Ovarian clear-cell carcinoma, or clear-cell carcinoma of the ovary, also called ovarian clear-cell adenocarcinoma, is one of several subtypes of

ovarian carcinoma Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different cel ...

– a subtype of

epithelial ovarian cancer Surface epithelial-stromal tumors are a class of ovarian neoplasms that may be benign or malignant. Neoplasms in this group are thought to be derived from the ovarian surface epithelium (modified peritoneum) or from ectopic endometrial or Fallopi ...

, in contrast to non-epithelial cancers. According to research, most ovarian cancers start at the epithelial layer which is the lining of the ovary. Within this epithelial group ovarian clear-cell carcinoma makes up 5–10%. It was recognized as a separate category of ovarian cancer by the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...

in 1973. Its incidence rate differs across various ethnic groups. Reports from the United States show that the highest rates are among Asians with 11.1% versus whites with 4.8% and blacks at 3.1%. These numbers are consistent with the finding that although clear-cell carcinomas are rare in Western countries they are much more common in parts of Asia.

Background

There are two subtypes of

– epithelial and nonepithelial; ovarian clear-cell carcinoma is an

. The other major subtypes within this group include high-grade serous, endometrioid, mucinous, and low-grade serous. The serous type is the most common form of epithelial ovarian tumors. Cord-stromal and germ cell belong to the nonepithelial category which are much less common.

Structure and function

Ovarian clear-cell carcinoma often occurs as a pelvic mass that rarely appears bilaterally. The cells usually contain glycogen with large clear cytoplasm. It is also associated with endometriosis, a disorder of abnormal tissue growth outside of the uterus. The tumor cells emerge in a stepwise manner from adenofibromas which are benign endometriotic cysts. They also hold molecular genetic mutations in both

ARID1A AT-rich interactive domain-containing protein 1A is a protein that in humans is encoded by the ''ARID1A'' gene. Function ARID1A is a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate ...

and PIK3CA, similar to other epithelial ovarian cancers. Mutations in ARID1A commonly contain

phosphatase and tensin homolog Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the ''PTEN'' gene. Mutations of this gene are a step in the development of many cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate ca ...

(PTEN) that are hypothesized to contribute to clear-cell tumorigenesis. However, research also shows that inactivation of ARID1A alone does not lead to tumor initiation. However, clear-cell tumors rarely carry

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...

, or

BRCA2 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...

mutations. In addition, they also test negative for estrogen and progesterone receptors and Wilm tumor suppressor 1. Studies have also suggested that clear-cell carcinoma can occur with thromboembolic complications and hypercalcemia. Recurrence of tumor cells have been reported to involve lymph nodes and parenchymal organs. Research continues to look for ways to understand clear-cell tumor progression. A suggested mechanism is the amplification and overexpression of

CCNE1 G1/S-specific cyclin-E1 is a protein that in humans is encoded by the ''CCNE1'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in prote ...

which is thought to promote the tumor's aggressive behavior. In addition, they also test negative for estrogen and progesterone receptors and Wilm tumor suppressor 1. The CCNE1 gene encodes for the cyclin E1 protein which accumulates at the

G1-S phase transition The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subs ...

point of the

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...

. Detecting the cancerous tumor progression can be difficult for pathologists. While some tumors will appear in the ovary, others spread over the outer lining of the ovary and to other organs such as the uterus, fallopian tube, and lymph glands.

Clinical relevance

Clear-cell tumors are frequently found at an early stage and therefore can be cured with surgery. Through clinical examination or preoperative imaging techniques, tumors have been reported to range from 3-20 cm. Most ovarian tumors are benign and rarely spread past the ovary. Therefore, surgical removal of the ovary or partial removal of the ovary is sufficient for treatment for malignant tumors. When diagnosed beyond FIGO (

International Federation of Gynecology and Obstetrics The International Federation of Gynaecology and Obstetrics, usually just FIGO ("fee'go") as the acronym of its French name Fédération Internationale de Gynécologie et d'Obstétrique, is a worldwide non-governmental organisation representing ob ...

) stage 1 patients usually have a poor prognosis. If the malignant tumors metastasize and spread throughout the body then they could potentially be fatal. Clear-cell tumors have been found to be resistant to conventional chemotherapy using

platinum Platinum is a chemical element with the symbol Pt and atomic number 78. It is a dense, malleable, ductile, highly unreactive, precious, silverish-white transition metal. Its name originates from Spanish , a diminutive of "silver". Platinu ...

and

taxane Taxanes are a class of diterpenes. They were originally identified from plants of the genus ''Taxus'' (yews), and feature a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents. Cabazitaxel was FDA ap ...

. Although the cause of this chemoresistance is unknown, there is research that provides partial explanation of this occurrence. For example, studies show that clear-cell tumor cells proliferate at lower rates than serous adenocarcinomas which then could aid in a lower response from clear-cell tumors to chemotherapies. Given that treatment options are limited for ovarian clear-cell cancer patients, researchers are studying biomarkers or specific pathways that could aid in developing future treatment. These patients are good candidates for targeted therapies since the standard does not adequately help their care. Some suggested therapeutic targets include the PI3K/AKT/mTOR,

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

, Il-6/STAT3, MET, and HNF-1beta pathways.Mabuchi, S., Sugiyama, T., Kimura, T. (2016). Clear cell carcinoma of the ovary: molecular insights and future therapeutic perspectives. Journal of Gynecologic Oncology, 27(3), 1-14. Better insight into genomic heterogeneity would also provide a personalized approach to identifying treatment targets for clear-cell tumor patients that share similar phenotypes. Developing stronger options is also beneficial because ovarian cancer is the fifth leading cause of cancer deaths for women and is one of the most lethal gynecological cancers.

References

{{DEFAULTSORT:Clear-Cell Ovarian Carcinoma Ovarian cancer