Are Epithelial Ovarian Cancers of the Mesenchymal Subtype Actually Intraperitoneal Metastases to the Ovary?

Ye Hu,Barbie Taylor-Harding,Joshua Millstein,Marcela Haro,Yael Raz,Maria Sol Recouvreux,Ann E Walts,Enes Taylan,Sandra Orsulic,Beth Y Karlan,Jenny Lester

doi:10.3389/fcell.2020.00647

Abstract

Primary ovarian high-grade serous carcinoma (HGSC) has been classified into 4 molecular subtypes: Immunoreactive, Proliferative, Differentiated, and Mesenchymal (Mes), of which the Mes subtype (Mes-HGSC) is associated with the worst clinical outcomes. We propose that Mes-HGSC comprise clusters of cancer and associated stromal cells that detached from tumors in the upper abdomen/omentum and disseminated in the peritoneal cavity, including to the ovary. Using comparative analyses of multiple transcriptomic data sets, we provide the following evidence that the phenotype of Mes-HGSC matches the phenotype of tumors in the upper abdomen/omentum: (1) irrespective of the primary ovarian HGSC molecular subtype, matched upper abdominal/omental metastases were typically of the Mes subtype, (2) the Mes subtype was present at the ovarian site only in patients with concurrent upper abdominal/omental metastases and not in those with HGSC confined to the ovary, and (3) ovarian Mes-HGSC had an expression profile characteristic of stromal cells in the upper abdominal/omental metastases. We suggest that ovarian Mes-HGSC signifies advanced intraperitoneal tumor dissemination to the ovary rather than a subtype of primary ovarian HGSC. This is consistent with the presence of upper abdominal/omental disease, suboptimal debulking, and worst survival previously reported in patients with ovarian Mes-HGSC compared to other molecular subtypes.

Highlights

High-grade serous carcinoma is the most common and most deadly type of ovarian cancer (Matulonis et al, 2016)
While only 20% of the primary ovarian high-grade serous carcinoma (HGSC) were classified as Mes, 79% of the concurrent and 58% of the recurrent HGSC metastases were classified as Mes (Figure 2B)
Using 2 large transcriptomic data sets in which subsets of samples have been annotated by the site of sample collection (GSE9891 and GSE2109), we showed that the average unweighted ratio of the z-scores from Omental metastasis/Primary HGSC stromal gene signatures was lower in tumors located retroperitoneally or in the pelvis than in tumors located outside of the pelvis (Figures 4C,D)

Summary

Introduction

High-grade serous carcinoma is the most common and most deadly type of ovarian cancer (Matulonis et al, 2016). The majority of ovarian cancer patients with HGSC are diagnosed with tumors involving one or both ovaries and various additional intraperitoneal sites including the upper abdomen/omentum (FIGO stage III) (Matulonis et al, 2016). We propose that in stage III HGSC, metastases and PPC in the upper abdomen/omentum shed cancer cell-stroma aggregates into the peritoneum, resulting in intraperitoneal dissemination that includes secondary metastases to the primary tumor in the pelvis (Figure 1B). Individual clones have been tracked using whole-genome and single-nucleus sequencing of patientmatched tumor deposits at different anatomic locations These studies identified evidence of metastases to the ovary or the fallopian tube in 4 out of 15 patients, thereby demonstrating that re-seeding of the primary tumor site by clones from peritoneal metastases is not a rare event (Eckert et al, 2016; McPherson et al, 2016)

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