and three 148 ª 2016 Royal College of Obstetricians and Gynaecologists

7 Aggarwal et al. sections are to be submitted to represent the isthmus, fimbriae and ampulla, respectively. For RRSO specimens, the entire fallopian tube is submitted for evaluation with special attention to the fimbrial end, similar to the SEE-FIM protocol. Ideally, the SEE-FIM protocol should be used routinely in all women undergoing risk-reducing prophylactic surgery. 34 There are limited data on management of cases with isolated STIC. Wethington et al. 10,13 reported data on 593 patients who underwent RRSO. Isolated STIC was diagnosed in 12 patients (2%) and a staging procedure was recommended in these patients. In some cases this entailed hysterectomy, omentectomy, peritoneal washings and pelvic and para-aortic nodal dissection. Only one out of seven patients who underwent the staging surgery had positive peritoneal washings. Invasive cancer and evidence of distant metastasis were not noted at time of surgical staging. No recommendation was made for adjuvant chemotherapy. Follow-up visits comprised of serum CA125 testing, imaging and office visits. No recurrences have been reported over a median period of 28 months and overall short-term outcomes were favourable for isolated STIC at time of RRSO. Controversy still exists as to the ideal management of these cases. In cases where peritoneal washings were performed at the time of RRSO and documented as negative, clinical follow-up without staging surgery or adjuvant treatment is not an unreasonable option. In cases where no peritoneal washings were obtained, where assessment of the upper abdomen and the remainder of the peritoneal cavity were not performed, or where the tubes were not extensively examined, the argument for staging surgery is stronger. Management of positive washings would also warrant further surgical staging. The adjuvant treatment would then have to be individualised based on final staging. Current preventative strategies One of the ways to successfully lower the rates of ovarian carcinoma worldwide is to come up with an effective preventative strategy. There are many studies showing the reduction in ovarian carcinoma risk with the use of oral contraceptives, with a longer duration of use associated with greater ovarian cancer protection The anovulatory state in women taking oral contraceptives corroborates the incessant ovulation theory of ovarian carcinogenesis. As more recent evidence suggests a tubal origin of ovarian carcinogenesis, clinicians have investigated the benefits of performing bilateral salpingectomy at the time of benign gynaecological surgery or at tubal sterilisation as a risk prevention strategy against ovarian cancer. Sterilisation can be performed via laparoscopic tubal interruption, bilateral salpingectomy or transcervical insertion of metal coils to occlude the tubal lumen. Women who underwent tubal sterilisation were noted to have a 29% decreased risk of all epithelial ovarian cancers, with a higher reduction in the clear cell and endometrioid histology types. 38 Lessard- Anderson et al. 39 also reported a reduction of serous ovarian carcinoma or primary peritoneal carcinoma by more than 60% after salpingectomy. A Canadian gynaecological group from British Columbia initiated a province-wide ovarian cancer prevention strategy that consisted of three recommendations: to consider surgical removal of the fallopian tubes at the time of hysterectomy, even when ovaries were conserved; to replace tubal ligation with excision bilateral salpingectomy for the purpose of permanent contraception and lastly to refer all patients with high-grade serous cancer for hereditary cancer counselling and genetic testing for BRCA1/2 mutations. 40 They demonstrated a significant increase in hysterectomies with bilateral salpingectomy and use of salpingectomy as the method of sterilisation. The additional surgical time required for incorporating salpingectomy into the procedure was not statistically significant an average of 16 minutes more in hysterectomies and 10 minutes more in tubal ligation. No significant differences in the rate of complications were noted between the two methods. This shows that bilateral salpingectomy does not increase operative risk or perioperative complications and is a safe procedure to perform. 40 It still remains to be seen whether these recommendations have a significant impact on the incidence or mortality of ovarian cancer. High-risk patients with BRCA1 or BRCA2 mutations are counselled for RRSO to reduce their risk of development of breast and ovarian cancers by 50% and 80 90%, respectively, and to decrease cancer-related mortality by approximately 60%. 41,42 However, these patients tend to be young and premenopausal and RRSO results in surgical menopause with the patients frequently experiencing vasomotor symptoms, urogenital atrophy, and an increased risk of osteoporosis and cardiovascular disease. This raises the question of whether there is a role for initial risk-reducing salpingectomy with conservation of ovaries followed by delayed oophorectomy as a measure to minimise the menopausal symptoms, especially in view of the distal fimbriae originating as the source of high-grade pelvic serous carcinomas. Kwon et al. 43,44 recently developed a Markov Monte Carlo simulation model to compare the three strategies for risk reduction in women with BRCA mutations bilateral salpingo-oophorectomy, bilateral salpingectomy and a staged procedure of initial bilateral salpingectomy followed by delayed oophorectomy at or close to the age of menopause. The conclusion was that bilateral salpingo-oophorectomy was associated with the lowest cost and highest life expectancy compared with the other two strategies. However, when quality of life measures were factored in, bilateral salpingectomy with delayed ª 2016 Royal College of Obstetricians and Gynaecologists 149

