Ovarian cancer is of epithelial origin in 60% of the patients. Most patients present at an advanced stage due to the lack of specific symptoms except for mucinous ovarian cancer where abdominal distension is so severe that patients present very early in the disease. Once the diagnosis is suspected, the patient usually undergoes a transvaginal ultrasonography, abdomen-pelvic CT scan and CA-125 concentration measurement. If an ovarian cyst or mass is identified, its characteristics should be noted and a risk of malignancy index can be calculated. Treatment involves neoadjuvant platinum-based chemotherapy with or without surgery.

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ct image of ovarian cancer

Image: “An ovarian cancer as seen on CT.” by James Heilman, MD – Own work. License: CC BY-SA 3.0


Definition and Epidemiology of Ovarian Cancer

Ovarian cancer can be defined as a primary malignancy of the ovaries that is usually of epithelial origin. Rarer forms of ovarian cancer include germ cell, sex cord and stromal tumors.

Ovarian cancer occurs in 22,500 women per year in the United States and is responsible for 14,000 deaths annually. The incidence of ovarian cancer is 9.4 per 100,000. Such a high incidence means that 1 out of 60 women is expected to develop ovarian cancer in their lifetime.

Unfortunately, the majority of the patients present late to the health care system. The median age of diagnosis is estimated to be 63 years making it a disease of menopause women. This is true, however, only for women without genetic mutations that are known to be associated with ovarian cancer. Women with genetic predisposition are usually 10 years younger than your typical patient.

Multiple pregnancies and the use of oral contraceptive pills are known to result in more anovulatory cycles which is believed to lower the risk of ovarian cancer.

Endometriosis might increase the risk of ovarian cancer. Additionally, tobacco smoking and human papilloma virus have been linked to an increased risk of ovarian cancer in some studies.

Several genetic mutations have been linked to different types of epithelial ovarian cancers. For instance, high-grade serous cancers are found more commonly in women with BRCA1 and 2 mutations. KRAS mutations are linked to an increased risk of mucinous ovarian cancers while PTEN mutations might increase the risk of endometrioid and clear cell cancer.

Etiology of Ovarian Cancer

Ovarian cancer is usually of unknown cause but several environmental and genetic risk factors have been identified. Tobacco smoking, history of human papilloma virus infection, and being nulliparous are thought to increase the risk of ovarian cancer significantly.

Genetic mutations in BRCA1/2, KRAS, PTEN or other less common genes are associated with primary ovarian cancer that is known to occur in younger patients compared to the general population. Peutz-Jegher disorder, a genetic disease associated with different forms of cancer, also increases the risk of ovarian cancer.

Pathophysiology of Ovarian Cancer

In almost all forms of ovarian cancer, impaired DNA repair is implicated in the pathogenesis. To understand the different pathological changes happening in ovarian cancer, we should classify epithelial ovarian cancers according to their histological patterns.

High-grade serous ovarian cancer

High-grade serous ovarian cancer is the most common form of epithelial ovarian cancers. All patients who have a high-grade serous ovarian cancer are expected to have abnormalities in the p53 gene. Mutations in the p53 gene are thought to be de novo in the majority of the cases, but BRCA1 and BRCA2 mutations are also known to cause high-grade serous ovarian cancer.

This type of ovarian cancer is the least differentiated and is the most malignant. High-grade serous ovarian cancer is sensitive to chemotherapy.

Low-grade serous ovarian cancer

This type of ovarian cancer is not as common as high-grade serous ovarian cancer but is known to behave less invasively. Several genes related to DNA repair are also impaired either de novo or due to hereditary and they include PI3KCA, BRAF and KRAS. These tumors are less responsive to chemotherapy.

Clear-cell ovarian cancer

high magnification of tubulocystic clear-cell carcinoma of ovary

Image: “High magnification of tubulocystic clear-cell carcinoma of ovary. Cyst is lined by hobnail cells with clear cytoplasm.” by Amarvinita – Own work. License: CC BY-SA 4.0

Endometriosis, when associated with ovarian cancer, is thought to coincide most commonly with clear-cell ovarian cancer. This form of ovarian cancer shows more differentiated cells. Unfortunately, these patients do not respond well to chemotherapy.

Mucinous ovarian cancer

Fortunately, mucinous ovarian cancers cause more symptoms and are the earliest to be detected while in stage 1 disease. KRAS mutations are found in all patients with mucinous ovarian cancer.

Risk of Malignancy Assessment in Ovarian Cancer

Many of the patients with ovarian cancer present with the incidental finding of an ovarian cyst on an ultrasonography that was ordered for other indications. Therefore, it is essential to differentiate between malignant and benign ovarian cysts.

Table 1 shows how to calculate the risk of malignancy index (RMI) for a patient with an ovarian cyst.

