Summary
Ovarian cancer is the most deadly gynecological neoplasm in the United States. Risk factors for developing ovarian cancer include genetic predisposition (e.g., BRCA1/BRCA2 mutation) and hormonal factors (e.g., increased number of lifetime ovulations). The ovaries consist of different types of tissue (epithelial, germ cells, and sex cord tissue), which may give rise to benign or malignant tumors. Symptoms depend on the type of tissue affected and range from local abdominal discomfort to endocrinological phenomena caused by hormone-producing tumors. Metastases of other tumors and lymphomas may also affect the ovaries. The most common malignant tumor of the ovaries is serous ovarian cancer, which primarily affects older women (median age of diagnosis is 63 years). The lack of early symptoms of ovarian cancer often delays diagnosis, resulting in an unfavorable prognosis. Ovarian cancers primarily metastasize intraperitoneally and later become noticeable mostly due to increasing abdominal girth caused by malignancy-related ascites. Treatment generally involves radical surgical removal of the tumor and chemotherapy.
Epidemiology
- Ovarian tumors are the most common ovarian mass in women > 55 years of age.
- Lifetime prevalence of malignant ovarian cancer: 1–2% [1]
- Ovarian cancer is the second most common gynecological cancer (after endometrial cancer) but causes the most deaths (with endometrial cancer causing the second most). [2]
- Median age at diagnosis of ovarian cancer: 63 years [1][3]
- Incidence rates highest in non-Hispanic white women [4]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
Risk factors [5]
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General
- Age: Incidence of ovarian cancer increases with age. [6]
- Asbestos [7]
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Genetic predisposition
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BRCA1/BRCA2 mutation [3]
- The lifetime risk of developing ovarian cancer is up to 44% for BRCA1-positive women and 17% for BRCA2-positive women.
- Positive family history and/or the occurrence of breast cancer at a younger age (i.e., < 30 years) increase the likelihood of carrying a mutation in these genes.
- HNPCC syndrome: The lifetime risk of developing ovarian cancer is ∼ 10%. [8]
- Family history
- Peutz-Jeghers syndrome [9]
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BRCA1/BRCA2 mutation [3]
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Hormonal factors
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Elevated number of lifetime ovulations ; [5]
- Infertility/low number of pregnancies [5][10]
- Early menarche; and late menopause [5][11]
- Endometriosis [12]
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Elevated number of lifetime ovulations ; [5]
Protective factors
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Surgical intervention
- Bilateral salpingo-oophorectomy [13]
- Hysterectomy [14]
- Tubal ligation [15]
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Hormonal factors
- Oral contraceptives [16]
- Breastfeeding [17]
- Parity [11]
Overview of ovarian tumors
Classification of ovarian tumors
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Epithelial ovarian tumors
- Arise from ovarian surface epithelium
- Most commonly benign
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Germ cell ovarian tumors
- Arise from the primordial germ cells (e.g., oocytes)
- Can be benign or malignant
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Subtypes are determined by structural differentiation
- Extraembryonic differentiation: yolk sac tumor
- Somatic differentiation: teratoma
- No differentiation: dysgerminoma
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Sex cord and stromal ovarian tumors
- Arise from sex cord cells (e.g., Sertoli or granulosa cells) or stromal cells (e.g., fibroblasts or primitive gonadal stroma)
- May be benign or malignant
Epithelial ovarian tumors [18][19]
-
Histological classification
- Benign: lack hyperproliferative and invasive behavior
- Borderline ovarian tumors: a histopathological term that describes an ovarian tumor of low malignant potential that expresses cytologic features of malignancy without frank invasion
- Malignant: evidence of invasion
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Clinicopathological classification [20]
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Type I ovarian tumors: low-grade, indolent tumors that typically manifest as large, unilateral, cystic neoplasms
- Histologic subtypes include low-grade serous, endometrioid, clear cell, mucinous carcinomas, and malignant Brenner tumors
- Account for ∼ 10% of ovarian cancer deaths
- Associated with low levels of chromosomal instability
- p53 mutations are uncommon.
