The cell of origin of ovarian cancer and the mechanisms by which cancer develops have been long debated. The traditional view of ovarian carcinogenesis has been that the various different tumors are all derived from the ovarian surface epithelium (mesothelium) and that subsequent metaplastic changes lead to the development of the different cell types (serous, endometrioid, clear cell, mucinous and transitional cell [Brenner]) which morphologically resemble the epithelia of the fallopian tube, endometrium, gastrointestinal tract or endocervix and urinary bladder, respectively. The normal ovary, however, has no constituents that resemble these tumors. Moreover, the cervix, endometrium and fallopian tubes are derived from the müllerian ducts whereas the ovaries develop from mesodermal epithelium on the urogenital ridge separate from the müllerian ducts. Therefore, an alternate theory proposes that tumors with a müllerian phenotype (serous, endometrioid and clear cell) are derived from müllerian-type tissue not mesothelium11
. This müllerian-type tissue (columnar epithelium, often ciliated) lines cysts located in paratubal and paraovarian locations that have been referred to collectively as the “secondary müllerian system”23
. According to this theory, ovarian tumors develop from these cysts. As the tumor enlarges, it compresses and eventually obliterates ovarian tissue resulting in an adenxal tumor that appears to have arisen in the ovary. More recently another theory has been advanced which argues that the majority of ovarian carcinomas, which are high-grade serous carcinomas, arise from high-grade intraepithelial serous carcinomas in the fallopian tube which then spread to the ovary. These conflicting views led us to undertake a review of the literature in an effort to determine which of the theories is best able to explain the various aspects of ovarian carcinogenesis.
Evaluating these theories is problematic because it is difficult to construct experimental systems, to test their validity. Accordingly, our evaluation is based on critical analysis of these studies in light of observations we have made in the course of pathologic examination of ovarian tumors. The discussion that follows is an attempt to distill the most plausible components from the various theories of cellular origin and integrate them with the clinicopathologic and molecular genetic data from the dualistic model in order to construct a unifying theory of ovarian carcinogenesis.
The theory of origin from ovarian surface epithelium (mesothelium) has a number of limitations. Histologically, the single layer of generally attenuated mesothelium overlying the ovaries bears no resemblance to serous, endometrioid, mucinous, clear cell or transitional (Brenner) carcinomas. As noted above in order to account for this apparent contradiction it was proposed that the mesothelium overlying the ovary invaginates into the underlying stroma to form so-called “cortical inclusion cysts”. These cysts under the influence of local factors, possibly steroid hormones, undergo a metaplastic change, which results in the mesothelium being converted to müllerian-type epithelium. These inclusion cysts, with their newly acquired müllerian phenotype, can then undergo malignant transformation resulting in carcinomas corresponding to the different cell types (serous, endometrioid and clear cell carcinomas)6
. Although cortical inclusion cysts lined by ciliated (müllerian-type epithelium) are frequently observed in the ovarian cortex, well documented examples of what can be interpreted as a transition from these cysts to carcinoma have not been reported. Moreover, cortical inclusion cysts lined by intestinal-type epithelium to account for the development of mucinous carcinomas are distinctly rare. The same can be said for the absence of transitional-type epithelium lining cortical inclusion cysts to account for the development of Brenner tumors.
The limitations of the secondary müllerian system theory are that precursor lesions resembling serous, endometrioid and clear cell carcinomas have rarely, if ever, been reported in paratubal and paraovarian cysts. Moreover, the vast majority of mucinous tumors display intestinal rather than endocervical-type mucinous differentiation and therefore do not qualify as müllerian-type tumors. A similar problem exists for transitional cell (Brenner) tumors which resemble urothelium which is not müllerian in origin.
The most compelling evidence suggests that the vast majority of what appear to be, primary ovarian cancers, namely serous, endometrioid and clear cell carcinomas, are derived from the fallopian tube and endometrium, not directly from the ovary. Sporadic reports of tubal carcinoma and “dysplasia” had been reported in the past15
but in 2001 a group of Dutch investigators described these lesions, which closely resemble high-grade ovarian serous carcinoma, in women with a genetic predisposition to ovarian cancer33
. This was a surprising finding, since numerous studies over the past two decades that carefully examined the ovaries of women with a genetic predisposition to ovarian cancer never reported similar lesions. In addition, other studies of normal appearing ovaries contralateral to sporadic (nonhereditary) unilateral ovarian carcinomas had never identified a convincing precursor lesion. These latter studies reported a number of morphologic changes in grossly normal appearing ovaries, such as an increased number of inclusion cysts, surface papillae, cortical inclusions, including some displaying minor degrees of atypia. The data, however, have been conflicting, some studies reporting a significant difference of these changes in cases versus controls and other studies reporting no difference. In any event, none of these changes, even remotely, resemble high-grade serous carcinoma. It was precisely because of a lack of convincing precursor lesions that the de novo
hypothesis was invoked.
