Ovarian cancer

Ovarian cancer is the seventh most common cancer in women. Although it is the third most common gynecological cancer, after cervical and uterine cancer, ovarian cancer has the worst prognosis and the highest mortality rate. The highest incidence is observed in developed countries, including North America and Central and Eastern Europe. Half of all ovarian cancers are diagnosed in women older than 65 years of age. Hormonal and reproductive factors have been associated with an increased risk for the development of ovarian cancer. Early age at menarche and late age at menopause increase the risk, while parity (number of pregnancies) and breastfeeding have a protective effect. The use of oral contraceptives in women in reproductive age also has a protective effect, while the hormone replacement therapy in postmenopausal women has not shown a clear effect in decrease of cancer risk. Obesity has been associated with an increased risk for ovarian cancer in both pre- and post-menopausal women. In addition, a history of pelvic inflammatory disease and ovarian endometriosis (ectopic endometrial tissue in the ovary) increase the risk of ovarian cancer, especially some of its subtypes. One of the most important risk factors is a family history of ovarian, breast, and uterine cancer in the first- or second-degree relatives, and up to 10% of cancers are familial. More than one-fifth of ovarian cancers result from the mutations in BRCA genes, which are responsible for 65-85% of familial ovarian tumors.

Ovarian cancer often does not become symptomatic until the disease has progressed and metastasized. Symptoms can be nonspecific, in the form of lower abdominal pain or symptoms associated with the compression of nearby organs. The level of CA-125 in serum is not recommended as a screening method, as it is not specific for ovarian cancer. Excessive hair growth on several areas of skin (hirsutism) can be associated with hormone production in certain types of ovarian tumors.

Most ovarian cancers (90%) are of epithelial origin (ovarian carcinoma), while germ-cell and sex cord tumors are less common. Ovarian carcinoma is bilateral (involving both ovaries) in one-third to one-half of the cases. Ovarian epithelial cancers are classified depending on histomorphologic features into the serous, mucinous, endometrioid, clear cell, transitional cell, mixed epithelial, and other carcinomas.

Serous carcinoma is the most common form of ovarian carcinoma (up to 75% of ovarian cancer). It is proven to originate in epithelial cells lining the Fallopian tube, especially its fimbria. A two-tier grading system based on nuclear grade divides ovarian serous carcinomas into low- and high-grade carcinomas. Only 5% of ovarian carcinomas are low-grade, while high-grade represent 70%. Low-grade serous carcinomas are composed of small cells with scant cytoplasm and mild to, at most, moderate nuclear atypia. Cells form small or complex papillae, compact nests, small, cystic, or cribriform glands, and solid sheets with slit-like spaces. Small, concentric collections of calcium (Psammoma bodies) are frequent. About half of the cases have mutations in KRAS and BRAF genes. High-grade serous carcinoma is composed of cells with significant nuclear atypia, often with large, bizarre, and multinucleated cells. Cells form solid sheets, branching papillae, and glands (including cribriform structures). Necrosis and mitotic activity are frequent. Mutations in TP53 gene are present in nearly all cases of high-grade ovarian serous carcinoma. Germline, or somatic mutations, or promoter hypermethylation of BRCA1 and BRCA2 genes is present in about half of the cases.

Mucinous carcinoma represents 35% of ovarian carcinomas. In a quarter of the cases, it is a primary tumor, while the rest are metastases from other sites, most often stomach, colon, and pancreas (also known as Krukenberg tumor). It is composed of cells with clear cytoplasm filled with mucin, forming glands, papillae, or solid nests. The grading is not standardized and has no prognostic significance. Mutations in KRAS gene are frequent.

Endommetrioid carcinoma represents 10% of ovarian carcinomas. Up to 15% of such carcinomas are associated with ovarian endometriosis. It is composed of large cells arranged in confluent glands or solid sheets, in less differentiated forms. Squamous metaplasia (morules or keratin pearls) are often found. A three-tiered histologic grading is the same as for endometrioid adenocarcinoma of the endometrium and is based on the percentage of the solid component in the tumor. More than half of the cases are associated with mutations in ARID1A and CTNNB1 genes.

Clear cell carcinoma accounts for around 10% of ovarian carcinomas. Half of the cases are associated with ovarian endometriosis and mutations in ARID1A gene. It is composed of low cuboidal, polyhedral, hobnail, or flattened cells with uniform nuclear atypia, often with clear cytoplasm. Cells grow in papillary, tubulocystic, or solid patterns. There is no grading system, as these carcinomas are considered high-grade by definition.

Diagnosis of ovarian cancer is often based on morphological features. Immunohistochemistry is used for better classification into subtypes, especially in the case of poorly differentiated tumors, as well as for the exclusion of metastatic tumors. Most of the ovarian epithelial tumors show expression of cytokeratin 7 (KRT7) and PAX8. Other markers for differentiation between subtypes of epithelial tumors include WT, hormone receptors (ER, PR), p16, Napsin A, ARID1A. Expression of p53 is observed in several types and is not diagnostic for high-grade serous carcinoma. Even more, three patterns of p53 expression correlate with TP53 mutation. A strong, diffuse nuclear staining in > 80% of cells is associated with a missense mutation. Mutations resulting in loss of function are associated with the complete absence of staining. Cytoplasmic p53 expression with intensity similar to that of internal nuclear controls is associated with loss of function mutation disrupting the nuclear localization domain. Molecular investigation and detection of mutations in BRCA genes have role in the detection of familial cancer in an appropriate clinical context. It also enables the selection of patients for the treatment with PARP inhibitors.

Therapy of ovarian cancer depends on the tumor stage, mainly. Ovarian cancer is typically denoted as silent cancer as symptoms occur late in the course of the disease. By the time of discovery, approximately 70% of the tumors have spread beyond the ovary. In such cases, treatment includes surgery combined with chemotherapy and/or radiation therapy. Prognosis depends on tumor stage, as well. Patients with localized disease have a 5-year survival of 92%, while the survival in the case of distant disease is 30%. Low-grade tumors have a somewhat better prognosis than high-grade tumors. Also, endometrioid carcinoma has the best survival among all epithelial tumors, while the worst survival is present in high-grade serous carcinoma.