Pelvic Serous Carcinoma Research Articles

An orthotopic model of fallopian tube serous carcinoma.

e15511 Background: Recent studies suggest that some high grade serous tumors of the pelvis, including a subset of ovarian serous carcinomas, originate from the fallopian tube (FT). These serous tumors typically harbor p53 mutations. Our goal was to develop an orthotopic model of metastatic FT carcinoma with characteristic features of serous pelvic tumors. Methods: After Institutional Review Board and Animal Care and Use Committee approvals, written informed consent was obtained from a patient with suspected metastatic pelvic carcinoma. At the time of surgery, non-necrotic tumors were transplanted via intraperitoneal (IP) injection into immunocompromised mice (passage, P1). Tumors were grown, harvested and re-implanted into a second cohort of mice (P2). Finally, tumors were passaged to a larger cohort (P3). P3 mice were treated with saline (n= 8) or cisplatin, 5mg/kg (n=8), weekly for 4 weeks. After sacrifice, tumors from each passage and treatment group were excised and frozen or paraffin-embedded. Patient information was obtained from the medical record. Results: The patient underwent optimal cytoreductive surgery for metastatic serous FT carcinoma in the presence of serous tubal intraepithelial carcinoma (STIC). The FT cancer, areas of STIC and a focus of normal FT, stained positive for p53 and mib-1. The patient was in remission after 6 months of taxane/platinum chemotherapy. IP tumor propagation was readily achieved up to P3 in the mice. Similar to the patient, orthotopic tumors were identified along peritoneal and mesenteric surfaces and confirmed by hematoxylin and eosin staining, p53 and mib-1. Cisplatin-treated mice had fewer tumor implants and fewer mib-1 stained cells compared to controls (p<0.05). Conclusions: Successful in vivo propagation of an orthotopic model of pelvic serous carcinoma arising from an identifiable precursor FT lesion was achieved. Histological characteristics of the patient’s metastatic FT cancer were maintained through P3 and the response to cisplatin in the mice reflected the patient’s response to therapy. This model is currently being used as a tool to study novel therapies for the treatment of p53 signature, serous carcinomas of the pelvis.

Abstract 1602: Mucinous adenocarcinoma developed from human fallopian tube epithelial cells through a combination of defined genetic modifications and tumor microenvironment

Abstract Epithelial ovarian cancer includes several distinct histologic types including serous, mucinous, endometrioid, and clear cell. The cell origin of these distinct epithelial ovarian cancers has been debated for many years. Recent studies have suggested that some ovarian and pelvic serous carcinomas could originate from the fimbrial end of distal fallopian tube, although direct experimental evidence supporting this hypothesis is still lacking. To test this hypothesis, we immortalized a normal human fallopian tubal epithelial (FTE) cell line by using a retrovirus-mediated infection expressing the early region of SV40 T/t antigen and the human telomerase reverse transcriptase. These immortalized FTEs were then transformed by ectopic expression of oncogenic human HRASV12. Tumorigenicity of the immortalized and/or transformed cells was subsequently tested by anchorage-independence assay and inoculation into nude mice via subcutaneous or intraperitoneal injections. As expected, the HRASV12-transformed FTEs produced tumors through both subcutaneous and intraperitoneal injections, while no tumor growth was observed in immortalized FTEs. To our surprise, however, while histopathologic examination of resulting tumor from subcutaneous injections revealed a largely undifferentiated carcinoma with focal mucin production, tumors from intraperitoneal injections showed mucinous adenocarcinoma with rich mucin production from an undifferentiated area. The mucinous differentiation of tumors was most prominent near the peritoneal fat and other peritoneal organs including the pancreas, spleen, and intestine. Immunohistochemical staining of tumor cells showed positive staining for the epithelial cell markers cytokeratin AE1/AE3 and CA125. Our study demonstrates that FTEs can generate mucinous adenocarcinoma through genetic modifications and that such mucinous differentiation is dependent on the peritoneal microenvironment. Thus, the experiment described here provided the first experimental evidence that fimbrial epithelial cells of the fallopian tube could be a potential source of ovarian mucinous adenocarcinoma, a distinct histologic entity of epithelial ovarian cancers whose origin is largely unknown. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1602. doi:10.1158/1538-7445.AM2011-1602

Molecular profiling of advanced pelvic serous carcinoma associated with serous tubal intraepithelial carcinoma

Molecular profiling of advanced pelvic serous carcinoma associated with serous tubal intraepithelial carcinoma

