Ovarian cancer is the leading cause of death from gynecological cancers. Ovarian neoplasms most commonly originate from epithelial cells and thus, about 90% of affected women are diagnosed with epithelial ovarian cancer (EOC). EOC is generally treated by surgery and chemotherapy, but this approach lacks efficacy in case of advanced-stage disease. Unfortunately, non-specific symptoms as well as false-negative serological and imaging findings complicate the early diagnosis of EOC. Mean five-year survival rates are therefore below 50%.
Ovarian cancer is sometimes referred to as "silent killer" and has the reputation of not causing illness or discomfort until advanced stages of the disease. Retrospective surveys, however, have shown that up to 80% of all patients do experience cancer-related symptoms . Unfortunately though, EOC-associated symptoms are frequently seen in the general population, they are explained by common gastrointestinal, genitourinary, and gynecological disorders, and are thus often ignored by patients and physicians . Characteristic yet unspecific symptoms of EOC comprise abdominal or pelvic pain, early satiety, bloating, urinary urgency and pollakisuria . Women may also present with a palpable abdominal mass.
Both hematogenic and lymphogenic spread are regularly observed in EOC patients, but it is even more likely that tumor cells are shed into the peritoneal cavity and implant on the omentum, visceral or parietal peritoneum. Depending on their location, metastases may cause additional symptoms. Advanced-stage EOC may also be associated with constitutional symptoms like fever, night sweats and chills, loss of appetite and weight.
Increased serum concentrations of tumor marker cancer antigen 125 may raise a suspicion of malignancy, but should not be considered an exclusion criterion for ovarian cancer. Indeed, diagnostic imaging is still the most important tool for EOC diagnosis. Imaging studies may either be carried out in symptomatic women or in the scope of surveillance programs, and they may provide valuable hints on the presence of an abdominal neoplasm. Sonography, computed tomography, and magnetic resonance imaging are usually employed to this end. Notwithstanding the usefulness of these techniques, they may lack sensitivity for the detection of early-stage EOC . Concerning characteristic findings, ovarian malignancies often appear as cyst-bearing, heterogeneous lesions .
Tissue samples have to be obtained in order to determine cellular origin, grade and histotype of the tumor. There are four main histotypes of EOC, namely serous, endometrioid, mucinous, and clear cell EOC. They differ with regard to their macroscopic and microscopic appearance, their gene expression, growth behavior and response to therapy. It is beyond the scope of this article to describe the histotypes of EOC in detail and the interested reader is referred to excellent literature available on this topic  . Briefly, the following features are characteristic of serous, endometrioid, mucinous, and clear cell EOC  :
With regard to EOC staging, the so-called FIGO staging system is generally applied. This system considers the following tumor stages  :
In order to realize a complete tumor staging, all features considered in the FIGO staging system have to be checked.
To date, EOC treatment is mainly based on surgery and chemotherapy: Women diagnosed with stage 1 EOC are generally referred for bilateral salpingo-oophorectomy or total abdominal hysterectomy. Those who wish to preserve fertility may possibly opt for unilateral salpingo-oophorectomy, but this approach requires close postoperative monitoring. Cytoreductive surgery is carried out in case of advanced-stage EOC and may be preceded by neoadjuvant chemotherapy. EOC patients should receive chemotherapy after tumor removal or debulking. Standard regimens comprise combination platinum-based chemotherapy with carboplatin and paclitaxel, carboplatin and gemcitabine, or carboplatin and pegylated liposomal doxorubicin. Monotherapy with carboplatin is associated with reduced toxicity and has been proven effective in multiple trials. Finally, monotherapy with paclitaxel, pegylated liposomal doxorubicin, or topotecan is another treatment option .
Cytoreductive surgery plus conventional chemotherapy may cure more than 70% of patients diagnosed with stage 1 or 2 EOC, but less than 20% of those suffering from stage 3 or 4 disease. Unfortunately though, only 25% of all tumors are detected in stages 1 and 2 . Additionally, multimorbid patients are often unfit for surgical interventions, but sole chemotherapy is not curative . Treatment options presented so far may be combined with radiation, immunotherapy and molecular targeted therapy. Genetic analyses should precede the decision for adjuvant chemotherapy with biologics since certain mutations may render the tumor more or less susceptible to certain compounds . Women carrying BRCA1 or BRCA2 mutations, for instance, may benefit from PARP inhibitors. Women who don't carry such mutations should rather receive niraparib .
