Ovarian cancer (OC) may correspond to distinct types of malignant ovarian neoplasms. The most common type of OC is epithelial ovarian cancer, which accounts for about 90% of all cases. The course of the disease is characterized by a prolonged period of non-specific, mild to moderate gastrointestinal and genitourinary symptoms, which are often ignored the affected women and their physicians. Accordingly, the majority of patients is diagnosed with advanced-stage OC, when distant metastases have formed. Metastatic OC is associated with a poor prognosis, and every possible effort should be made to facilitate the early detection of ovarian malignancies.
The clinical presentation does neither allow for the diagnosis of OC, nor the identification of the specific type of neoplasm. What's more, women may be diagnosed incidentally when suspicious findings are noted on preventive examination or imaging. This is due to most patients being free of symptoms for prolonged periods of time.
Symptomatic patients present with non-specific complaints, which are mostly of insidious onset. Women may claim pain in the lower abdomen or pelvic region, and constitutional symptoms such as fever, night sweats, chills, loss of appetite and weight may be reported. Functional OC may induce distinct symptoms, depending on its endocrine profile, the patient’s age and reproductive status. Menstrual disorders and irregular uterine bleeding are the most common .
Furthermore, ovarian neoplasms may displace or exert pressure on adjacent structures, thereby provoking digestive disorders and changes in the urinary frequency. Gastrointestinal, genitourinary, and gynecological symptoms may also be produced by metastatic OC. Tumor cells shed from the ovarian surface tend to implant on the serous membranes lining the peritoneal cavity, and additional mass lesions may become palpable. Ascites may occur with metastatic OC or may be present earlier .
About 70% of OC patients are only diagnosed when metastases have formed in the upper abdomen or beyond the abdominal cavity. Yet, retrospective studies have shown that most women do present symptoms long before reaching this stage of the disease . It is thus of utmost importance to determine the cause of persistent abdominal or pelvic pain, nausea, early satiety, bloating, urinary urgency, and pollakisuria .
The patient's medical and family history provide the backbone of OC diagnosis. When obtaining information regarding the occurrence of cancer in family members, it should be kept in mind that those mutations associated with hereditary OC may also predispose to breast cancer, prostate cancer, pancreatic cancer, and melanoma . Notwithstanding, the international standard of care is to offer genetic testing to all women in whom OC is diagnosed, regardless of age, medical and family history .
Sonography is the methods of choice to assess ovarian lesions, and it may be complemented by more sophisticated imaging techniques such as computed tomography and magnetic resonance imaging. Diagnostic imaging not only allows for the evaluation of the ovaries but also the fallopian tubes, uterus, adjacent tissues, lymph nodes, and distant organs. It should be kept in mind that the sensitivity of imaging techniques may be insufficient for the detection of early-stage OC. Concurrent measurements of tumor markers may support the tentative diagnosis of OC, with common panels including cancer antigen 125, carcinoembryonic antigen, and carbohydrate antigen 19-9 .
Finally, tissue samples have to be obtained to confirm the diagnosis, to determine the tumor's cellular origin, grade, and histotype. Core biopsy specimens are preferred to this end, but fine-needle aspiration samples from mass lesions or ascitic fluid may be used if the former are not feasible .
The FIGO staging system is applied to determine the patient's prognosis and to allow for a well-founded decision regarding treatment strategies :
Stage 0: Tumor in situ
Stage 1: OC involves one (1A) or both (1B) ovaries, whose capsule remains intact. There are no tumor cells on the ovarian surface, and peritoneal washings yield negative results. If the capsule is raptured or tumor cells are detected on the ovarian surface or washings are positive, stage 1C has been reached.
Stage 2: Pelvic extension can be confirmed. Metastases have formed in the uterus or fallopian tubes (2A) or other pelvic structures (2B). Positive peritoneal washings warrant the diagnosis of OC stage 2C.
Stage 3: Peritoneal implants are detected outside the pelvis and/or regional lymph nodes are involved. Stages 3A, 3B, and 3C are assigned according to the size of peritoneal metastases.
Stage 4: Distant metastases other than peritoneal metastases are detected, or the patient is found to suffer from malignant pleural effusion.
Laparoscopic assessment may be necessary to define the stage of OC and to determine whether primary resection is feasible.
Debulking surgery, performed as bilateral salpingo-oophorectomy or total hysterectomy, has long since been the foundation of OC management. Unilateral salpingo-oophorectomy may be considered in women who wish to preserve fertility but should be carefully weighed against the risks of recurrence. In any case, surgery aims at the complete resection of degenerated tissues, which is associated with the best outcomes. Subsequently, patients are referred for chemotherapy with carboplatin and paclitaxel. These drugs are administered intravenously every 3 weeks. Paclitaxel may be replaced by pegylated liposomal doxorubicin if taxane-free regimens are required. By derogation to the aforedescribed standard procedure of surgery plus adjuvant chemotherapy, patients may benefit from neoadjuvant chemotherapy if the complete resection of neoplasms cannot be achieved by up-front surgery .
In recent years, biological agents have increasingly been used to complement the therapy of OC:
Most patients will achieve remission, but many will eventually experience a recurrence of OC. In order to reduce the risk of relapses, maintenance therapies are often incorporated into the therapeutic paradigm. Maintenance strategies comprise the single use of bevacizumab or PARP inhibitors, although no guidelines have yet been established to this end. As a general rule, patients with poor prognostic factors are most likely to benefit from maintenance .
