HGSC has no known morphologic precursor lesion in the ovary, and therefore, little was known of the early molecular/genetic events of serous carcinogenesis, a major obstacle in identifying markers of predisposition or of early stage ovarian cancer. Epidemiological studies of ovarian cancer risk factors, such as infertility, and protective factors, such as increased parity and oral contraceptive use, suggested that an increased number of lifetime ovulations may play a role in the development of ovarian carcinoma [12–15]. The importance of reproductive risk factors seemed to support the traditional theory of ovarian cancer origin, the incessant ovulation theory, first proposed by Fathalla in 1971 [16]. In the absence of native epithelium in the normal ovary, the ovarian surface epithelium (OSE) was the favored ovarian cancer cell of origin . OSEs are a modified mesothelial layer, express calretinin, are PAX8 negative, and are non-ciliated, with few immune cells associated with the monolayer [17]. It was suggested that with each ovulatory event, OSE damage and subsequent repair eventually led to acquisition of genetic abnormalities leading to carcinogenesis. This theory required that OSE undergo metaplasia to an epithelial cell type prior to the events of malignant transformation, often within ovarian cortical epithelial inclusion cysts [18]. In further support of the OSE cell of origin , there were reports that (1) atypia (reported as dysplasia or ovarian intraepithelial neoplasia) was present in surface epithelium adjacent to early stage ovarian carcinoma, (2) an increased number of cortical inclusion cysts were present in nonmalignant ovaries contralateral to ovarian cancer (histotype not specified), and (3) OSE adjacent to ovarian cancer had a higher incidence of metaplastic and hyperplastic changes [19–22]. For the most part, however, common histological changes associated with cancer precursors, such as cytological atypia, cellular stratification, and mitotic activity, have not been identified or of present are extremely rare in the ovary, indicating that if OSE was indeed the cell of origin of ovarian serous carcinoma, any precursor lesion must be very transient or the molecular progression of the disease is not associated with a morphological counterpart. Most of the publications describing early cancers or noninvasive cancer precursors within the ovary were reported prior to the routine histological examination of the fallopian tube. It is possible that the few images published purporting to represent dysplasia and early intraepithelial carcinoma within cortical inclusions actually represent cancerization of cortical cysts [23].

Convincing evidence in support of the fallopian tube epithelium (FTE) as the cell of origin emerged as pathologists began to examine the ovaries and fallopian tubes after risk-reducing surgery in women at high genetic risk of ovarian cancer. The two candidates for cell of origin, FTE and OSE , share common embryological origin, as well as close anatomic proximity. The Mullerian duct, which forms the fallopian tube, uterus, and endocervix, is formed by invagination of the embryonic coelomic epithelium, which also gives rise to mesothelium, including the OSE. The tube, lined by the hormonally sensitive FTE, has functions in ovum pickup and transport, facilitation of fertilization, and support of preimplantation embryo dev elopment in the first days after fertilization. It is divided into the interstitial portion (within the uterus), the isthmus, the ampulla, and the fimbria. Of particular note, and an important candidate for the source of serous carcinoma, is the FTE covering the fimbria, which has fingerlike projections in close contact to the OSE and ovarian surface and directly exposed to the peritoneal cavity (Fig. 1.1). It is of interest to note that genetic mouse models deleting BRCA1, Rb1, and TP53 genes from the OSE resulted in leiomyosarcomas [24] not high-grade serous carcinoma, and in contrast, targeted deletion of BRCA1, TP53, and PTEN in fallopian tube epithelia resulted in high-grade serous carcinoma with phenotypic and genomic alterations congruous with human HGSC [25].

A major advance in our understanding of HGSC tumorigenesis was the discovery in the mid-1990s that more than 90 % of hereditary ovarian cancers were associated with inherited germline mutations of BRCA1 and BRCA2. BRCA1/BRCA2 proteins have multiple functions including a critical role in the repair of double-stranded DNA breaks through homologous recombination. Loss of either BRCA1 or BRCA2 protein leads to deficient double-stranded DNA repair, which in turn increases the risk of chromosomal rearrangements. The lifetime risk of developing ovarian cancer is 40–60 % for BRCA1 mutation carriers and 10–20 % for BRCA2. Epidemiological studies indicated a predominance of HGSC in hereditary ovarian cancer, with a lack of mucinous carcinomas and borderline tumors [26, 27]. Blinded histopathological review using current definitions of histological classification demonstrates that the BRCA-deficient cancers are exclusively HGSC type [28–30].

The efficacy of risk-reducing salpingo-oophorectomy in women at high risk based on family history or germline mutations of BRCA1 or BRCA2 in preventing HGSC has been demonstrated, reducing the lifetime risk of HGSC to 5 % and decreasing mortality from all causes by 77 % [31, 32]. Because women with BRCA mutations are at the highest risk of developing HGSC, one might expect that if morphologic precursors of HGSC exist within the ovary, they would be detected in prophylactic oophorectomy specimens. However, a preliminary non-blinded report of histological features differentiating “cancer-prone” ovaries from ovaries at lower risk was not validated by other authors in more carefully controlled studies, nor was a reproducible histologic cancer precursor identified in the ovaries from high-risk patients [20, 33–38].