Parameter Scoring Scheme Notes
Ultrasonography of the ovarian cyst Multilocular or solid: 0 or 1

Ascites: 0 or 1

Suspected metastasis: 0 or 1

0 is NO while 1 is YES. Total score ranges from 1 to 3
Menopausal state Premenopause: 1

Postmenopause: 3

This score is multiplied by the previous score.
CA-125 serum concentration Numerical value This value is multiplied by the previous product of multiplication.

Table 1: RMI = Ultrasonography Score X Menopausal Score X CA-125 Concentration. When RMI > 200, the risk of ovarian cancer is high.

Clinical Presentation and Diagnostic Work-up of Ovarian Cancer

The most common presentation of ovarian cancer is abdominal pain and distension. The picture can highly resemble that of irritable bowel syndrome and accordingly any woman who presents with irritable bowel syndrome symptoms after the age of 50 years should be screened for ovarian cancer by measuring serum CA-125 concentration. Unfortunately, there are no specific symptoms or signs of ovarian cancer and a pelvic ultrasound scan is recommended whenever in doubt.

Patients with known family history of ovarian or breast cancer should be screened for BRCA1 or 2 mutations. The risk of ovarian cancer in this population is really high as up to 60% of these women will develop the disease.

The first step in the assessment of a patient presenting with an ovarian cyst or with symptoms that could be explained by an ovarian cancer is to measure serum CA-125. Cancer antigen-125 is very useful in the assessment of the risk of malignancy index described above and should be always measured in these patients.

Transabdominal ultrasonography is indicated to assess for possible metastasis while pelvic transvaginal ultrasound should be used to assess ovarian cysts and suspicious lesions.

Abdomino-pelvic computerized tomography (CT) scan is indicated when malignancy is suspected to assess other organ involvement and for staging purposes. Abdominal magnetic resonance imaging (MRI) is indicated in few patients also for staging purposes but ultrasonography combined with CA-125 concentration remain the best diagnostic modality for ovarian cancer.

Staging of Ovarian Cancer

The international federation of gynecology and obstetrics has put a recent staging system for ovarian cancer that is very relatable to the management. Disease I indicates cancer that is limited to the ovaries which can be unilateral Ia, bilateral Ib, or unilateral or bilateral but associated with ascites, Ic.

diagram showing stage 1 ovarian cancer

Image: “Diagram showing stage 1 ovarian cancer.” by Cancer Research UK – Original email from CRUK. License: CC BY-SA 4.0

Disease II indicates cancer that involves other pelvic organs. IIa is ovarian cancer extending to the fallopian tubes or uterus. IIb disease indicates extension to other pelvic organs such as the rectum. IIc includes IIa or IIb disease with ascites.

diagram showing stage 2 ovarian cancer

Image: “Diagram showing stage 2 ovarian cancer.” by Cancer Research UK – Original email from CRUK. License: CC BY-SA 4.0

Disease III indicates involvement of the abdominal peritoneal surface IIIa, a tumor that is 2 cm in diameter IIIb, or a tumor that is above 2 cm with lymph node involvement IIIc. Disease IV disease indicates distant metastasis.

diagram showing stage 3 ovarian cancer

Image: “Diagram showing stage 3 ovarian cancer.” by Cancer Research UK – Original email from CRUK. License: CC BY-SA 4.0

Treatment of Ovarian Cancer

The purpose of the surgery is to provide more information for staging, provide an excisional biopsy for histopathological assessment and to remove the tumor. The surgery involves hysterectomy, bilateral salpingo-oophorectomy, tumor debulking, and removal of the omentum. Patients who are confirmed to have stage I disease do not need chemotherapy.

Patients with stage IV disease are not good surgical candidates and they might benefit from chemotherapy alone. In these patients, percutaneous biopsy is indicated to assess the histopathological type of the tumor. Additionally, neoadjuvant chemotherapy may render some of these patients operable.

Premenopausal women with stage Ia disease that are confirmed to have a low-grade serous cancer or a mucinous tumor might benefit from unilateral oophorectomy to preserve fertility.

Chemotherapy for ovarian cancer includes carboplatin combined with either paclitaxel or docetaxel. This regimen has been found to be successful for patients with early stage disease and advanced disease. Newer treatments are emerging for ovarian cancer such as the antiangiogenic antivascular endothelial growth factor bevacizumab and pazopanib.

Patients with recurrent disease are identified by an increase in their CA-125 concentration, double the normal upper limit. These patients usually undergo another cycle of chemotherapy as the tumor is more difficult to localize by CT scan, hence surgical intervention is usually not possible.

Tamoxifen, an estrogen receptor antagonist, is not useful in ovarian cancer regardless of the estrogen receptor state in the tumor. Premenopausal women who undergo bilateral ovarian removal need estrogen based hormonal replacement therapy. Postmenopausal women who also have a hysterectomy can have an estrogen only replacement therapy, otherwise estrogen should be used with caution due to the increased risk of endometrial cancer in these women.

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