Join us on December 20, 2018 at 1pm ET for live CME about ovarian cancer, worth 1.0 AMA PRA Category 1 Credit™.
According to the CDC, ovarian cancer is the second most common gynecologic cancer, comprising 3% of all cancers in women. Approximately 11 out of every 100,000 women are diagnosed with new cases annually (over 20,000), and 7 out of every 100,000 (over 14,000) will die of the disease in the same time period. The 5-year survival rate is approximately 46.7%.
Ovarian cancer is often diagnosed in later stages because the early symptoms are often vague and non-specific. Signs and symptoms include:
- Abdominal discomfort or distension
- The effects of pressure on the bladder or rectum
- Vaginal bleeding
- GERD symptoms
- Weight loss
- Early satiety
- An Abdominal mass
In contrast to tumors in other locations, those located in the ovaries have more heterogenous histologic types: in the ovaries, not only do epithelial tumors develop, but germ-cord stromal tumors and germ cell tumors do as well. In the majority of cases, ovarian cancer is multi-cystic despite the histologic type. When the cysts rupture, cancer cells leak into the peritoneal cavity where they can be fatal. The most common type of ovarian cancers are the surface epithelial-stromal tumors. There are four main histologic subtypes, including serous, mucinous, endometriod, and clear cell. Lesser subtypes include transitional and squamous cell. Cancer cells typically grow inward but when the thin cyst wall ruptures, cells are released into the peritoneal cavity. However, some may grow outward in papillary form directly in contact with the peritoneal cavity. Hence, ovarian cancers tend to metastasize to surfaces in the peritoneal cavity, including the omentum. Another type appears to be endometriosis-associated ovarian cancers (EAOC) and thought to be caused by dysregulated inflammation.
The treatment and prognosis is determined by the stage of the cancer.
Stage IA: The cancer is found only in 1 ovary.
Stage IB: The cancer is located in both ovaries.
Stage IC: Cancer can be in one or both ovaries, and there are cancer cells found outside the ovaries.
Stage IIA: Cancer has spread to the fallopian tubes or uterus.
Stage IIB: Cancer has extended to other pelvic organs.
Stage IIIA: Microscopic cancer cells are found in the upper abdomen or lymph nodes.
Stage IIIB: Visible tumor is seen in the upper abdomen and is less than 2 cm in size.
Stage IIIC: Visible tumor is found in the upper abdomen, including the surface or the spleen or liver, and is greater than 2 cm in size.
Stage IVA: Cancer is found in the fluid around the lungs.
Stage IVB: Cancer is found inside the lungs, liver, or spleen.
Approximately ¾ of epithelial ovarian cancers (EOC) are found in Stage III or IV, which usually carries a 5-year survival rate of <30%. It has been found that a common feature of these tumors is pH dysregulation. In order to grow, cancer cells must adapt to the acidic microenvironment that is associated with the tumor. To control the intracellular pH, the Na+/H+ exchanger isoform 1 (NHE1) must be activated. One recent study found that NHE1 is overexpressed in EOC. This was found to be true in serous, mucinous, clear cell, and endometriod tumors. This increased expression was found to be associated with progression of the tumor and was associated with a poorer prognosis. 
Ovarian clear cell and endometriod cancers are believed to derive from endometrosis. Loss of ARID1A has been shown to be responsible for promoting endometriosis carcinogenesis. In another study, expression of biomarkers was found in differing levels in endometriosis and endometriod cancer. Only VEGF expression was associated with a significant increase in carcinogenesis versus endometriosis. Additionally, PARP-1 corresponded to a worse progression-free survival and overall survival. 
Treatment of ovarian cancer depends on the stage but often involves a combination of surgery and chemotherapy. Surgery may include the removal of an ovary or both and the corresponding fallopian tube. If the cancer is advanced, chemotherapy is done first to reduce the size of the tumor. Targeted therapy is now being widely studied and used more often. If the cancer is too advanced, palliative care may be the only option.
Recently, Poly (ADP-ribose) polymerase (PARP) inhibitors have been investigated for their use in ovarian cancer. These agents are thought to augment cytotoxic therapy without increasing the side effects. Because some tumors are genetically instable, PARP inhibitors can selectively kill these cells without damaging the normal ones. PARP inhibitors seem to be especially effective for BRCA -related ovarian, as well as breast, cancers. They also seem to have some activity against high grade serous ovarian cancers. There have been several agents developed in this class. 
There are several clinical studies on-going. However, we still have no effective screening tests and these cancers continue to be diagnosed in advanced stages. Perhaps, we also need to spend efforts to develop more valid screening tests rather than just focusing on the cure.
- Amith SR, Wilkinson JM, Baksh S, Fliegel L. The Na⁺/H⁺ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells. Oncotarget. 2014;6(2):1262-75.
- Barreta A, Sarian LO, Ferracini AC, et al. Immunohistochemistry expression of targeted therapies biomarkers in ovarian clear cell and endometrioid carcinomas (type I) and endometriosis. Human Pathology. 2018. doi:10.1016/j.humpath.2018.10.028.
- Weil MK, Chen AP. PARP inhibitor treatment in ovarian and breast cancer. Curr Probl Cancer. 2011;35(1):7-50.
About the Author
Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter @DrLindaMD.