Ovarian cancer

Ovarian cancer is the second most common gynecological cancer and has the highest mortality rate of any gynecological cancer in the United States. Incidence increases with age (peak incidence at 55–64 years of age). Risk factors for ovarian cancer include genetic predisposition (e.g., BRCA1/BRCA2 mutation) and hormonal factors (e.g., early menarche, late menopause). The most common type of ovarian cancer is epithelial cell carcinoma. Symptoms of ovarian cancer are usually nonspecific (e.g., abdominal pain and distension), and over half of those with ovarian cancer have metastatic disease at the time of diagnosis. Transvaginal ultrasound is the imaging test of choice for the evaluation of suspected ovarian cancer; other imaging modalities (e.g., CT scan, MRI) are typically reserved for staging. CA-125 is elevated in ∼ 80% of malignant tumors; the positive predictive value and specificity of CA-125 is higher in postmenopausal women. Surgery is recommended for a definitive diagnosis of ovarian cancer; maximal cytoreduction should be performed to improve long-term outcomes. Most patients with ovarian cancer should receive adjuvant chemotherapy with a platinum-based agent and a taxane. Prognosis is primarily based on the disease stage, with an overall 5-year survival rate of 50%. Routine screening with CA-125 or transvaginal ultrasound is not recommended in individuals with an average risk.

For information about specific ovarian cancer subtypes, see “Overview of ovarian tumors”.

• Incidence ^[1]
  • Second most common gynecological cancer (after endometrial cancer)
  • Incidence increases with age
• Prevalence: the lifetime risk of developing malignant ovarian cancer is ∼1% ^[2]
• Age
  • Peak incidence: 55–64 years of age ^[3]
  • Women with genetic mutations are typically diagnosed at a younger age.
• Mortality: highest mortality rate of any gynecological cancer in the US ^[1]

Epidemiological data refers to the US, unless otherwise specified.

Risk factors ^[4]

• General
  • Increasing age
  • Cigarette smoking
  • Asbestos exposure ^[5]
• Genetic predisposition
  • BRCA mutation
    • Positive family history and/or the occurrence of breast cancer at a younger age increase the likelihood of carrying a mutation in these genes.
    • The lifetime risk of developing ovarian cancer is approx. 44% for BRCA1-positive individuals and 17% for BRCA2-positive individuals. ^[6]
  • HNPCC syndrome: The lifetime risk of developing ovarian cancer is ∼ 10%. ^[7]
  • Positive family history
  • Ashkenazi Jewish descent ^[8]
• Hormonal factors
  • Elevated number of ovulatory cycles: early menarche and/or late menopause
  • Nulliparity
  • Endometriosis
  • Hormone replacement therapy ^[9]

Protective factors ^[4]

• Surgery
  • Risk-reducing bilateral salpingo-oophorectomy
  • Tubal ligation
  • Hysterectomy
• Hormonal factors
  • Oral contraceptives ^[10]
  • Breastfeeding
  • Parity

Classification of ovarian cancer

Ovarian malignancies can be either primary (i.e., arising from the different types of ovarian tissue) or secondary (i.e., metastases from other primary tumors).

Primary ovarian cancer

• Epithelial cell tumors
  • Cystadenocarcinoma (serous or mucinous)
  • Clear cell tumors
  • Endometrioid carcinoma
• Germ cell tumors
  • Immature teratoma
  • Yolk sac tumor of the ovary (endodermal sinus tumor)
  • Dysgerminoma
  • Nongestional choriocarcinoma
• Sex cord tumors: granulosa cell tumor

High-grade cystadenocarcinoma is the most aggressive ovarian cancer.

Secondary ovarian cancer

Most common primary cancers: gastrointestinal tract (e.g., Krukenberg tumor), breast, and endometrium. ^[11]

• Krukenberg tumor: secondary ovarian tumor that most commonly arises from metastatic spread of gastric carcinoma ; ^[12]
  • 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.

Symptoms of ovarian cancer are usually nonspecific, which often delays the diagnosis. Early-stage ovarian cancer is usually asymptomatic. ^[9][13]

Abdominal and pelvic symptoms ^[9][13]

• Early satiety
• Abdominal distension and/or bloating
• Abdominal, pelvic, and/or lower back pain
• Changes in urination (e.g., frequency, urgency)
• Abnormal bleeding (rare) ^[14]
  • Postmenopausal bleeding
  • Rectal bleeding

Advanced disease ^[9][13]

Over half of those with ovarian cancer have metastatic disease at the time of diagnosis. ^[13]

• Locally advanced disease
  • Ascites
  • Malignant pleural effusion (resulting in dyspnea and pleuritic chest pain)
  • Bowel obstruction (resulting in severe nausea and vomiting)
• Metastatic disease ^[15][16]
  • Omentum: abdominal pain from infiltration of omental fat
  • Liver: nausea, jaundice, ascites (see “Metastatic liver disease”)
  • Distant lymph nodes: supraclavicular or inguinal lymphadenopathy
  • Lung: cough, hemoptysis, chest pain (see “Lung metastases”)
  • Brain: headaches, seizures, focal motor deficits (see “Brain metastases”)
  • Bone: local pain and swelling, pathologic fractures (see “Bone metastases”)

Paraneoplastic syndromes ^[13][17]

Although rare, these syndromes may be seen in patients with ovarian cancer. ^[17]

• Paraneoplastic sensory neuronopathy
• Paraneoplastic cerebellar degeneration
• Dermatomyositis
• Hemolytic anemia
• Leser-Trélat sign

Imaging

Transvaginal ultrasound (TVUS)

• Imaging test of choice for evaluation of suspected ovarian cancer ^[13][18]
• If TVUS cannot be performed or there are patient-related factors that limit its accuracy (e.g., postsurgical adhesions, masses extending beyond the pelvis), abdominal ultrasound can be performed instead. ^[18]

Computed tomography (CT) ^[18]

• CT scan of the pelvis, abdomen, and chest is useful for staging.
• Not recommended in the initial evaluation of adnexal masses

Omental caking (thickening) is a radiologic sign that indicates advanced peritoneal ovarian cancer and is due to tumor infiltration of the greater omentum.

