Tubal origin of ovarian endometriosis and clear cell and endometrioid carcinoma

Abstract

Current research has strongly proposed that contrary to prior beliefs, many ovarian epithelial cancers (OECs) do not, as their name suggests, originate in the ovaries. Recent findings regarding both high-grade and low-grade serous carcinomas has implicated the fallopian tube as a cell source for these OECs, but until now, there has been little insight into the cellular source for clear cell and endometrioid carcinomas. In this commentary review article, we aimed to discuss the new findings that support the possible contribution from the fallopian tube in clear cell and endometrioid carcinomas. Specifically, we have provided results that showcased ovarian surface epithelia (OSE) and ovarian epithelial inclusions (OEIs) as having mesothelial and tubal origins and have strongly recognized the secondary müllerian system and the ability for tubal epithelia to implant upon the ovarian surface as contributing to fallopian tube-derived OEIs (F-OEIs). We have provided initial indications of these F-OEIs and their relationship to endometriosis and then clear cell and endometrioid carcinomas and subsequently offer our new proposal of a probable tubal origin. This new proposal is a paradigm that drastically changes the understanding behind the origin of these OECs and has significant clinical implications in the near future.

Keywords: Fallopian tube; clear cell carcinoma; endometrioid carcinoma; endometriosis; secondary müllerian system.

Figures

Figure 1

Morphologic transitions between endosalpingiosis and endocervicosis. A single ovarian epithelial inclusion (A) shows mucinous epithelial cells (endocervicosis) on the left and serous epithelia (endosalpingiosis) on the right. A similar finding of such a transition between endosalpingiosis (left) and endocervicosis (right) was found in another ovary (B).

Figure 2

Comparison of immunophenotype between OEIs and the fallopian tube. The fallopian tube and two types of OEIs (A, D, G) were immunohistochemically stained with PAX8 and calretinin. The mesothelium-derived OEI (M-OEI) was negative for PAX8 (E) but positive for calretinin (F). Conversely, the fallopian tube-derived OEI (F-OEI) was positive for PAX8 (H) but negative for calretinin (I), a result that is identical for the stainings of the tubal secretory cells (B and C).

Figure 3

Tubal ovarian adhesions serve as a common process to spread tubal epithelia on the ovarian surface before forming endosalpingiosis. Tubal epithelial cells are commonly seen on the ovarian surface, particularly when tubal ovarian adhesions are present (top panel). This panoramic picture shows magnified tubal epithelia (A), adherent tubal epithelia (B) on the ovarian surface, residual original ovarian surface epithelia that is mesothelial in nature (C), a newly formed ovarian epithelial inclusion (OEI) with surface adhesions (D), and a better formed and dilated OEI (E), which dynamically depicts the process of fallopian tube-derived OEI formation. Morphologically, the epithelial cells on the ovarian surface (B) are identical to tubal epithelia (A). The cells in panels (D and E) show more secretory cells and less ciliated cells compared with the original tubal epithelia (A). This is in contrast to the residual mesothelia (C), which are flat without any cilia and is apparently different from the tubal epithelia. PAX8 staining provides further clarification of the epithelial cells on the ovarian surface as well as the process of OEI formation (bottom panel). The tubal derived epithelial cells are positive for PAX8 (A, B, D, E) while the residual mesothelium on the ovarian surface is negative (C). Interestingly, the top half of the OEI (far right side) shows negative for PAX8 staining, indicative that part of the epithelial cells were entrapped into the OEI during the process of OEI formation due to adhesion.

Figure 4

Initial endometriosis. Initial endometriosis is the earliest morphologic indicator of endometriosis and can be seen near the surface of the ovary (A-D). These lesions are commonly seen from the transition of OEI or endosalpingiosis to the initial formation of endometriosis, which illustrates the stromal cellular changes from spindle to oval or round in shape and significantly increased microvessel density immediately adjacent to the epithelia, which are similar to those tubal derived cells. Additionally, the early onsets of eventual OEI formation can be seen by the deep invagination near the ovarian surface (arrows in panel B). Original magnifications: 100 × (A, B) and 200 × (C, D).

Figure 5

Ciliated epithelia seen in endometriosis are similar to tubal mucosa cells. There are two types of cells within the fallopian tube: ciliated cells and secretory cells (non ciliated). Part of the tubal fimbria (A) and magnified picture (B) from the boxed area of A clearly show ciliations (arrows) in the luminal borders. Ciliated cells are also seen in a case of well-formed endometriosis (arrows, C).

Figure 6

Clear cell and endometrioid carcinomas are associated with endometriosis and atypical endometriosis. A representative sample of an ovarian clear cell carcinoma (upper right corner, A) shows atypical endometriosis in adjacent area (left side with a single arrow, A). The area of atypical endometriosis is better viewed under 200 × magnification (B) and the clear cell carcinoma is magnified 100 × in panel (C) An example of endometrioid carcinoma (upper right corner, (D) also shows endometriosis (mid-left with arrow, (D). The area of endometriosis is magnified in (E) (200 ×) and the endometrioid carcinoma is magnified in (F) (200 ×).

Figure 7

Proposed model of the development of clear cell and endometrioid carcinoma from tubal-derived endometriosis. BTE-benign tubal epithelia; OSE-ovarian surface epithelia; OEIs-ovarian epithelial inclusions; M-OEI-mesothelium-derived OEI; F-OEI-fallopian tube-derived OEI. It is the F-OEI, not M-OEI, which has the potential to develop into clear cell or endometrioid carcinoma through multi-steps of endometriosis.