Int J Gynecol Pathol. 2013 Sep;32(5):444-53.

The stem-cell profile of ovarian surface epithelium is reproduced in the oviductal fimbriae, with increased stem-cell marker density in distal parts of the fimbriae.

Auersperg N.

Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada. auersper@mail.ubc.ca

 

Abstract

High-grade serous ovarian carcinomas are the most common and most lethal ovarian cancers, but their histologic origin is still controversial. Current evidence suggests that they may originate in the ovarian surface epithelium (OSE) and/or epithelium of oviductal fimbriae (FE). To further investigate this question we compared the stem-cell profiles of these epithelia. Formalin-fixed sections of normal FE (N=21) and ovaries (N=21) were stained immunohistochemically for the stem-cell markers NANOG, SFRP1, LHX9, ALDH1A1, and ALDH1A2. All markers were detected in both OSE and FE. A total of 75% to 100% of surface OSE expressed all markers except ALDH1A1, which occurred in about 25% of cells. Among epithelial inclusion cysts with flat-to-cuboidal epithelium, resembling OSE, ALDH1A1 was significantly increased, whereas SFRP1 was reduced compared with surface OSE, suggesting an increased trend towards malignant transformation. Similarly, among cysts lined by columnar cells resembling FE, SFRP1 expression was low, whereas ALDH1A1 approached 100% of the cysts. FE exhibited considerable variation between and within specimens. In about half of the samples, SFRP1 and NANOG were detected in ≤25% FE. The most widespread markers were ALDH1A1 and ALDH1A2. The highest proportion of all markers occurred in the distal parts of the FE, the site of the putative ovarian cancer precursors. Marker expression in tubal ampullae was low or absent except for ALDH1A1 and ALDH1A2. The results provide an explanation for the characteristic distal location of fimbrial high-grade serous ovarian carcinoma precursor lesions, and indicate that both OSE and FE have the capacity to undergo neoplastic transformation.

PMID: 23896717

 

SUPPLEMENT

Ovarian cancer is the prime cause of death from gynecological malignancies in the Western world. In spite of its importance, it is among the least understood among the major human malignancies, and its prognosis remains a poor 5-year survival of only about 40%. One of the main obstacles to improvements of its clinical management is that there is still uncertainty about the cell type of origin of ovarian carcinomas, which limits means of early detection and prevention.

For many years it was accepted that most, if not all, ovarian epithelial cancers arise in the ovarian surface epithelium (OSE), i.e. the pelvic mesothelium which overlies the ovary and lines ovarian epithelial inclusion cysts (Figs 1, 2). Recently, this view of ovarian carcinogenesis has been questioned, in particular as a result of evidence that the high grade serous ovarian carcinomas (HGSC), which are the most common and most lethal of all ovarian epithelial neoplasms, may arise in the oviductal fimbriae (Figs. 1, 2) and are only secondarily deposited on the ovary.

Nelly Auersperg-1Figure 1. Diagram of the female reproductive tract. Note the close apposition between the oviductal fimbriae and the ovary.

 Nelly Auersperg-2Figure 2.  The two proposed sources of the HGSOCs: On the left, the ovarian surface epithelium (OSE) which is the part of the pelvic peritoneum that overlies the ovary.  Two epithelial inclusion cysts are pictured in the figure: ‘a’ is lined with OSE, ‘b’ is lined with columnar epithelium that can be interpreted as either metaplastic OSE or fimbrial epithelium that has been displaced into the ovarian stroma.  On the right, oviductal fimbriae. The star at the junction of the ovary and the fimbriae is a site of attachment of an ovarian fimbria and transitiob from OSE to fimbria epithelium. It may be mistaken for an adhesion, but this in unlikely in view of the absence of other nearby indications of adhesions. Hematoxylin/eosin, except for the lower, high power view of the fimbriae which has been stained for cilia with antibody LhS28 (Abcam). Reproduced, with permission, from Front Biosci (Schol Ed). 2013 Jan 1; 5:709-19.