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

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

The impact of tissue block sampling on the detection of p53 signatures in fallopian tubes from women with BRCA 1 or 2 mutations (BRCA+) and controls

The tubal p53 signature is a putative precursor to pelvic serous carcinoma, but its frequencies in women with inherited mutations in the BRCA1 or BRCA2 genes (BRCA+) and controls has been controversial. An initial section and two levels (100–200 μm) from every block in BRCA+ (24) and control tubes (40) were stained for p53. The frequency of p53 signatures was computed between the populations and across the three levels from each block, and analyzed by Fisher exact test. A total of 17 (71%) BRCA+ and 20 (50%) control tubes were p53 signature positive (P=0.12); 21 and 16% of all tissue blocks sectioned harbored signatures (P=0.29), and 76 and 67% were found in the fimbria. In 49 and 32% of p53 signature positive cases in the two groups, the p53 signatures were not discovered until the second or third round of sectioning. In all, 38 and 40% of BRCA+ and control subjects harbored p53 signatures in more than one focus in a single block. In one case (BRCA+), a highly atypical proliferation was identified in one serial section. The p53 signatures are more common than previously reported and the frequency of detection increases as a function of sectioning through the tissue block, both in absolute frequency and in numbers of p53 signatures detected in a given block. There is a trend for a higher absolute frequency of p53 signatures (71 vs 50%; P=0.12) in BRCA+ subjects, but this is not reflected in a greater average number of p53 signatures or positive blocks per case. This study underscores the importance of systematic immunohistochemical examination of fallopian tubes when conducting epidemiological studies that compare the frequency of p53 signatures in different populations. Attention to this detail is critical when exploring risk factors germane to early serous carcinogenesis.

Are All Pelvic (Nonuterine) Serous Carcinomas of Tubal Origin

Are All Pelvic (Nonuterine) Serous Carcinomas of Tubal Origin

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

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

Mucosal carcinoma of the fallopian tube coexists with ovarian cancer of serous subtype only: a study of Japanese cases

Previous studies in Western countries have revealed that mucosal carcinoma of the fallopian tube frequently coexists with pelvic (ovarian, tubal, and peritoneal) serous carcinomas, and early tubal carcinoma is now regarded as a possible origin of these tumors. However, the relationship between early tubal carcinoma and non-serous ovarian cancer, such as clear cell adenocarcinoma, has not been studied in detail. In this study, we sought to examine the coexistence of mucosal carcinoma of the fallopian tube in Japanese ovarian cancer cases. We submitted the fallopian tubes in toto for histological examination in 52 ovarian carcinoma cases and three peritoneal serous carcinoma cases. The ovarian tumors included 12 serous adenocarcinomas, 23 clear cell adenocarcinomas, nine endometrioid adenocarcinomas, three mucinous adenocarcinomas, and four mixed epithelial carcinomas. Mucosal carcinoma of the fallopian tube did not coexist with non-serous adenocarcinoma (n = 40). In contrast, mucosal carcinoma of the fallopian tube was observed in six cases of ovarian serous adenocarcinoma and one case of peritoneal serous adenocarcinoma. In these cases, the p53 immunophenotypes were similar in tubal lesions and invasive ovarian or peritoneal carcinomas. Tumors were negative for p53 in four of seven cases, and one of the p53-negative serous adenocarcinomas showed low-grade morphology. We believe that some ovarian and peritoneal serous adenocarcinomas develop from early tubal carcinomas. However, it should be noted that early tubal carcinomas are not always p53-positive immunohistochemically. Finally, it is unlikely that early tubal lesions are involved in the carcinogenesis of clear cell adenocarcinoma and other non-serous adenocarcinomas.

A Pathologist's Road Map to Benign, Precancerous, and Malignant Intraepithelial Proliferations in the Fallopian Tube

The fallopian tube has recently emerged as an important site of origin for not only early serous cancer in women with inherited mutations in BRCA1/BRCA2 but as a source of many pelvic serous carcinomas. With this increased attention has come the inevitable need to sort out what epithelial abnormalities are clinically important and how they should be reported by the practicing pathologist. This review addresses 4 categories of tubal epithelial change: (1) metaplasias; (2) nonmalignant atypias; (3) potential precursors, including secretory cell outgrowths and p53 signatures; and (4) tubal intraepithelial carcinomas. A modified protocol for sectioning the fallopian tube (SEE-FIM) is discussed and each of the above topics is covered in the context of its differential diagnosis and recommendations for reporting are included. Finally, the rationale for close inspection of the tube, both in presumed benign and malignant disease, is discussed, with reference to an ongoing multi-institutional web-based project (Pelvic-ovarian Cancer Interception project).

Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary

Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2–11 and intron–exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/123) of HGPSC cases. Molecular and pathological review of mutation-negative cases showed evidence of p53 dysfunction associated with copy number gain of MDM2 or MDM4, or indicated the exclusion of samples as being low-grade serous tumours or carcinoma of uncertain primary site. Overall, p53 dysfunction rate approached 100% of confirmed HGPSCs. No association between TP53 mutation and progression-free or overall survival was found. From this first comprehensive mapping of TP53 mutation rate in a homogeneous group of HGPSC patients, we conclude that mutant TP53 is a driver mutation in the pathogenesis of HGPSC cancers. Because TP53 mutation is almost invariably present in HGPSC, it is not of substantial prognostic or predictive significance. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The origin of serous ovarian cancer may be found in the uterus: A novel hypothesis

Since 1971 the incessant ovulation theory by Fathalla is widely accepted as theory for ovarian carcinogenesis, supported mainly by epidemiological findings. However, this theory cannot explain the protective effect of hysterectomy and tubal ligation on the incidence of ovarian cancer. Furthermore, never a precursor lesion has been identified in the ovary itself. Although recently the fallopian tube has been proposed as possible site of origin, there are reasons to believe that a precursor lesion for ovarian and pelvic serous carcinoma is located within the uterus. Uterine serous papillary carcinoma (UPSC) resembles serous ovarian and pelvic carcinoma in behavior and prognosis. Its precursor lesion endometrial intraepithelial carcinoma (EIC) is non-invasive and often multifocal in origin. Importantly, these premalignant cells have a loosely cohesive nature and are able to spread to intraperitoneal surfaces easily, thereby often found on the surface of ovaries or in the fallopian tube. We hypothesize that EIC is a precursor lesion of serous ovarian carcinoma, originating in the uterus and spreading into the intraperitoneal cavity via a mechanism as is accepted for endometriosis. To illustrate this, some cases of serous ovarian carcinoma with concordant EIC in the endometrium as only precursor lesions are presented. A paradigm shift with respect to the origin of ovarian cancer from the ovary to the endometrium could have enormous consequences for primary and secondary preventive strategies to decrease the mortality from this disease.

The emerging role of the distal Fallopian tube and p53 in pelvic serous carcinogenesis

In their paper in this issue of the Journal, Xian et al have analysed in detail the Fallopian tubes from two patients with Li-Fraumeni syndrome (germline TP53 mutation) in order to investigate further the possible role of p53 signatures in the development of high-grade pelvic serous carcinoma. They find an increased frequency of p53 signatures, with associated evidence of DNA damage and loss of heterozygosity at the wild-type TP53 allele, but postulate, as Li-Fraumeni syndrome is not associated with an increased risk of pelvic serous carcinoma, that these events are not sufficient for the development of carcinoma. Rather, they put forward a model postulating that further events, particularly loss of BRCA1/2 function, are required for lesion progression. This paper exemplifies how the hypothesis-driven study of a rare syndrome can be highly effective at answering specific questions about disease processes. It is of note that recent evidence from the same group provides convincing evidence that the distal Fallopian tube may, in fact, be the commonest site of origin for high-grade pelvic serous carcinomas, most of which may originate at this site rather than from the ovary. In addition to its biological significance, this, if proven, has clear clinical implications.

Seröse Genitalkarzinome

Serous carcinomas develop at various sites of the Mullerian system, in particular, the ovaries, the peritoneum, the uterus and the fallopian tubes. Currently, two distinctive molecular genetic pathways are distinguished for serous tumorigenesis: type I tumors are typically well differentiated and gradually develop from cystadenoma through borderline tumor to low grade carcinoma and are characterized by B-raf and K-ras mutations, whereas the poorly differentiated type II tumors develop from intraepithelial carcinoma and show p53 mutations. Infrequently, p53 mutations occur as a late event in the type I pathway and lead to a high grade tumor phenotype. A histologically inconspicuous possible precursor lesion of the intraepithelial carcinoma is the p53 signature that shows p53 overexpression without cell cycle deregulation. Whereas in the ovaries both pathways may occur and develop from inclusions of the surface epithelium, the fallopian tube has recently been described as an important site for the type II pathway. High grade serous carcinomas and intraepithelial carcinomas of the tubal fimbria are particularly found in patients with BRCA1/BRCA2 germ line mutations. Since an advanced tumor stage is frequent and often makes the determination of the origin impossible, the term pelvic serous carcinoma was recently proposed for high grade serous (adeno)carcinomas involving multiple sites.