The lack of a premalignant phase and effective strategies for early detection combined with the non-specific presentation of the disease result in detrimental diagnostic delays. Most patients are diagnosed with advanced-stage OC, which is associated with a poor prognosis. The overall five-year survival rate has been estimated at 44% for all stages - the worst prognosis among all types of gynecological malignancies . Favorable outcomes are mainly observed when the tumor is detected during early stages of the disease.
The precise causes of OC remain largely unknown and most likely comprise a series of environmental and genetic factors. Concerning the former, estrogen replacement therapy has repeatedly been shown to augment the risk of OC in postmenopausal women, while the prolonged reduction of estrogen levels, namely during pregnancy or under oral contraceptives, is ascribed a protective role in OC. These facts argue in favor of a role of ovulation in the etiology of ovarian malignancies, and it has been hypothesized that repeated damage and trauma to the ovarian epithelium during ovulatory cycles may increase the likelihood of mutations and malignant degeneration . Beyond that, obesity, smoking, and the genital use of talcum powder may predispose to OC .
Strong genetic influences are most easily recognized in patients suffering from family cancer syndromes such as BRCA-associated hereditary breast and ovarian cancer syndrome, whose lifetime risk of developing malignancies of the ovaries may be as high as 63% . Other hereditary conditions predisposing to OC include Lynch syndrome, Li-Fraumeni syndrome, and mutations in genes like CHEK2, RAD51C, RAD51D, BRIP1, BARD1, PALB2, MRE11, MLH1, PMS2, MSH2, MSH6, and NBN  . In sum, about 20% of OC cases can be related to genetic factors, and three-quarters of these patients carry mutations in the BRCA1 or BRCA2 genes .
OC accounts for about 30% of all malignancies of the female genital system and is the leading cause of death from gynecological cancers. In Western Europe and North America, where age-adjusted incidence rates are highest, 90% of affected women are diagnosed with epithelial OC. Higher shares of germ cell tumors are reported in some Asian countries .
In general, the individual risk of developing OC increases with age, and the mean age at the time of diagnosis is 62 years . Notwithstanding, some types of OC preferentially affect younger patients: Germ cell OC tends to occur in teenage girls and young women, and patients developing OC due to hereditary conditions are typically diagnosed in their fourth or fifth decade of life .
The pathogenesis of OC is a complex process that has yet to be fully explored. It certainly involves host genetic factors, which serve as a basis for the interplay of hormones, inflammatory mediators, and environmental influences . According to the hypothesis of incessant ovulation, as mentioned above, repetitive injury to the ovarian surface epithelium may predispose to inflammation and is associated with changes in hormone levels, thereby leading to oxidative stress and DNA damage. Then again, epithelium harboring unresolved DNA damage would represent a prime target for neoplastic transformation. This hypothesis has not been unchallenged, though: High-grade serous ovarian carcinoma, the most common type of OC, may not even arise from the ovarian surface epithelium. Fallopian tube secretory cells have been identified as their cells of origin, and they are not subjected to the repetitive trauma associated with ovulation .
These observations allow for the following conclusions:
High parity and the prolonged use of oral contraceptives are generally associated with reduced risks of developing epithelial OC . The use of genital talcum powder should be avoided, and medical conditions that may predispose to OC, such as endometriosis and pelvic inflammatory disease, should be treated accordingly .
Moreover, the risk of OC can be substantially reduced by bilateral oophorectomy . While this procedure is not routinely carried out, it should seriously be considered in patients known to carry gene defects that are associated with a very high lifetime risk of ovarian malignancies. Alternatively, these women should be included in surveillance programs comprising regular clinical examinations, laboratory analyses for tumor markers, and diagnostic imaging. Such ovarian cancer screenings should be carried out from the age of 35, and all patients should be informed about its limitations: As implied above, the sensitivity of available techniques for detecting early-stage OC may be non-satisfactory .
The current classification of the World Health Organization considers a large number of OC types. There are five main groups of ovarian neoplasms, namely surface epithelial-stromal tumors, sex cord-stromal tumors, germ cell tumors, tumors of the rete ovarii, and miscellaneous tumors. Each group comprises multiple subtypes of neoplasias, which differ with regards to their tissue of origin, histological features, and malignant potential. Additionally, lymphoid and hematopoietic tumors may affect the ovaries . It is beyond the scope of this article to provide a detailed description of all types of OC, which is why it will focus on the general aspects of the more common variants of ovarian malignancies.
Malignant ovarian neoplasm refers to any type of ovarian cancer, a rather common disease in industrialized nations. Women suffering from ovarian cancer may be asymptomatic for prolonged periods of time, or they may experience non-specific gastrointestinal and genitourinary complaints. Lower abdominal or pelvic pain, nausea, early satiety, bloating, and changes in the urinary frequency are most common. In case of persistent discomfort, it is paramount to clarify the causes of these symptoms: If patients are during the early stages of the disease, their prognosis is significantly better than that of women with advanced-stage ovarian cancer. Indeed, the outcome of metastatic ovarian cancer is generally poor.