 

The arguments for the origin of ovarian cancers in the OSE are based on histopathologic evidence, its developmental history, and experimental models. Dysplastic lesions and early stage HGSCs contiguous with the OSE have been observed. Furthermore, tubal metaplasia of OSE demonstrates its capacity to undergo oviductal differentiation. Importantly, OSE from asymptomatic women with BRCA mutations that predispose them to ovarian cancer, shows preneoplastic changes. Finally, several animal models have demonstrated that OSE, upon the introduction of various tumor-promoting agents, forms malignant tumors in vivo, which resemble human ovarian carcinomas (1).

The concept that HGSCs arise in the oviduct and then metastasize to the ovary originated with the discovery of serous tubal intraepithelial carcinomas (STICs) in the distal parts of the oviductal fimbriae in prophylactic salpingo-oophorectomy specimens from BRCA mutation carriers and also, subsequently, in a significant proportion of women with ovarian or peritoneal serous carcinomas, irrespective of family history. STICs exhibit frequent strong imunohistochemical p53 staining indicative of p53 inactivation/mutation, as well as other markers which are characteristic for ovarian HGSCs. Arguments for the origin of HGSCs in STICs are strongly supported by the presence of cases where identical p53 mutations were found in the STICs and in coexisting  HGSCs  (2).

The controversy regarding these two opposing hypotheses, which is still ongoing, is due in part to the traditional concept that the ovary and the oviduct are two separate organs, greatly differing in structure and function, which seems to make it unlikely that identical tumors would originate in both. However, in the case of epithelial ovarian carcinomas this may be a misconception because of the developmental history of these tissues: Early in embryogenesis, OSE and the oviductal fimbriae orginate in adjacent parts of the embryonic coelomic epithelium  (Fig. 3).  The section of the coelomic epithelium which covers the future ovary becomes the OSE. Near the presumptive OSE, an invagination forms which elongates into a tube and will eventually merge with the contralateral tube to form the oviductal and uterine epithelium. The part of this tube which is closest to the original invagination site and thus to the OSE, differentiates into the oviductal fimbriae. Though they subsequently undergo divergent differentiation in response to different inductive influences, the origin of the OSE and fimbriae in adjacent parts of the coelomic epithelium may allow them to give rise to similar neoplasms in the adult (3). This relationship suggests a third hypothesis, namely that HGSCs arise in both sites, i.e. in the OSE and the fimbriae. Previous studies support this hypothesis by demonstrating that fimbrial and ovarian surface epithelial differentiation markers overlap and retain common features (4). This reflects their common origin and suggests that these epithelia are not fully determined and differentiated in the adult, which may predispose them to neoplastic progression (Fig. 4) (3, 4).

Nelly Auersperg-3Figure 3. Diagram representing stages in the embryonic development of the ovaries, and the Mullerian ducts which will differentiate into the epithelia of the oviduct and uterus. The gonadal ridge will differentiate into the stromal component of the ovaries, and the part of the coelomic epithelium overlying the gonadal ridges will form the OSE. TheMullerian ducts will form through invagination of the coelomic epithelium close the OSE. Reproduced, with permission, from Front Biosci (Schol Ed). 2013 Jan 1; 5:709-19.

Nelly Auersperg-4Figure 4.  Overlap of differentiation between OSE and fimbriae. A. Calretinin is a known marker for mesothelia, including OSE, while fimbriae are generally negative. But occasionally (B), fimbriae show a mixture of calretinin-positive and calretinin-negative epithelial cells. C. E-cadherin is abundant in fimbriae, while OSE is generally E-cadherin negative (arrow). But occasionally, regions of OSE are positive for E-cadherin (asterisk). Reproduced, with permission, from Front Biosci (Schol Ed). 2013 Jan 1; 5:709-19.