The addition of carcinoma of the fallopian tube to the list of BRCA1-/BRCA2-associated malignancies led to more comprehensive examination of the fallopian tube in prophylactic specimens. Support for the role of FTE in HGSC tumorigenesis was soon discovered, by the discovery of occult carcinomas and descriptions of putative cancer precursors in the fallopian tube epithelium [39–46].

Historically, precursor lesions of FTCa were not well defined, and the terms mucosal epithelial proliferation (MEP) , hyperplasia, and dysplasia have been applied variably in the literature to histological lesions of the FT epithelium (FTE). Mild hyperplasia of the FTE was reported to be a frequent finding and considered to be a normal, non-pathologic finding, but epithelial proliferation with nuclear atypia, which was described in moderate and severe MEP of FTE, was abnormal [47].

The finding of occult cancers and cancer precursors in the fallopian tubes of women at genetic high risk of serous carcinoma indicated an important and previously unsuspected role of the tubal epithelium (FTE) in BRCA mutation-associated serous carcinogenesis. These findings suggested an etiology of hereditary serous carcinoma other than that of malignant transformation of OSE cells. Early spread from a small clinically undetected carcinoma of the tubal fimbria, which is in direct contact with the peritoneal cavity and with the ovarian surface, would explain the lack of early detection by current technologies and the formation of ovarian masses, because the ovary is a fertile soil for growth of metastatic carcinomas from multiple sites. It would also explain the frequent peritoneal spread early in the disease course and many cases of presumed primary peritoneal carcinoma. While the observations leading to this hypothesis pertain to carriers of germline mutations, it seemed possible they would also apply to the more common sporadic serous carcinomas, which share molecular alterations with hereditary epithelial ovarian cancer, including loss of function of BRCA proteins [10, 48, 49].

The rare finding of clinically incidental serous carcinoma was first reported in 1965 and was described further in a larger series by Bell and Scully in 1994[50]. It was noted in these early reports of “early de novo carcinoma” that despite the small size of the lesions, present within the ovarian cortex or on the ovarian surface and measuring up to 7 mm, an adverse outcome including recurrence and death was possible. The increase in prophylactic surgery in mutation carriers and the more comprehensive histological examination of salpingectomy specimens in recent years has led to the discovery of an increasing number of low-volume cancers at an early stage.

By definition , occult carcinoma is not detected preoperatively, and transvaginal ultrasound and serum CA125 are frequently reported as normal within the year prior to risk-reducing salpingo-oophorectomy (RRSO) . The first reports of occult carcinoma in BRCA mutation carriers indicated a range of 2.3–10.4 % incidence of occult carcinoma at the time of RRSO, and there was a surprisingly high incidence of carcinomas involving the distal end, fimbria, of the fallopian tubes [41, 45, 51, 52]. Ovarian involvement was also detected, but, in at least some of the cases, if the tube was carefully examined, the ovarian involvement was metastatic from the fallopian tube (Fig. 1.2). The frequency is higher in reports when examination of the fallopian tubes and ovaries is performed by meticulous fine sectioning and by consistent review limited to gynecologic pathologists at a single institution and lower in multi-institution studies without centralized pathology review. The incidence also varies with age of the patient at the time of RRSO and is more frequent with documented germline mutations of BRCA1/BRCA2 and more frequent with BRCA1 than BRCA2 mutations; it varies with the type of mutation (known deleterious, etc.) and, according to some studies, on whether the patient has a prior history of breast cancer [53, 54].

Intraepithelial lesions with morphological features of malignancy but no evidence of stromal invasion, now known as serous tubal intraepithelial carcinoma (STIC) , are detected in any one of the three clinical settings : (1) HGSC of presumed ovarian, tubal, peritoneal origins, (2) in prophylactic salpingectomy specimens from BRCA1/BRCA2 mutation carriers, and (3) rarely as an incidental finding in routine surgical specimens. These lesions have been recognized and reported in the past and were thought by some to represent evidence of multicentric tumorigenesis in Müllerian-type epithelium [60]. Other terms used in the literature include dysplasia, atypical mucosal epithelial proliferation, and carcinoma in situ [39, 47, 60].

Serous tubal intraepithelial carcinoma is defined as a localized lesion characterized by morphological atypia, abnormal p53 expression (reflecting the presence of a p53 mutation), and increased proliferation rate [18, 61]. Tubal intraepithelial carcinoma has been seen in association with HGSC for many years, but this finding was interpreted as evidence of a “field effect” of tumorigenesis —the secondary Müllerian system [60]. Careful examination of the fallopian tubes prophylactically resected from BRCA1/BRCA2 mutation carriers led to the description of STIC in the absence of invasive disease, an important finding which, along with the description of “dysplasia” in the RRSO specimens , supported the concept that HGSC, at least in BRCA mutation carriers, had its origin in the fallopian tube. Subsequently, STIC was reported in up to 61 % of tubes from patients with clinically evident HGSC, supporting the currently favored theory that STIC is the immediate precursor of HGSC in both hereditary and sporadic forms of HGSC [62–64].