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Type II ovarian tumors: high-grade, aggressive tumors that typically involve both ovaries and are diagnosed at an advanced stage
- Histologic subtypes include high-grade serous, carcinosarcoma, and undifferentiated carcinoma
- Account for ∼ 90% of ovarian cancer deaths
- Associated with high levels of chromosomal instability
- p53 mutations are common
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Type I ovarian tumors: low-grade, indolent tumors that typically manifest as large, unilateral, cystic neoplasms
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Frequency [4]
- Most common benign and malignant ovarian tumor subtype
- Epithelial tumors account for ∼ 90% of all ovarian malignancies
Types of epithelial ovarian tumors | ||||||||
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Type | Cystadenoma | Brenner tumor [21] | Cystadenocarcinoma | Endometrioid carcinoma [4][22] | Clear cell tumors [4][23] | |||
Ovarian serous cystadenoma | Ovarian mucinous cystadenoma | Serous | Mucinous [24] | |||||
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Pathology | Gross examination |
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Histology |
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Tumor marker |
CA-125 is used as a tumor marker for epithelial ovarian cancer but can also be elevated in endometriosis, cirrhosis, and malignancies (e.g., uterine leiomyoma).
Most ovarian tumors are benign, not malignant.
Ovarian germ cell tumors [18]
- Frequency: ∼ 5% of all ovarian tumors [4]
Types of ovarian germ cell tumors | ||||||
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Type | Teratoma | Yolk sac tumor of the ovary (endodermal sinus tumor) [26] | Dysgerminoma [27] | Nongestational choriocarcinoma [28] | ||
Dermoid cysts (mature cystic teratoma) | Struma ovarii (mature teratoma) [29] | Immature teratoma [30] | ||||
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Sex cord-stromal tumors of the ovary [18]
- Frequency: < 5% of all ovarian tumors [40]
Types of sex cord-stromal tumors of the ovary | |||||
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Type | Ovarian fibroma [41] | Theca cell tumor (thecoma) [42] | Sertoli-Leydig cell tumor [43][44][45][46] | Granulosa cell tumor [43][47][48] | |
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Pathology | Gross examination |
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Call-Exner bodies are characteristic of Granulosa cell tumors: “Call your Ex and Grandparents!”
Subtypes and variants
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Krukenberg tumor: secondary ovarian tumor that most commonly arises from metastatic spread of gastric carcinoma ; [51]
- Often bilateral
- Characteristic mucin-secreting signet ring cells on histology
- The exact route of metastatic spread (i.e., lymphatic, hematogenous, or peritoneal) is still debated.
Clinical features
Overview [52][53]
- Traditionally, ovarian cancer was considered an asymptomatic “silent killer.”
- However, up to ∼ 90% of patients do present with symptoms before diagnosis. [52][54]
Subacute symptoms [53][54]
Ovarian cancer most commonly manifests with subacute symptoms, which occur in women with early-stage disease. These symptoms are nonspecific and often difficult to attribute to ovarian cancer.
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Adnexal mass
- Can be asymptomatic
- Often found on routine pelvic examination or imaging
- Pelvic and abdominal symptoms
- Abnormal bleeding [55]
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Paraneoplastic syndromes [56]
- Polyneuritis
- Cerebellar degeneration
- Dermatomyositis
- Hemolytic anemia
Acute presentations and symptoms of metastatic disease [53]
Acute symptoms typically occur in patients with advanced disease and are an indication for immediate evaluation and treatment.
- Extrapelvic symptoms
- Hematologic complications: venous thromboembolism [57]
- Intrapelvic symptoms: ovarian torsion
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Metastatic dissemination [58]
- Liver: nausea, jaundice, ascites (see “Metastatic liver disease”)
- Brain: headaches, seizures, focal motor deficits (see “Brain metastases”)
- Omentum: omental caking (i.e., disease infiltration of omental fat) resulting in abdominal pain
- Distant lymph nodes: supraclavicular or inguinal lymphadenopathy
The first symptom of ovarian cancer is often increasing abdominal girth (clothes no longer fit at the waist).