Intercepting early pelvic serous carcinoma by routine pathological examination of the fimbria

Recent evidence indicates that the distal fallopian tube is the principal site of early serous cancer in women with a hereditary risk for ovarian cancer. Moreover, the fimbria is involved by early cancer in a significant minority of pelvic serous carcinomas, irrespective of whether the patient has a hereditary BRCA1 or BRCA2 mutation. In addition, the distal tube has been identified occasionally as a site of concurrent endometrioid tumors in women with endometrial carcinoma. Although the risk of sporadic fimbrial tumors in otherwise healthy women without genetic risk is unknown, routine histological examination of the fimbria provides the opportunity to determine the risk of such an event. To illustrate this point, a case of a woman who underwent surgery for an ovarian fibroma is presented. The distal tube was submitted, and found to harbor a focus of serous tubal intraepithelial carcinoma (STIC) with a 2-mm invasive tumor. Incidentally discovered carcinomas underscore the potential risk, albeit low, of concurrent unsuspected malignancy in the distal fallopian tube and emphasize the importance of routine pathological examination of the fimbria in all salpingectomies. The rationale for this strategy, and its potential effect on early detection and in uncovering persons or families potentially at risk for ovarian cancer, is discussed.

Coexisting Intraepithelial Serous Carcinomas of the Endometrium and Fallopian Tube: Frequency and Potential Significance

Most serous adenocarcinomas involving both the endometrium and ovary are presumed to arise in the endometrium. Recently, serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. This study explored the potential relationship between STIC and uterine serous carcinoma. Twenty-two consecutive cases of serous carcinoma involving the endometrium were studied. In each case, fallopian tubes were submitted in toto according to the protocol for sectioning and extensive examination of the fimbriated end. Extent of the endometrial tumor and presence/absence of STIC were documented. Immunostaining for p53 and Wilms tumor-1 was performed on all cases with STIC. p53 mutation analysis was performed in a subset of matched STICs and endometrial tumors. Eleven cases showed concurrent endometrial and adnexal involvement, including 6 with endosalpingeal involvement; STIC was confirmed in 5. In all 5, the concurrent endometrial tumor was either noninvasive, or exhibited only superficial (<5%) myometrial invasion. In 2 cases, identical p53 mutations were shared by both tubal and endometrial lesions. This study shows that noninvasive, genetically related serous carcinomas may coexist in both tube and endometrium. As management of serous neoplasms is predicated on site of origin, we propose that the sectioning and extensively examining the fimbria protocol be applied to all endometrial serous carcinomas and that tumors with concurrent STIC be classified as a distinct subset of pelvic serous carcinomas pending a clearer understanding of tumor origin.

Serous Tubal Intraepithelial Carcinoma and the Dominant Ovarian Mass

Pelvic serous cancer is a diverse disease, and the assignment of primary site -- ovarian, tubal, or peritoneal -- is often problematic. Recent studies indicate that a proportion of these tumors arise from the distal fallopian tube, originating as serous tubal intraepithelial carcinoma (STIC). This study examined the relationship of 2 parameters for assigning origin -- endosalpingeal involvement and dominant ovarian mass -- in the context of STIC. Endometrioid carcinomas served as a reference. Eighty-seven consecutive pelvic serous cancers in which the tubes and ovaries were completely examined (SEE-FIM protocol) were analyzed. The presence of a dominant ovarian mass (DOM+), involvement of the fimbrial mucosa (FIM+), and STIC were correlated. In addition, tumor categories were compared with respect to PAX8, p73, p53, and p16 immunohistochemistry. Of the 27 DOM+ cases, 13 (48%) were FIM+ and a STIC was present in 3 (11%). Of the 60 DOM(-) cases, 48 (78%) were FIM+ and 28 (45%) harbored a STIC. In 92% of all cases, tumor distribution was extensive with bilateral ovarian and extraovarian peritoneal involvement. All tumor categories were immunophenotypically similar. In contrast, DOM+, FIM+, and STIC were found in 81%, 19%, and 0% of ovarian endometrioid carcinomas. In conclusion, there is a significant inverse relationship between DOM+ and STIC (P=0.001), indicating both parameters are of value in grouping pelvic serous carcinomas more likely to be ovarian [DOM+/FIM(-)] versus fimbrial [DOM(-)/STIC], and ovarian or peritoneal surface (DOM-/FIM-) in origin. Nevertheless, the shared immunophenotype suggests a common cell of origin for all categories, irrespective of site.

