The term ovarian cancer is used to describe a heterogeneous group of malignant tumors found in the ovary (there is also a wide assortment of benign tumors derived from the ovary). Ovarian cancer is the most lethal gynecological cancer in industrialized countries, and is the sixth leading cause of cancer deaths in women worldwide. Ovarian cancer typically occurs in peri- and postmenopausal women, with an average of 54 years at diagnosis. Histologically, ovarian cancer is complex but can be broadly divided into epithelial ovarian cancer, which accounts for up to 90% of all the ovarian malignancies, and non-epithelial tumors (Sex-Cord Stromal Tumors and Ovarian Germ Cell Tumors). Epithelial ovarian tumors have been assumed to be derived from the ovarian surface epithelium, but new evidence suggest that some of these tumors may actually originate from extraovarian tissues, such as the fallopian tube epithelium and endometrial tissue.
See also Epithelial ovarian cancer, synonym ovarian carcinoma, can be divided according to histological appearance (Ovarian Cancer Pathology):
See also Ovarian serous carcinoma, the most common type (composed of epithelium resembling that of fallopian tubes)
See also Endometrioid carcinoma (composed of epithelium resembling that of the endometrium)
See also Ovarian clear cell carcinoma (composed of clear cell epithelium and resembling gestational endometrium)
Transitional cell tumors (composed of epithelium resembling urothelial cells)
See also Ovarian mucinous carcinoma (composed of epithelium resembling that of the endocervix)
Squamous cell (squamous epithelial cells)
Mixed epithelial tumor (mixture of two or more of the above subtypes)
Undifferentiated (no recognizable differentiation features)
Some epithelial tumors (especially serous tumors) can develop as borderline tumor or low malignant potential (LMP) tumor that exhibit an absence of stromal invasion and a much better prognosis.
Non-epithelial tumors are much rarer, highly heterogeneous and include the following groups:
See also Sex-cord stromal tumors (Granulosa Cell Tumors, Thecoma/fibroma tumors, Sertoli stromal cell tumors, Sertoli-Leydig Cell Tumor)
See also Ovarian germ cell tumors (Dysgerminoma, yolk sac tumors, choriocarcinoma, gonadoblastoma)
There is now strong pathological and genetic evidence suggesting that high-grade ovarian carcinoma may actually originate from the fallopian tube epithelium, instead of the ovarian surface epithelium, as was previously believed. A fallopian tube lesion known as serous tubal intraepithelial carcinoma (STIC) has been suggested as a possible precursor to high-grade serous epithelial ovarian cancer. This precursor may have the ability to implant to the ovary to give rise to serous ovarian cancer. Similarly, low-grade clear cell and endometrioid ovarian carcinoma may originate through implantation of endometrial tissues present in the ovary following retrograde menstruation. Therefore, a significant portion of what we refer to epithelial ovarian cancer would be extraovarian in origin.
Grading of epithelial ovarian cancer is based on degree of differentiation, cytologic atypia and mitotic index. Ovarian cancer is staged according to the following International Federation of Gynecology and Obstetrics (FIGO) guidelines.
Stage I: restricted to the ovaries
Stage II: involvement of ovaries and pelvic extension
Stage III: involvement of ovaries with peritoneal implants outside the pelvis
Stage IV: involvement of ovaries with distant metastasis, such as liver, lung, or brain
The age-adjusted incidence for ovarian cancer is approximately 15 per 100,000 and the total number of cases is expected to increase as the overall population ages (Ovarian Cancer Epidemiology).
Ovarian cancer is a disease for which early detection represents an intervention of choice in reducing morbidity. Several putative ovarian cancer serological markers have been identified, including CA125, TATI, CEA, mesothelin, and HE4. Of those, CA125 has proven to be the most clinically useful, as it has been used to monitor recurrence in patients with CA125-positive tumors. Unfortunately, CA125 is associated with a high false positive rate among patients with benign gynecological conditions and has very low sensitivity for the detection of stage I disease. Overall, CA125 lacks the specificity and sensitivity required for the screening of the general population, but it has been suggested that CA125 in combination with other markers or other approaches may someday become useful in the detection of ovarian cancer. An intense area of ovarian cancer research has focused on the identification of novel biomarkers for the early detection of this disease.
The etiology of ovarian cancer is not well understood but the following risk factors have been identified:
Age: half the cases occur in women of 65 and older.
Lifetime ovulation history: ovarian cancer risk increases with increasing numbers of menstrual cycles. This is known as the incessant ovulation theory of ovarian cancer.
Oral contraceptive pill: use for at least 5 years lowers the risk of ovarian cancer.
Pregnancy: up to 40% reduction in ovarian cancer risk with the first term pregnancy and a further 10–15% reduction for each successive term pregnancies.
Hysterectomy and tubal ligation: these procedures have been reported to reduce the risk of ovarian cancer by 40–80%.
