Tubal Origin of 'Ovarian' Low-grade Serous Carcinoma

Jie Li; Nisreen Abushahin; Shujie Pang; Li Xiang; Setsuko K Chambers; Oluwole Fadare; Beihua Kong; Wenxin Zheng

Disclosures

Mod Pathol. 2011;24(11):1488-1499. 

In This Article

Discussion

'Ovarian' low-grade serous carcinomas are thought to evolve in a stepwise fashion, from ovarian epithelial inclusions or benign serous cystadenoma to serous borderline tumor, and eventually to carcinoma.[11] This model is supported by the following facts: (1) similar mutations of KRAS and BRAF genes are present in serous borderline tumors and in adjacent serous cystadenoma epithelium;[30] (2) compared with ovarian epithelial inclusions from ovaries with serous borderline tumors, ovarian epithelial inclusions from ovaries without non-neoplastic disease show significantly lower levels of epithelial cell aneusomy;[31] and (3) the majority of low-grade serous carcinomas are associated with serous borderline tumors.[32] The majority of serous cystadenomas are also thought to be derived from ovarian epithelial inclusions, as both display similar epithelial linings, and the diagnostic criteria dividing ovarian epithelial inclusions from serous cystadenoma are arbitrarily made at the 1 cm size threshold.[33] The origin of ovarian epithelial inclusions can therefore provide insights into the origin of low-grade serous carcinoma. The coelomic metaplasia hypothesis has traditionally been used to explain the development of ovarian epithelial inclusions. In this hypothesis, the mesothelium overlying the ovary is assumed to invaginate into the underlying stroma to form ovarian epithelial inclusions. These cystic structures undergo metaplasia that results in the mesothelium being converted to Mullerian-type epithelium.[33] These ovarian epithelial inclusions, with their newly acquired Mullerian phenotype, can then undergo malignant transformation. However, the aforementioned arguments against the ovarian surface epithelium as the origin of most ovarian epithelial cancers are similarly applicable to ovarian epithelial inclusions if it is assumed that ovarian epithelial inclusions are derived from the ovarian surface epithelium. In the present study, we evaluated the morphologic and immunophenotypic features of ovarian epithelial inclusions, ovarian surface epithelium, serous tumors, and distal tubal epithelium to gain a significant insight into the origin of low-grade serous carcinoma that are presently classified as ovarian origin by contemporary criteria. Based on the findings in this study, we discuss the following points.

First, we found that there are two types of ovarian epithelial inclusions and two types of ovarian surface epithelium, and both significantly differ in their proportional distribution. The first had mesothelial phenotype with an extremely low proliferative index: mesothelium-derived ovarian surface epithelium and mesothelium-derived ovarian epithelial inclusions. Mesothelium-derived ovarian surface epithelium was present in all ovarian sections studied. In contrast, mesothelium-derived ovarian epithelial inclusions were detected in only 22% of 856 ovarian epithelial inclusions studied. The second had tubal phenotype with a comparatively higher proliferative index: fallopian tube-derived ovarian surface epithelium and fallopian tube-derived ovarian epithelial inclusions. These cells were morphologically and immunophenotypically similar to tubal fimbria epithelial cells. The infrequent (4%) finding of 'tubal-type' epithelium in ovarian surface epithelium stands in stark to the high frequency (78%) of detecting this epithelial type in ovarian epithelial inclusions. These findings provide strong support for the concept that most of ovarian epithelial inclusions, and therefore lesions derived therefrom, are of tubal origin. The fact that the epithelial cells covering the ovarian surface can actually originate from the fallopian tube was an unexpected finding. Although this was only found in 2 (4%) of the 48 cases we studied, it does show that benign tubal epithelia are able to implant on the ovarian surface and architecturally simulate 'ovarian surface epithelium' microscopically. The small percentage of such fallopian tube-derived ovarian surface epithelium found in this study is similar to a recent study addressing the origin of high-grade serous carcinoma from patients with BRCA mutations.[34] Additionally, we speculate that tubal epithelia implanted on the ovary are unstable and are easily sloughed off, as the ovaries are in a state of near-perpetual motion and agitation within the peritoneal cavity. In contrast, epithelia that are entrapped in the ovarian cortex are less amenable to easy physical detachment. This small proportion of fallopian tube-derived ovarian surface epithelium, and the notion that it is that population that has the most neoplastic potential, is supported by studies that have shown evidence of 'oncogenic stress' in only a small subset of ovarian epithelia interpreted as 'ovarian surface epithelium'.[29,35]

