Molecular Analysis of High-Grade Serous Ovarian Carcinoma Exhibiting Low-Grade Serous Carcinoma and Serous Borderline Tumor

Abstract

Ovarian cancer is classified as type 1 or 2, representing low- and high-grade serous carcinoma (LGSC and HGSC), respectively. LGSC arises from serous borderline tumor (SBT) in a stepwise manner, while HGSC develops from serous tubal intraepithelial carcinoma (STIC). Rarely, HGSC develops from SBT and LGSC. Herein, we describe the case of a patient with HGSC who presented with SBT and LGSC, and in whom we analyzed the molecular mechanisms of carcinogenesis. We performed primary debulking surgery, resulting in a suboptimal simple total hysterectomy and bilateral salpingo-oophorectomy due to strong adhesions. The diagnosis was stage IIIC HGSC, pT3bcN0cM0, but the tumor contained SBT and LGSC lesions. After surgery, TC (Paclitaxel + Carbopratin) + bevacizumab therapy was administered as adjuvant chemotherapy followed by bevacizumab as maintenance therapy. The tumor was chemo-resistant and caused ileus, and bevacizumab therapy was conducted only twice. Next-Generation Sequencing revealed KRAS (p.G12V) and NF2 (p.W184*) mutations in all lesions. Interestingly, the TP53 mutation was not detected in every lesion, and immunohistochemistry showed those lesions with wild-type p53. MDM2 was amplified in the HGSC lesions. DNA methylation analysis did not show differentially methylated regions. This case suggests that SBT and LGSC may transform into HGSC via p53 dysfunction due to MDM2 amplification.

Keywords: MDM2; high-grade serous carcinoma; low-grade serous carcinoma; ovarian cancer; serous borderline tumor.

Figure 2

Copy number alterations. (a) SBT; (b) LGSC; (c) HGSC. The difference between MDM2 is greater in HGSC compared to SBT and LGSC.

Figure 3

Epigenetic analysis of cancer-related genes. Green-colored cells indicate hypermethylated genes. Red-colored cells indicate hypomethylated genes. Blue-colored cells indicate equally methylated genes. No oncogenes are hypomethylated and no tumor suppressor genes are hypermethylated specifically in HGSC.

Figure 1

Hematoxylin and eosin (HE) staining of each lesion. (a) The SBT lesion at 200× g magnification. (b) The LGSC lesion at 200× g magnification. (c) HGSC lesion at 200× g magnification. (d) The arrow indicates junction of SBT and LGSC. SBT is contiguous with LGSC at 400× g magnification. (e) The arrow head indicates junction of LGSC and HGSC. LGSC is contiguous with HGSC at 100× g magnification.