Diagnostics
Imaging
Pelvic ultrasound [59]
- Imaging test of choice for evaluation of adnexal masses and suspected ovarian cancer. [60]
- Both transabdominal and transvaginal modalities should be utilized.
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Ultrasound examination should assess the following:
- Size and structural characteristics
- Laterality
- Mass margins
- Vascularity
- Pelvic fluid
Ultrasound workup of ovarian masses | ||
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Benign | Malignant | |
Internal structure | Uniform, thin walls | Irregularly thickened septa |
Margins | Smooth | Indistinct borders; papillary projections |
Echogenicity | Anechoic | Hypoechoic, anechoic, and hyperechoic components |
Content | Cystic | Cystic or solid components |
Vascularization | Unremarkable | Possible central vascularization |
Pouch of Douglas | Unremarkable | Possible free fluid (ascites) |
Pelvic ultrasonography should be the first step in evaluating women with suspicious ovarian masses.
Magnetic resonance imaging (MRI) [59]
- Not routinely recommended for evaluation of suspected ovarian cancer
- May be helpful in determining the origin of pelvic masses that are not clearly arising from the ovary
- Useful for assessing the feasibility of surgical resection
Computed tomography (CT)
- Not recommended in the initial evaluation of adnexal masses
- Useful for determining the extent of ovarian metastases (e.g., omental, liver, and lung lesions)
Tumor markers
- General: See “Overview of ovarian tumors” above.
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Epithelial ovarian tumors: CA-125 is elevated in ∼ 80% of malignant tumors. [61]
- The specificity and positive predictive value of CA-125 are different in premenopausal and postmenopausal women. [59]
- Premenopausal women: Elevated CA-125 points to a benign process.
- Postmenopausal women: Elevated CA-125 > 35 units should raise concern for malignancy.
- Should only be used to monitor disease progression or recurrence after treatment
- Germ cell tumors
Serum markers of germ cell tumors | |
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Type of tumor | Tumor marker |
Dysgerminoma | |
Yolk sac tumor | |
Immature teratoma | |
Choriocarcinoma |
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Embryonal carcinoma |
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Sex cord-stromal tumors
- Granulosa cell tumor: inhibin
- Others: none
Tissue diagnosis
- Noninvasive biopsy: not recommended due to the risk of tumor seeding and, as a result, advancing the stage of disease [62]
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Surgical evaluation
- Recommended method for diagnosing ovarian cancer [63]
- Should only be utilized in patients with a high probability of a malignant ovarian mass
- If a malignancy is found, it can be staged and cytoreduction can be performed (see “Surgery” in “Treatment” below).
Fine needle aspiration is absolutely contraindicated in ovarian tumors because it may directly spread tumor cells to the peritoneum!
Differential diagnoses
Gynecologic [59]
- Benign causes
- Malignant cause: metastatic cancer
Nongynecologic [59]
- Benign causes
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Malignant causes
- Retroperitoneal sarcoma
- Gastrointestinal cancer
- Metastatic cancer
The differential diagnoses listed here are not exhaustive.
Stages
Staging of epithelial ovarian cancer including fallopian tube cancer and primary peritoneal cancer [18]
Staging is based on the 2017 International Federation of Gynecology and Obstetrics (FIGO) and the Tumor, Node, Metastasis (TNM) classification systems.
Management approach | FIGO Stage | Description | |
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Curative |
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Palliative |
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Treatment
Surgery [64][65]
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Surgical staging: used to obtain pathologic specimens and evaluate the extension of cancer spread (see “Stages” above) [66]
- Peritoneal cytology
- Hysterectomy with bilateral salpingo-oophorectomy
- Pelvic and paraaortic lymph node dissection
- Omentectomy
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Surgical debulking: Whenever possible, maximal cytoreduction (i.e., removal of visible tumor) should be completed to improve long-term outcomes. [67]
- Residual disease < 1 cm defines optimal debulking. [68]
- Utilized in disease stages I–III
For the best patient outcomes, surgical staging and debulking should be performed by expert gynecological oncologists.