Prognosis largely depends on tumor grade and stage at the time of diagnosis. For EOC in stages 1 to 4, five-year survival rates have been estimated to 85, 65, 30, and 15% respectively. Stage-independent five-year survival rates range between 35 and 45%, which is due to the fact that most women are diagnosed in advanced stages of the disease .
The etiology of ovarian cancer remains largely unknown. Slight differences regarding epidemiological parameters have been observed between different ethnicities, but few of them allow to infer possible causes of the disease:
The overall incidence of ovarian cancer is approximately 11-12 per 100.000 women in Europe and North America, with 85-90% of all tumors being classified as EOC. The individual risk of EOC increases with age and postmenopausal women account for the majority of patients .
Multiple genetic and epigenetic abnormalities have been detected in EOC. Both the activation of proto-oncogenes as well as the inactivation of tumor suppressor genes may contribute to cancer development, but the latter seems to be more common in EOC. TP53 and PTEN are among the best known tumor suppressor genes involved in EOC pathogenesis, but mutations have also been found in genes OPCML and WWOX, among others. The expression of other genes is altered due to promoter hypermethylation or transcription downregulation. High-grade advanced-stage EOC is characterized by a myriad of gene and chromosomal aberrations, and this fact highlights that genetic stability is decreasing over the course of the disease . There are no universal abnormalities to be found in the majority of EOC - their genetics are as heterogeneous as their radiological and histological appearance.
Few recommendations can be given to prevent the onset of EOC, and none can be provided to avoid sporadic disease. However, members of families affected by ovarian cancer due to hereditary cancer susceptibility may benefit from a personalized risk management. They should be tested for mutations predisposing to EOC and other malignancies. Women who test positive for BRCA1 or BRCA2 mutations, or other genetic defects predisposing to ovarian cancer, should be referred for clinical and radiological surveillance. However, no consensus has been reached about the optimum design of surveillance: Tumors may metastasize before reaching a minimum size for sonographic detection and the serum level of cancer antigen 125 has not been proven to be a reliable marker either. A combined approach based on more sensitive imaging techniques, the inclusion of additional serum biomarkers may yield better results .
Even in the absence of pathological findings, carriers may undergo prophylactic salpingo-oophorectomy, but infertility and premature menopause argue against such an intervention . Maintenance of the ovaries until the age of natural menopause may at least alleviate the symptoms of premature menopause. In this context, recent studies point out that high-grade ovarian cancers often originate from the Fallopian tubes and that sole salpingectomy may pose a valuable alternative to salpingo-oophorectomy: The risk of life-threatening ovary cancer would be reduced, but women wouldn't have to suffer the complications of estrogen deficiency .
There are distinct types of ovarian cancer and they are classified according to the type of cell from which they originate. In this context, ovarian cancer includes epithelial, germ cell, and stromal tumors, among others . Epithelial malignancies are most common and account for about 90% of all cases. They derive from cells on the surface of the ovary. In clinical practice, however, the differentiation of EOC and epithelial tumors arising from the Fallopian tube, foci of endometriosis, or the peritoneum may pose a major challenge .
Although EOC patients are far from asymptomatic, they aren't usually diagnosed with ovarian cancer until advanced stages of the disease . EOC-associated symptoms often resemble those of common gastrointestinal and gynecological disorders, and early-stage EOC is difficult to identify by means of sonography. Still, every effort should be made to identify ovarian neoplasms as early as possible: The tumor stage at the time of diagnosis is the most important prognostic factor. Women who are diagnosed with stage 1 or 2 EOC are likely to survive for more than five years, but mortality is high among those diagnosed with advanced-stage disease . Therapy mainly relies on surgery and adjuvant chemotherapy.
Malignant neoplasms of the ovary may originate from distinct types of cells. Tumors that arise from cells on the surface of the ovary are classified as epithelial ovarian cancer. It is the most common type of ovarian cancer. Affected women may suffer from abdominal or pelvic pain, a premature feeling of fullness, bloating, urinary urgency and frequency for prolonged periods of time before the disease is diagnosed. It is important not to ignore these symptoms although they may just be caused by common gastrointestinal or gynecological disorders. Women who are diagnosed in early stages of the disease have a much better prognosis than those presenting with advanced-stage ovarian cancer.