In hindsight, because it was assumed that precursors of ovarian carcinoma would logically be in the ovaries, the fallopian tubes were not carefully examined42, 10
. Subsequent studies in which fallopian tubes were more carefully examined confirmed that in situ and small, early invasive tubal carcinomas occurred in women with a genetic predisposition for the development of ovarian cancer4, 5, 8, 12, 27, 29, 41
. This led to fallopian tube carcinoma being included as part of the cancer spectrum associated with inherited BRCA mutations. It was subsequently proposed that a proportion of ovarian carcinomas might develop as a result of implantation of malignant cells from the tubal carcinoma to the ovary34–35
. The next important step linking what had been termed “tubal intraepithelial carcinoma” (TIC) and subsequently “serous tubal intraepithelial carcinoma” (STIC) with ovarian carcinoma was the observation that over 70% of sporadic (nonhereditary) ovarian and peritoneal high-grade serous carcinomas demonstrated mucosal tubal involvement including STICs19
. This observation gave substantial support to the proposal that STICs, which almost always are detected in the fimbria, may be the source of ovarian high-grade serous carcinoma in both women with hereditary mutations in BRCA
as well as women who did not have a known genetic predisposition for ovarian cancer. Although it can be argued that mucosal tubal involvement could represent secondary spread from an ovarian carcinoma present in the same specimen, the presence of focal noncontiguous intraepithelial lesions (STICs), would be an unusual manifestation of metastasis. Furthermore, the identification of STICs in prophylactic specimens from women with a hereditary predisposition to ovarian cancer, in which complete microscopic evaluation of the fallopian tubes and ovaries failed to identify invasive carcinoma in these organs, lends additional support to the concept that the serous neoplastic process may well begin in the fallopian tube rather than the ovary. Further support for this argument is the finding that nearly all STICs overexpress p53 similar to high-grade serous carcinoma (). Laser capture microdissection studies of these lesions have demonstrated that they harbor mutated TP5319
. In addition, STICs associated with a concomitant ovarian carcinoma share not only morphologic features but also identical TP53
mutations indicating a clonal relationship between them. Adnexal malignant mixed mesodermal tumors (another type II tumor) have also been associated with STICs supporting the existence of a common precursor lesion for type II tumors14
. Further evidence implicating the fallopian tube rather than ovarian surface epithelium as the site of origin of serous neoplasms comes from a gene profiling study showing that the gene expression profile of high-grade serous carcinoma is more closely related to the fallopian tube than to ovarian surface epithelium25
. In addition high-grade serous carcinomas express PAX8, a müllerian marker, but not calretinin, a mesothelial marker43
Serous tubal intraepithelial carcinoma (STIC). A. High magnification. Hematoxylin and eosin stain. B. Immunohistochemical stain for p53. An asterisk defines the boundary of the lesion.
A recent finding has been the identification of benign tubal epithelium, specifically secretory as opposed to ciliated cells, that express p53 and in which laser capture microdissection studies have reported TP53
mutations in 57% of cases24
. These lesions termed “p53 signatures” are found in association with STICs and in normal appearing fallopian tubes of women without STICs or carcinoma; they have been observed in approximately one third of women with and without BRCA
mutations13, 17, 41
. Like STICs, p53 signatures express γ-H2AX which localizes to areas of DNA damage in nuclei24
. When associated with STICs and ovarian carcinoma, the p53 signature has had the identical TP53
mutation as the STIC and the carcinoma in some cases but not in others. Based on these findings, a sequence of pathogenetic events has been proposed, beginning with genotoxic DNA damage, followed by TP53
mutation and progressive loss of cell cycle control, which then eventuates in the development of carcinoma24
. There are a number of questions that must be resolved, however, before this hypothesis can be completely accepted. First, as noted in some instances, TP53
mutations, when present in the p53 signature, are not always identical with the mutations in the STICs and carcinomas in the same specimen. Second, women at high risk have the same frequency of p53 signatures as women who are not at high risk. Third, the high prevalence of p53 signatures (a third of all women) compared to the low prevalence of high-grade serous ovarian carcinoma suggests that either a small minority of p53 signatures progress or that they are not related to carcinoma. It is conceivable that p53 signatures reflect an appropriate and physiological upregulation of p53 in response to DNA damage, based on the observation that TP53
mutations are absent in nearly half of p53 signatures. Although the proposal that the p53 signature is a precursor lesion is intriguing, its role in the genesis of ovarian high-grade serous carcinoma is far from clear at this time. As fallopian tubes are more carefully examined and these lesions studied, the nature of p53 signatures and their relationship to STICs will become better defined.