While approximately 90% of ovarian cancers are sporadic, 10% are found in women with a family history of ovarian cancer and are therefore considered to be hereditary. These hereditary cases are due to germline mutations in cancer susceptibility genes. There are two main manifestations of hereditary ovarian cancer: the breast/ovarian cancer syndrome, which account for up to 90% of the familial cases, and the hereditary nonpolyposis colorectal cancer syndrome (HNPCC; Lynch syndrome). The breast and ovarian cancer syndrome is caused by mutations in BRCA1 or BRCA2 (BRCA1/BRCA2 Germline Mutations and Breast Cancer Risk), while HNPCC is due to mutations in genes of the mismatch repair system.
The molecular mechanisms leading to ovarian cancer are not clearly established and appear to be different for different subtypes of ovarian cancers. For epithelial ovarian cancer, a two-pathway model was recently suggested, that proposes that low-grade and high-grade ovarian carcinomas arise through two different and mostly independent pathways (Fig. 1). Type I tumors, which mostly include low-grade cancers, are typically genetically stable and rarely exhibit TP53 mutations. These tumors are typically indolent and have a favorable prognosis. Type II tumors include the conventional high-grade serous ovarian carcinoma, the most common and lethal ovarian cancer. Type II tumors are genetically unstable and have poor prognosis. In terms of molecular changes, type I tumors frequently exhibit mutations in several oncogenes. For example KRAS, BRAF1, and ERBB2 (HER2/neu), are mutated in low-grade serous carcinoma, CTNNB1, PTEN, and PIK3CA in low-grade endometrioid, KRAS in mucinous, and PIK3CA and ARID1A in clear cell carcinomas. All these type I tumors rarely exhibit TP53 alterations. High-grade ovarian cancer rarely show mutation in these genes, but have a high frequency of TP53 mutations and frequent amplification of CCNE1 (encoding cyclin E1).
Overall, ovarian cancer prognosis is poor. In spite of aggressive treatments, 5-year survival rates for patients with advanced ovarian cancer (Stage III and IV) have remained low and ranges between 5% and 30%. However, the outcome is much more favorable for stage I patients where 5-year survival can reach 90–95%. Unfortunately, because the symptoms are subtle in early-stage ovarian cancer, the vast majority of patients (over 75%) are diagnosed as stage III-IV. By that time, the tumor growth causes the compression of pelvic structures, leading to symptoms such as increased urinary frequency, constipation, pelvic discomfort, and painful sexual intercourse. If undiagnosed, the tumor can increase to a size of 15 cm, leading to a noticeable abdominal enlargement.
The most significant prognostic indicators are the extent of disease at diagnosis (stage) and the degree of abnormality (grade) of the tumor. Typically, treatment for advanced ovarian cancer consists of surgical cytoreduction (Debulking Surgery) followed by ovarian cancer chemotherapy. The rare patients with early-stage ovarian cancer may not require chemotherapy. In advanced disease, the amount of residual disease following surgery is a prognostic indicator. Chemotherapy almost always consists of a combination of platinum complexes (most often carboplatin) and paclitaxel.
Unfortunately, approximately half of the ovarian cancer patients have tumors that are intrinsically resistant to these drugs (Ovarian Cancer Chemoresistance) and, among the women with tumor that are initially sensitive, a large number will develop resistance (acquired drug resistance). The mechanisms of drug resistance are not well understood, but in the case of platinum, may include the downregulation of CTR1, a copper transporter which appears to also transport platinum compounds into the cells. Changes in DNA repair pathways have also been implicated in platinum resistance. In any case, the problem of drug resistance has led to significant efforts in the field to gain a better understanding of the mechanisms of drug resistance and to develop new targeted therapies for ovarian cancer. For example, bevacizumab, a recombinant monoclonal antibody that targets vascular endothelial growth factor (VEGF), has been shown to prolong progression-free survival when added to conventional chemotherapy.
The next few years will likely lead to significant changes in our understanding of ovarian cancer as we continue to elucidate the mechanisms of cancer initiation and progression. In particular, a better understanding of the early events in ovarian tumorigenesis, including identification of the exact tissue(s) of origin, will likely lead to new approaches for the detection and therapy of this disease.
See also Early-Stage Ovarian Cancer; Granulosa Cell Tumors; Optimal Treatment for Women with Ovarian Cancer; Ovarian Cancer Chemoresistance; Ovarian Cancer Chemotherapy; Ovarian Cancer Clinical Oncology; Ovarian Cancer Drug Resistance; Ovarian Cancer Epidemiology; Ovarian Cancer Hormonal Therapy; Ovarian Cancer Immunotherapy; Ovarian Cancer Pathology; Ovarian Stromal and Germ Cell Tumors; Ovarian Tumors During Childhood and Adolescence
22.1 Introduction Since the 1970s, management of advanced ovarian cancer was largely improved through the succession of both an extensive debulking s
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