8 Fallopian tube origin of pelvic high-grade serous carcinoma oophorectomy was calculated to have the highest qualityadjusted life expectancy and cost effectiveness. Controversies and future research topics Fimbriae as the site of origin can account for only a proportion of high-grade serous carcinomas. In a small percentage of women who have had previous RRSO, the development of primary peritoneal carcinoma has led to questions about other potential sites of origin. This also raises some doubt about whether a simple salpingectomy is sufficiently effective as a risk-reducing procedure for highrisk individuals. Kwon et al. 43 concluded that bilateral salpingectomy with delayed oophorectomy results in the highest quality-adjusted life expectancy, but with new theories and pathogenesis pathways, such as extrauterine m ullerian epithelium, maximal protection may not be achieved with salpingectomy alone. 31 There have been studies looking at early detection of ovarian and fallopian tube cancers by examination of the cytological samples from the endometrial cavity. A study by Otsuka et al. 45 reported that in 122 women with ovarian, tubal or peritoneal cancers, five had malignant cells identified in the endometrial cytology that did not show any abnormality on imaging. Four of these five women were asymptomatic. They also reported that high-grade serous subtypes were more likely to have positive endometrial cytology results compared with the other histological types. Hence, the use of endometrial cytology in detecting early HGPSC may develop to become a better detection and screening tool in the future. Interesting work is being done to develop FTE-based experimental models to corroborate the pathogenesis theories proposed by histological studies. Levanon et al. 46 described primary ex vivo cultures of human FTE as a model for serous ovarian carcinogenesis for the first time in These ex vivo models were developed by seeding the fallopian tube cells (ciliated and secretory) from a fresh surgical sample of fallopian tube on to a cell culture membrane. The models are viable for a few weeks and are a good platform to study the cellular responses following genotoxic stress and tumour biology. However, they are limited by the need for fresh tissue each time a culture is required. To overcome this issue, Karst et al. 47 demonstrated development of immortal human FTE cell lines using forced expression of telomerase (htert) and dual targeting of the p53 and retinoblastoma protein pathways. They also showed that these immortal cell lines could be further transformed by expression of c-myc or oncogenic Ras. On injection into immunocompromised mice, these transformed cells led to the development of tumours mimicking HGPSC (evidenced by positivity for the markers PAX8, WT1 and CK7) spread throughout the peritoneal cavity. Drapkin et al. 48 have recently described transgenic mouse models targeting the fallopian tube secretory epithelial cell. They used a PAX8 promoter to drive a cre-mediated recombination of BRCA1, BRCA2, TP53 and PTEN, the genes commonly altered in HGPSC as seen in The Cancer Genome Atlas Research findings. They demonstrated the development of precursor lesions in mouse FTE that resembled human STIC and progressed to widespread peritoneal disease resembling HGPSC. With the development of these experimental models, exciting new prospects have emerged to study the early events in serous carcinogenesis, identify serum biomarkers for early detection and study therapeutic targets for future drug development. Conclusion The new classification of ovarian carcinoma into Type 1 and Type 2 tumours has had a significant impact on clinical outcomes and management. For Type 2 HGPSCs, there is convincing evidence to show that a significant proportion originate from the distal fimbrial end of the fallopian tubes. These high-grade tumours have been proven to develop from specific molecular pathways arising from TP53 mutation, and have specific precursor lesions, such as STIC, before aggressive transformation into invasive serous carcinoma. However, the exact trigger or the timescale that these precursor lesions require to develop into a malignant tumour still needs to be determined. Other hypotheses include origin from coelomic and extrauterine m ullerian epithelium. This new information could have a significant clinical impact on development of new therapies to target and treat specific types of pelvic serous carcinomas, especially with the prospects of exciting new laboratory techniques such as ex vivo culture of human FTE and development of transgenic mouse models. Studies on early events in serous carcinogenesis could also help us explore whether there are any situations where these precursor lesions could possibly regress spontaneously, as has been noted in pre-invasive lesions in the cervix. RRSO in high-risk women with BRCA mutations is one of the major strategies in prevention of ovarian and breast cancer, but it often comes with significant menopausal side effects. A new approach of bilateral salpingectomy with delayed oophorectomy in such patients has benefits of improved quality of life with minimal decrease in life expectancy, and also excellent cost effectiveness. However, no prospective data from randomised controlled trials are available for effectiveness and safety of alternative methods to RRSO in preventing ovarian cancer. In low-risk women undergoing tubal sterilisation or hysterectomy for benign gynaecological causes, salpingectomy could be considered as a preventative measure. However, careful counselling of the woman regarding risk-reduction benefits on mortality and 150 ª 2016 Royal College of Obstetricians and Gynaecologists

9 Aggarwal et al. cancer development is important to ensure that she is given all the information necessary to make an informed decision. Disclosure of interests The authors have no conflict of interest to declare. Contribution to authorship IMA made substantial contributions to the conception, design and drafting of the article. IMA gave final approval of the version to be published. YHL contributed significantly to the literature search and drafting and revision of the article. YHL agreed for the final version to be published. TYKL contributed to the revision of the article and gave approval of the final version. Acknowledgements Our sincere thanks to Dr Ronny Drapkin, Assistant Professor, Department of Pathology, Harvard Medical School for his contribution to the illustrations (Figure 1, 2 and 3) in the article. 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