Generally, before a carcinoma acquires the ability to metastasize it must first invade and gain access to blood vessels or lymphatics. We have observed that the fimbria contain a rich angiolymphatic vasculature. Moreover, they are in almost direct contact with the basement membrane of the tubal epithelium and therefore a tubal carcinoma may not need to attain a very large size in order to invade this highly accessible angiolymphatic network. In addition, invasion in the case of a STIC may not be a necessary prerequisite for dissemination. Tubal intraepithelial carcinomas are similar morphologically and immunohistochemically to endometrial intraepithelial carcinomas, which are regarded as precursors or early forms of uterine serous carcinoma. These lesions have also been termed “uterine surface serous carcinomas”. They have been shown to disseminate throughout the peritoneal cavity presumably by passage of malignant cells through the fallopian tube without requisite myometrial invasion46
. The cells that comprise both endometrial and tubal intraepithelial carcinomas are highly anaplastic and identical morphologically to high-grade serous carcinoma. The lesions form papillary tufts and the constituent cells are loosely cohesive. Presumably these cells can shed and implant on the surface of the ovary and the peritoneum in the absence of invasive growth in the fallopian tube. Evidence supporting this possibility are reports of positive pelvic washings in women whose only lesion was a STIC4
As previously noted, in studies of ovarian and primary peritoneal high-grade serous carcinomas in which the entire fallopian tubes were carefully sectioned, mucosal involvement of the tube, including STICs, were identified in approximately 70% of cases19
. The question arises as to the source of the remaining ovarian carcinomas that lack evidence of tubal involvement. There are a number of possible explanations. First, despite thorough sectioning, a small STIC could have been missed (unpublished data). Second, on occasion high-grade serous carcinomas are intimately associated with serous borderline tumors and low-grade serous carcinomas. In these cases the high-grade tumors have had KRAS
mutations identical to those in the serous borderline tumors and lacked TP53
. This finding suggests that some high-grade serous carcinomas arise from low-grade serous tumors and not by the usual (type II) pathway that begins with a TP53
mutation. Third, clear-cut mucosal tubal involvement could have been obscured by overgrowth of the pelvic carcinoma. Fourth, the fimbria of the fallopian tube normally is in intimate contact with the ovarian surface at the time of ovulation. It is conceivable that when the ovarian surface epithelium is disrupted at the time of ovulation, normal tubal epithelial cells from the fimbria may be dislodged and implant in the ovary to form an inclusion cyst () from which a high-grade serous carcinoma could develop (see below). Evidence to support this notion is the observation that fallopian tube epithelial cells are easily obtained for culture by flushing the fallopian tube34, 43
. This mechanism could also explain the development of endosalpingiosis, a lesion composed of glands and papillary structures lined by tubal-type epithelium that is found on peritoneal surfaces in the pelvis, omentum and beneath the capsule of pelvic and para-aortic lymph nodes. Endosalpingiosis is frequently found in association with low-grade serous tumors and has been viewed as a possible precursor of these tumors. Finally, the possibility that some high-grade serous carcinomas arise in cortical inclusion cysts as a metaplastic process from the ovarian surface epithelium rather than from implantation of normal fallopian tube epithelium cannot be entirely dismissed.
Figure 2 Transfer of normal tubal epithelium to the ovary. A. Anatomical relationship of fallopian tube to the ovary at the time of ovulation. The fimbria envelops the ovary. B. Ovulation. The ovarian surface ruptures with expulsion and transfer of the oocyte (more ...)
Direct implantation of tubal epithelium into the ovary to form an inclusion cyst, which in turn is the site of origin of ovarian serous carcinoma, although not yet demonstrated, is an attractive alternative theory to that of metaplasia from the surface epithelium (mesothelium). Implantation of fallopian tube epithelium from the fimbria at the time of ovulation when the surface epithelium is disrupted can explain the derivation of low- and high-grade serous carcinomas. In the case of a low-grade serous carcinoma the process develops slowly from a serous cystadenoma and then a serous borderline tumor after a KRAS or BRAF mutation whereas in the case of a high-grade serous carcinoma the process evolves rapidly, presumably from a cortical inclusion cyst after a TP53 mutation with the development of an intraepithelial carcinoma as an intermediate step. According to this view both low- and high-grade serous carcinomas are ultimately of tubal (müllerian) origin and in a sense the ovary is involved secondarily ().
Figure 3 Proposed development of low-grade (LG) and high-grade (HG) serous carcinoma. A. One mechanism involves normal tubal epithelium that is shed from the fimbria, which implants on the ovary to form an inclusion cyst. Depending on whether there is a mutation (more ...)
