The highs and lows of serous ovarian cancer

Abstract

Low-grade serous ovarian cancer was initially described as a distinct type of rare epithelial ovarian cancer 20 years ago; however, only recently have physicians begun to leverage the understanding of the clinical behavior and molecular profile of this disease for treatment. The use of routine next-generation sequencing has allowed a deeper understanding of the molecular drivers of this disease and shown how molecular alterations in mitogen-activated protein kinase pathway genes such as KRAS and BRAF can affect overall prognosis and disease behavior. The use of targeted therapies, including MEK inhibitors, BRAF kinase inhibitors, and other investigational targeted therapies are changing the way this disease is viewed and treated. In addition, endocrine therapy can provide prolonged disease stability with generally mild toxicity, as well as promising response rates in recent studies examining combination therapy with CDK 4/6 inhibitors in the upfront and recurrent setting. Once seen merely as a chemo-resistant form of ovarian cancer, recent studies have worked to harness the unique features of low-grade serous ovarian cancer to provide individualized treatment options for patients with this disease.

Keywords: Low-grade serous; MAPK; MEK; ovarian cancer; rare tumors.

Figure 1

Histologic features of low-grade serous ovarian neoplasms and high-grade serous ovarian cancer. (A-D) The stepwise sequence of progression of low-grade serous ovarian tumors: (A) Serous cystadenoma lined by benign tubal-type epithelium. Occasional papillary projections likely represent the earliest morphologic changes preceding development of serous borderline tumor (SBT). (B) SBT, composed of hierarchically branching papillary structures. (C) Micropapillary SBT is considered a more advanced form of SBT, characterized by long slender papillae emanating directly from fibrous cores. (D) Finally, low-grade serous ovarian cancer (LGSOC) is defined by stromal invasion by tumor cells, arranged in nests and micropapillae. The nuclei are small, round and monotonous. (E) In contrast, high-grade serous ovarian cancer (HGSOC) show marked nuclear pleomorphism, including tumor giant cells, and abundant mitotic figures (inset: higher magnification of boxed area with mitoses indicated by arrowheads). (F) Immunohistochemistry for p53 shows a wildtype (heterogeneous) expression pattern in LGSOC and aberrant (diffuse) overexpression in a representative case of HGSOC.

Figure 2

Simplified schematic of the Mitogen-Activated Protein Kinase (MAPK) pathway. A key signaling pathway that regulates a wide variety of cellular processes including proliferation, apoptosis, and stress responses, the MAPK pathway plays a crucial role in LGSOC and serves as an important target for therapies such as MEK and RAF inhibitors. This figure was made using BioRender.