A case of non-invasive serous adenocarcinoma at unilateral fimbria with spread to the peritoneal/uterine cavity: case report

Recently, fimbriae have been identified as a possible arising site for the pelvic serous carcinoma (PSC) both in BRCA-positive and BRCA-negative women. Although non-invasive (intraepithelial) serous adenocarcinoma of the fimbria has been found in specimens obtained from prophylactic salphingo-oophorectomies in BRCA-positive women, there has not been any case report in clinical situation, since this type of tumor is usually detected after stromal invasion/widespread dissemination. We describe a 67-year-old woman with non-invasive serous adenocarcinoma located solely in the left fimbria. This case may suggest the benefit of endometrial cytology and detailed gross examination of fimbria for the early detection of fimbrial carcinoma. This case may provide evidence suggesting fimbrial intraepithelial adenocarcinoma is one cause of PSC.

The Fallopian Tube: Primary Site of Most Pelvic High-grade Serous Carcinomas

Epithelial ovarian cancer is the most common cause of mortality from gynecologic malignancy, and most of epithelial cancers are of serous type. The site of origin of pelvic high-grade serous carcinoma has been the subject of debate for 60 years. This paper reviews the evidence that pelvic serous carcinoma originates from the fallopian tube mucosa and puts forward a theory that inflammation in the tube, caused by menstrual cytokines or infection, is critical to the genesis of these tumors. Other risk factors for pelvic serous carcinoma will be reviewed, including oral contraceptive use, parity, infertility, and tubal ligation.Studies were identified for this review by searching the English language literature in the MEDLINE database between the years 1995 and 2007 using the following keywords: fallopian tube neoplasia, ovarian serous adenocarcinoma, pregnancy, oral contraceptive, infertility, pelvic inflammatory disease, cytokines, menstruation, and tubal ligation, followed by an extensive review of bibliographies from articles found through the search.The clinical implications of this theory are discussed, and a change in surgical practice is recommended, with salpingectomy at the time of simple hysterectomy. This theory also has implications for the development of new methods of screening for pelvic serous carcinomas, as there are no screening methods that are currently available to find this form of cancer in an early stage. Inflammatory markers could be detected in the vagina from the fallopian tube indicating possible chronic inflammation and a risk factor for mutagenesis leading to serous carcinoma.

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

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

Chromosomal instability in fallopian tube precursor lesions of serous carcinoma and frequent monoclonality of synchronous ovarian and fallopian tube mucosal serous carcinoma

Objectives Pelvic serous carcinomas are classified according to the location of greatest mass of tumor as ovarian, peritoneal or fallopian tube. Recent studies suggest these cancers may arise in the fallopian tube. This study explores the relationship between ovarian cancers and fallopian tube mucosal involvement. Methods Sixteen consecutive cases of epithelial ovarian malignancy were prospectively identified and the fallopian tubes submitted in toto for histopathological examination for tubal mucosal involvement. Immunohistochemical staining for p53 and Ki-67, and fluorescent in situ hybridization (FISH) analysis for chromosomal copy number changes were performed on 10 cases. Three cases of mucosal epithelial abnormalities identified in risk-reducing salpingectomy specimens were similarly characterized. Results Of sixteen cases, twelve were high-grade serous carcinoma, stage III, and four cases were stage I, two borderline mucinous, one borderline serous, and one low-grade mucinous carcinoma. Ten cases of high-grade serous carcinoma showed either unilateral fallopian tube mucosal involvement ( n = 7) or tubal obliteration ipsilateral to the dominant ovarian mass ( n = 3), compared to none of the other carcinomas. FISH analysis showed similar copy number changes in the ovarian and fallopian tube mucosal carcinoma in 3 cases, suggesting a unifocal origin; one case had differences suggesting multifocal origin of cancer. One case had equivocal FISH results. From risk-reducing salpingectomy cases, the multiple foci of tubal intraepithelial carcinoma and focus of invasive carcinoma showed similar gene copy number changes within each case, suggesting monclonality. Both cases of epithelial atypia/dysplasia showed gene copy number changes. Conclusions Fallopian tube mucosal and ovarian tumors have similar genetic abnormalities in most cases, indicating a monoclonal origin that may originate either from the ovary, peritoneum or fallopian tube. In situ epithelial lesions of the fallopian tube from risk-reducing salpingectomies show gene copy abnormalities consistent with these being early lesions of serous carcinoma and suggest that chromosomal instability is a very early event in serous carcinogenesis.