It has been well established both by morphologic and more recently molecular genetic studies that low-grade endometrioid and clear cell carcinomas develop from endometriotic cysts (endometriomas), which are frequently associated with implants of endometriosis elsewhere in the pelvis45
. Although the precise origin of endometriosis has not been completely established, specifically, whether it develops in situ in the peritoneum through a process of metaplasia or from retrograde menstrual flow, the preponderance of data favor the latter mechanism3
. Admittedly, the former theory is more difficult to prove experimentally. Thus, if retrograde menstruation accounts for most cases of endometriosis, it is logical to assume that endometrioid and clear cell tumors develop from endometrial tissue (müllerian derived) that implanted on the ovary and therefore the ovary is involved secondarily26
(). Of further interest has been the observation that the eutopic endometrium in women with endometriosis exhibits intrinsic molecular abnormalities including activation of oncogenic pathways. Presumably, these changes permit the endometrial tissue to implant, survive and invade on ovarian and peritoneal surfaces3
. This hypothesis by which endometrioid and clear cell carcinoma develop from endometrial tissue implanted on the ovary is supported by epidemiologic evidence showing that a protective effect for tubal ligation was seen only for endometrioid and clear cell carcinoma of the ovary37
Figure 4 Proposed development of low-grade endometrioid and clear cell carcinoma. Endometrial tissue, by a process of retrograde menstruation, implants on the ovarian surface to form an endometriotic cyst from which a low-grade endometrioid or clear cell carcinoma (more ...)
Finally, the derivation of mucinous tumors of gastrointestinal type and transitional cell (Brenner) tumors may also not involve the ovaries directly. The origin of these tumors is puzzling since unlike serous, endometrioid and clear cell tumors, they do not display a müllerian phenotype. Although it has been argued that these mucinous tumors bear some relationship to the endocervix, the mucinous epithelium that characterizes these neoplasms more closely resembles gastrointestinal mucosa. It seems most unlikely that they develop from cortical inclusion cysts since mucinous metaplasia involving cortical inclusion cysts is a very rare finding. On the other hand, the association of Brenner tumors and mucinous tumors has been recognized for many years. In a provocative study of mucinous cystadenomas and Brenner tumors it was reported that after extensive sectioning, mucinous cystadenomas contained foci of Brenner tumor in 18% of cases40
. Interestingly, mucinous tumors were frequently associated with Walthard cell nests, which are composed of benign transitional-type epithelium, frequently found in paraovarian and paratubal locations. This raises the possibility that mucinous tumors and Brenner tumors have the same histogenesis, arising from these microscopic transitional cell nests at the tubal-mesothelial junction in keeping with their nonmüllerian appearance. The study reported that Brenner tumors are small (median size 0.5 cm, range 0.02–20 cm) whereas mucinous cystadenomas are large (median size 9 cm, range 1–30 cm). The investigators speculated that as a small Brenner tumor grows, the mucinous component becomes dominant resulting in the development of a mucinous cystadenoma, which as it enlarges, compresses and eventually obliterates the adjacent ovary giving the appearance that it arose in the ovary. The findings in this study are intriguing but must be regarded as preliminary. Additional morphologic and molecular genetic studies are necessary to determine whether this concept is valid.
In summary, none of the existing theories adequately reconciles all aspects of ovarian carcinogenesis. All of them have something to offer in explaining the development of ovarian carcinomas but none are all inclusive. It does appear that the vast majority of what have been thought to be primary epithelial ovarian and primary peritoneal carcinomas are, in fact, secondary. Thus, the most persuasive data support the view that serous tumors develop from the fimbriated portion of the fallopian tube, endometrioid and clear cell tumors from endometrial tissue passing through the fallopian tube resulting in endometriosis and mucinous and Brenner tumors from transitional-type epithelium located at the tubal-mesothelial junction where the fimbria makes contact with the peritoneum. The concept that the majority of epithelial ovarian carcinomas originates outside the ovary and involves it secondarily has emerged only recently because in the past the default diagnosis of carcinomas involving the pelvis and abdomen was that they were ovarian. A carcinoma was classified as tubal in origin only when the bulk of the tumor involved the fallopian tube rather than the ovary and there was evidence of an intraepithelial (in situ) tubal carcinoma39
. A diagnosis of primary peritoneal carcinoma is even more restrictive. Even with extensive tumor involving the peritoneum, omentum and other abdominal organs, a carcinoma is classified as primary ovarian if there is as little as 5 mm of tumor involving the ovaries. Thus, there has been an inherent bias in classifying pelvic tumors as being ovarian in origin.
Although the data suggesting that epithelial ovarian carcinoma arises in extraovarian sites and involves the ovaries secondarily are compelling, serous neoplasms (low- and high-grade) involve the ovaries and other pelvic and abdominal organs, such as the omentum and mesentery, much more extensively than the fallopian tubes. Similarly, although endometrioid carcinomas develop from endometriosis, which frequently involves multiple sites in the pelvis, these neoplasms are almost always confined to the ovaries. It is likely that the propensity for growth in the ovary is mulifactorial but the precise reasons for this are unknown.