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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

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

Epidemiology

Ovarian cancer occurs in more than 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. This means that 1 out of 60 women will develop ovarian cancer in her lifetime.

Unfortunately, most patients present to the health care system in the advanced stages of the disease. The median age of diagnosis is approximately 63, making it a disease common in women who are already experiencing menopause. This is true, however, only for women without genetic mutations that are known to be associated with ovarian cancer. Women with a genetic predisposition to ovarian cancer are usually 10 years younger than typical patients.

Etiology

The cause of ovarian cancer is unknown; however, several environmental and genetic risk factors have been identified.

Women who have not carried a pregnancy to term or who become pregnant after the age of 35 have a higher risk of ovarian cancer.

Endometriosis might increase the risk of ovarian cancer. Additionally, some studies have linked smoking tobacco and human papillomavirus 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.

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 cancer. All patients who have high-grade serous ovarian cancer are expected to have p53 gene abnormalities. Mutations in the p53 gene are thought to be de novo in most 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 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 it is less invasive. Several genes related to DNA repair are also impaired either de novo or due to heredity, including 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 the ovary. The cyst is lined by hobnail cells with clear cytoplasm.” by Amarvinita – Own work. License: CC BY-SA 4.0

When endometriosis is associated with ovarian cancer, it is very likely that the person has a clear-cell ovarian cancer, which shows more differentiated cells. Unfortunately, these patients do not respond well to chemotherapy.

Mucinous ovarian cancer

Mucinous ovarian cancers cause more symptoms and tend to be detected while in stage 1. KRAS mutations are found in all patients with mucinous ovarian cancer.

Risk of Malignancy Assessment in Ovarian Cancer

Many patients with ovarian cancer are diagnosed after the accidental finding of an ovarian cyst on 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

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 should be screened for ovarian cancer by measuring the serum CA-125 concentration. There are no specific symptoms or signs of ovarian cancer and a pelvic ultrasound scan is recommended whenever in doubt.

Patients with a 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 as high as 60%.

Diagnostic Work-up

The first step in the assessment of a patient presenting with an ovarian cyst or with symptoms that could be explained by ovarian cancer is to measure serum CA-125. Cancer antigen-125 is very useful for assessing the risk of malignancy index described above and should always be 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. An abdominopelvic 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 a few patients for staging purposes, but ultrasonography, combined with CA-125 concentration, remains the standard diagnostic modality for ovarian cancer.

Staging of Ovarian Cancer

The international federation of gynecology and obstetrics recently came up with the staging system for ovarian cancer that is related to the management of the condition. Stage 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

Stage II indicates cancer that involves other pelvic organs. IIa is ovarian cancer extending to the fallopian tubes or uterus. Stage IIb disease indicates an extension to other pelvic organs such as the rectum. Stage 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

Stage III indicates an involvement of the abdominal peritoneal surface (IIIa), a tumor that is 2 cm in diameter (IIIb), or a tumor that is larger than 2 cm with lymph node involvement (IIIc).

Stage IV disease indicates distant metastasis, often to the abdomen, liver, and spleen. It can also metastasize to distant organs, such as the skin, lungs, and brain.

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

Surgical Management

Surgery will provide more information for staging, facilitate an excisional biopsy for histopathological assessment, and remove the tumor. The surgery involves hysterectomy, bilateral salpingo-oophorectomy, tumor debulking, and omentum removal. Patients who are confirmed to have stage I disease do not need chemotherapy.
Patients with stage IV disease are not good surgical candidates; however, they might benefit from chemotherapy alone. In these patients, a percutaneous biopsy is indicated to assess the tumor’s histopathological type. Additionally, neoadjuvant chemotherapy may render some of these patients operable.

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

Chemotherapy

Chemotherapy for ovarian cancer includes carboplatin combined with either paclitaxel or docetaxel. Patients with both early-stage and advanced disease have responded to this regimen. 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 increased serum CA-125 concentration, often double the normal upper limit. These patients usually undergo another cycle of chemotherapy because the tumor is more difficult to localize by CT scan; hence, surgical intervention is usually not possible.

Medical Management

Tamoxifen, an estrogen receptor antagonist, is not effective for ovarian cancer regardless of the estrogen receptor state in the tumor. Premenopausal women who undergo bilateral ovary 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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