 

The present publication addresses this hypothesis by investigating the presence and distribution of stem cells in these two epithelia. In recent years there has been intense interest in cancer stem cells (CSCs) which have been defined as small subpopulations of cells within tumors that have the capacity to self-renew but also to give rise to the heterogenous cancer cell lineages that comprise malignant tumors. Being stationary or slow dividing, they tend to be resistant to therapy and are thought to be a major factor in the development of drug resistance. Stem cells in normal tissues are considered to be likely precursors of CSCs and their derivatives, the tumor cells. Therefore, CSCs are commonly identified by their resemblance to stem cells of their normal precursors. The purpose of the present study was to determine whether normal OSE and/or fimbriae contain stem cells, and if so, to compare stem cell characteristics between these epithelia by immunohistochemistry.

The study demonstrated that five widely different stem cell markers are present in both the OSE and the fimbriae. In the OSE, they seemed to be distributed randomly on the ovarian surface (Fig. 5), but in OSE-lined inclusion cysts the proportions of the five stem cell markers were different from those on the surface. This is significant because the change in stem cell marker expression from the OSE on the ovarian surface was suggestive of premalignant changes, and histologically, most premalignant changes in ovaries have previously also been observed in epithelial inclusion cysts. In the oviductal fimbriae, the highest proportion of stem cells was located in the distal parts of the fimbriae (Fig. 6). Importantly, this is the location of most STICs, i.e. the putative ovarian cancer precursors. Interestingly, the location of the stem cells in both the OSE and the distal parts of fimbriae agrees well with the known requirements of a ‘stem cell niche’, i.e. a location that provides the necessary environment which will allow cells to maintain their stem-cell status. This status includes a state of proliferative quiescence and incomplete differentiation. OSE is isolated basally from stromal and circulatory growth–and differentiation-promoting factors and metabolites by the collagenous tunica albuginea (Fig. 2). It thus has little access to agents that would foster growth and/or differentiation. Similarly, cells at the tip of fimbriae are the ones that are farthest removed from sources of nutrients, hormones and other factors that are required for growth and differentiation, which would interfere with the maintenance of the stem cell status.

Nelly Auersperg-5

Figure 5. Expression of stem cell markers in the ovarian surface epithelium (OSE), at low magnification on the left, at high magnification on the right. (A) NANOG, (B) LHX9 (C) SFRP1, (D) ALDH1A1, (E) ALDH1A2. At the lower magnification, ALDH1A1 is shown to illustrate the transition from negative (left) to positive (right) OSE. NANOG and LHX9 are localized predominantly in the nuclei, while the location of SFRP1, ALDH1A1 and ALDH1A2 is cytoplasmic. Reproduced, with permission, from Int. J.Gyn. Pathol. (2013) 32:444-453.

Nelly Auersperg-6Figure 6.  Apical (distal) staining of a fimbria for the stem cell marker LHX9. Reproduced, with permission, from Int. J.Gyn. Pathol. (2013) 32:444-453. Reproduced, with permission, from Int. J.Gyn. Pathol. (2013) 32:444-453.

 

This study represents the first comparison of the stem cells which characterize two putative sources of ovarian cancers, the OSE and fimbriae. It further provides an explanation for the characteristic location of STICs on the distal ends of the fimbriae: these are the sites where most stem cells are located. The results suggest, on the basis of their similar stem cell profiles, that both OSE and fimbriae have the capacity to undergo neoplastic transformation and thus support the hypothesis that HGSOCs can originate in both epithelia. Once the origin of HGSOC’s is firmly established, it will be possible to provide clear guidelines for further steps in clinical management, such as choices between prophylactic salpingectomies and salpingoophorectomies, which will hopefully lead to improvements in the outcomes of this deadly disease.


References

1. Auersperg N. Ovarian surface epithelium as a source of ovarian cancers: Unwarranted speculation or evidence-based hypothesis? Review. Gynecol. Oncol. (2013) 130:246–251.

2. Vang R, Shih IeM, Kurman RJ. Fallopian tube precursors of ovarian low- and high-grade serous neoplasms.Histopathology. (2013) 62:44-58. Review.

3. Auersperg N. The origin of ovarian cancers – hypotheses and contraversies . Front. Biosci. (Schol. Ed). (2013) 5:709-19.

4. Auersperg N. The origin of ovarian carcinomas: a unifying hypothesis. Int. J. Gyn. Pathol. (2011) 30:12-21.

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