Second, ovarian epithelial inclusions are common in ovarian cortex including 22% of mesothelial and 78% tubal type. The question is now whether these fallopian tube-derived ovarian epithelial inclusions were derived from mesothelium-derived ovarian epithelial inclusions through a commonly believed metaplasia process. Although this possibility cannot be completely ruled out because of the descriptive nature of our study, we believe that the fallopian tube-derived ovarian epithelial inclusions are likely derived from tubal epithelia. The fact that we found more tubal-like epithelium in ovarian epithelial inclusions than in ovarian surface epithelium makes a strong argument that the fallopian tube-derived ovarian epithelial inclusions are not derived from the ovarian surface epithelium. The most straightforward explanation is that fallopian tube-derived ovarian epithelial inclusions represent intraovarian endosalpingiosis, which is well in line with the ideas expressed by Dubeau[3] and Crum.[10] Furthermore, if 78% fallopian tube-derived ovarian epithelial inclusions were truly originating from mesothelium-derived ovarian epithelial inclusions through a Mullerian metaplasia, the metaplastic process must be a common event and hybrid type of ovarian epithelial inclusions should be commonly found in the ovary. The fact that no hybrid or intermediate type of ovarian epithelial inclusions with both mesothelial and tubal phenotypes makes another strong argument that mesothelium-derived ovarian epithelial inclusions forming fallopian tube-derived ovarian epithelial inclusions through metaplasia is very unlikely. This is also supported by one previous observation that there were two types of ovarian epithelial inclusions, with one positive for calretinin and one negative for calretinin.[36] In addition, mesothelium-derived ovarian epithelial inclusions seem not able to grow into a tumor mass as all these cystic structures have an extremely low cellular proliferative index and they are very unlikely to be the precursors of serous cystadenomas, borderline tumors, and low-grade serous carcinomas for the same reasons discussed above. In contrast, fallopian tube-derived ovarian epithelial inclusions showed comparable proliferative activity and immunophenotypes that were similar or identical to 'ovarian' serous tumors. From these perspectives, fallopian tube-derived ovarian epithelial inclusions are the more likely precursors to low-grade serous carcinoma.

Third, we found that ciliated cells, as are normally present in the fallopian tube, were also present in fallopian tube-derived ovarian surface epithelium, fallopian tube-derived ovarian epithelial inclusions, serous cysadenomas, and borderline tumors, with a significant increase in secretory-to-ciliated cell ratio from normal fallopian tube to fallopian tube-derived ovarian epithelial inclusions (P<0.001), but were very rare in low-grade serous carcinoma. The secretory-to-ciliated cell ratio was very similar between fallopian tube-derived ovarian epithelial inclusions and serous cystadenoma, and the secretory-to-ciliated cell ratios of both were only slightly lower than the secretory-to-ciliated cell ratio in serous borderline tumors. This was in contrast to low-grade serous carcinomas, whose epithelial component comprised almost entirely the secretory-type cells. High-grade serous carcinomas arising from the fallopian tube are thought to evolve via a clonal expansion of the secretory cell component of the tubal epithelium.[14,37,38] Our findings suggest that low-grade serous carcinoma is similarly a clonal expansion of tubal-type secretory cells. The statistically significant increase in secretory-to-ciliated cell ratio that was observed between normal tubal epithelium and fallopian tube-derived ovarian epithelial inclusions suggests that a molecular event facilitating secretory cell expansion or ciliated cell suppression is present in fallopian tube-derived ovarian epithelial inclusions. The reduction in cilia with advancing tumor development might simply indicate an impaired maturation program. The similarity in the secretory-to-ciliated cell ratio between fallopian tube-derived ovarian epithelial inclusions and serous cystadenomas is consistent with the arbitrarity of the pathologic criteria (size threshold of 1 cm) by which these lesions are distinguished. Finally, the very high secretory-to-ciliated cell ratio in low-grade serous carcinoma, in conjunction with all of the aforementioned findings, is all consistent with the concept of a stepwise progression.

In summary, this study provides morphologic and immunophenotypic evidence that ovarian low-grade serous carcinoma is most likely originated from the tubal fimbria. In conjunction with evidence in the published literature, we propose a sequence of low-grade serous carcinoma development as follows: first, fallopian tubal epithelia, mostly from fimbriated end, implant on the ovarian surface. Two possibilities exist for how this detachment and implantation occurs: (1) given the close spatial relationship between the ovarian surface and the tubal fimbriated end, ovulation or non-ovulation-induced disruption of the ovarian surface may offer an opportunity for the adjacent tubal epithelium to detach and implant in the ovarian stroma;[11] and (2) adhesion of tubal epithelium on the ovarian surface, from inflammation or other factors, and dynamic stromal growth around it may eventuate in fallopian tube-derived ovarian epithelial inclusion formation. The acquisition of KRAS or BRAF and possibly other mutations in fallopian tube-derived ovarian epithelial inclusions and serous cystadenomas result in their transformation to serous borderline tumors and ultimately, low-grade serous carcinomas.[39–43] A small proportion of high-grade serous carcinomas may develop from low-grade serous carcinomas after the acquisition of additional mutations such as TP53[11] and some high-grade serous carcinomas may arise in fallopian tube-derived ovarian epithelial inclusions when TP53 gene mutations occur in women with BRCA mutations.[29] The secretory cell proliferations probably give rise to both low- and high-grade serous carcinomas and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation. Given that high-grade serous carcinomas are also increasingly accepted to be of tubal origin, our findings lend further credence to the concept that the cell of origin of most ovarian carcinomas is not a normal ovarian component. These findings may have significant implications for current 'ovarian' cancer-prevention strategies. Genetic and molecular studies are needed to further confirm the tubal origination of ovarian serous cancers.

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