Chemotherapy [65]
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Indications
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Early-stage disease [69]
- Patients with high-risk disease (e.g., stage IC, stage II) [70]
- Only used as adjuvant therapy after initial debulking surgery [71]
- Advanced stage disease (e.g., stages III–IV): all patients after initial cytoreductive surgery
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Early-stage disease [69]
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Preferred regimens
- Carboplatin/paclitaxel: Taxane salts are the mainstay of therapy and the preferred first-line regimen. [72]
- 5-FU/oxaliplatin
- Carboplatin/paclitaxel/bevacizumab
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Routes of administration
- Intravenous
- Intraperitoneal [73]
Targeted molecular therapy
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Indications
- BRCA1- or BRCA2-positive disease [74]
- Maintenance therapy after surgical debulking and chemotherapy
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Targeted agents: poly (ADP-ribose) polymerase inhibitors
- Olaparib: first-generation oral PARP inhibitor [75]
- Niraparib: oral, highly selective PARP1/PARP2 inhibitor [76]
- Veliparib: oral PARP inhibitor used in combination with chemotherapy [77]
Radiation therapy [78]
- Not the preferred treatment modality for ovarian cancer
- Reserved as symptomatic treatment for recurrent or metastatic disease
Prognosis
Outcomes for epithelial ovarian cancer [1]
- Very poor overall prognosis as a result of late diagnosis
- 5-year survival rate of all stages: ∼ 50%
FIGO | Anatomic extension | 5-year survival rate |
---|---|---|
I | Limited to one or both ovaries | 80–90% |
II | Infiltration of the lesser pelvis | 50–70% |
III | Extension outside pelvis | 30–40% |
IV | Distant metastases | 10–20% |
Prevention
Ovarian cancer screening [79][80]
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Indications
- Routine screening with CA-125 or transvaginal ultrasound is not recommended in individuals with an average risk of ovarian cancer. [81][82]
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In high-risk individuals ; , familial risk assessment should be performed, after which genetic counseling and subsequent genetic testing for hereditary cancer syndromes (e.g., BRCA1, BRCA2, or Lynch syndrome) may be indicated.
- Some of the tools used for familiar risk stratification include the Ontario Family History Assessment Tool, the Manchester Scoring System, the Referral Screening Tool, and the Pedigree Assessment Tool. [83]
- In patients with high-risk mutations:
- Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is a preventive treatment option for patients who do not wish to conceive in the future. [13]
- Periodic screening for ovarian cancer (e.g., annual transvaginal ultrasound, pelvic exam, and CA-125 levels) is an alternative to rrBSO [84]
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Potential benefits
- Reduction in mortality
- Diagnosis of ovarian cancer at an earlier stage
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Potential harms
- False positives
- Psychological distress
- Morbidity or mortality from surgery
Strategies to reduce the risk of ovarian cancer
See “Protective factors” in “Etiology” above.
Special patient groups
Pregnant women
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Pregnancy luteoma [85]
- Definition: rare, benign tumors that arise in response to elevated hormone levels (e.g., β-hCG) during pregnancy
- Clinical features
- The majority of patients are asymptomatic.
- Occasionally, they are functionally active (i.e., cause androgen hypersecretion) and manifest with symptoms of virilization of the mother or the fetus.
- Diagnostics
-
Pelvic ultrasound
- Solid adnexal mass
- Can be unilateral or bilateral
- Significant venous or arterial flow
- 4–10 cm in diameter
- Luteomas are often diagnosed incidentally during cesarean delivery.
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Pelvic ultrasound
- Treatment
- Observation
- Most regress spontaneously post partum.
- Theca lutein cysts
- Corpus luteum cyst
If surgical removal of an ovarian tumor is indicated during pregnancy, surgery should, if possible, be scheduled for after the 10th week of gestation, as the secretion of progesterone by the corpus luteum is essential for the maintenance of the pregnancy. The placenta takes over this function from approximately the 10th week of pregnancy onwards.