Magnetic resonance imaging (MRI) ^[18]

• Useful for assessing disease spread and the feasibility of surgical resection
• Not routinely recommended for initial evaluation of suspected ovarian cancer

Tumor markers

• Epithelial ovarian tumors: CA-125 is elevated in ∼ 80% of malignant tumors. ^[13][18]
  • The positive predictive value and specificity of CA-125 are higher in postmenopausal women.
  • Premenopausal women: Elevated CA-125 may point to a benign process (e.g., endometriosis, pregnancy, pelvic inflammatory disease)
  • Postmenopausal women: Elevated CA-125 (> 35 U/mL) raises concern for malignancy. ^[18]
  • Should be used to monitor disease progression or recurrence after treatment
• Germ cell tumors
  • Dysgerminoma: LDH, β-hCG
  • Yolk sac tumor: AFP
  • Immature teratoma: AFP, LDH, CA-125
  • Choriocarcinoma: β-hCG
  • Embryonal carcinoma: AFP, β-hCG
• Sex cord-stromal tumors:
  • Granulosa cell tumor: inhibin

Tissue diagnosis

• Needle biopsy
  • Not recommended because of the risk of tumor seeding, which can advance the stage of disease ^[18]
  • There is an exception for patients with clinical and radiographic findings of advanced ovarian malignancy who are not fit for surgery.
• Surgical evaluation
  • Recommended for definitive diagnosis of ovarian cancer ^[9]
  • Should be performed on patients with clinical, radiographic, and/or laboratory findings that suggest ovarian cancer
  • Laparoscopic removal is the preferred surgical procedure.
  • Allows staging and cytoreduction (see “Surgery” in “Treatment” below)

Fine needle aspiration is absolutely contraindicated in ovarian tumors because it can directly spread tumor cells to the peritoneum!

Nongynecological ^[18]

• Benign causes
  • Appendiceal abscess
  • Pelvic kidney
  • Complicated diverticulitis
  • Bladder diverticulum
• Malignant causes
  • Retroperitoneal sarcoma
  • Gastrointestinal cancer
  • Metastatic cancer (e.g., breast, gastric, colorectal) ^[12]

Gynecological ^[18]

• Benign causes
  • Benign ovarian tumors
    • Ovarian cystadenoma (serous or mucinous)
    • Brenner tumor
    • Dermoid cyst (mature cystic teratoma)
    • Struma ovarii (mature teratoma)
    • Ovarian fibroma
    • Theca cell tumor (thecoma)
    • Sertoli-Leydig cell tumor
  • Ovarian cysts
  • Pelvic inflammatory disease
  • Tuboovarian abscess
  • Hydrosalpinx
  • Leiomyoma
  • Endometrioma
• Malignant cause: metastatic cancer (e.g., endometrial) ^[12]

During pregnancy

• Additional conditions to consider in pregnant individuals:
  • Pregnancy luteoma ^[20]
    • 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.
    • 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 10^th 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 10^th week of pregnancy onwards.

The differential diagnoses listed here are not exhaustive.

Staging of epithelial ovarian cancer including fallopian tube cancer and primary peritoneal cancer ^[21]

Staging is based on the 2017 International Federation of Gynecology and Obstetrics (FIGO) and the Tumor, Node, Metastasis (TNM) classification systems.

Surgery ^[22][23]

• Surgical staging: to obtain pathological specimens and evaluate the extent of cancer spread (see “Stages” above)
  • Hysterectomy with bilateral salpingo-oophorectomy
  • Pelvic and paraaortic lymph node dissection
  • Omentectomy
  • Peritoneal cytology
• Surgical debulking: Whenever possible, maximal cytoreduction (i.e., removal of visible tumor) should be performed to improve long-term outcomes. ^[24]
  • Optimal debulking is defined as < 1 cm of residual tumor. ^[25]
  • Used in disease stages I–III, and, occasionally, IV.

For the best patient outcomes, surgical staging and debulking should be performed by a gynecological oncologist. ^[26]

Chemotherapy ^[9]

• Indications
  • Most patients with ovarian cancer should receive adjuvant chemotherapy except for patients with low-grade, stage I disease.
  • Neoadjuvant chemotherapy followed by interval debulking surgery can be considered in patients with advanced-stage disease and high perioperative risk. ^[27]
• Commonly used regimens: platinum-based agent (e.g., carboplatin) + taxane (e.g., paclitaxel) ± bevacizumab

Targeted molecular therapy

• Indications
  • BRCA1- or BRCA2-positive disease ^[28]
  • Maintenance therapy after surgical debulking and chemotherapy
• Targeted agents: poly (ADP-ribose) polymerase inhibitors
  • Olaparib: first-generation oral PARP inhibitor ^[29]
  • Niraparib: oral, highly selective PARP1/PARP2 inhibitor ^[30]

Radiotherapy

• Reserved for patients with dysgerminomas or metastatic disease

Prognosis is primarily based on the disease stage. ^[2]

• Overall 5-year survival rate: 50%
• 5-year survival rate of metastatic ovarian cancer: ∼ 31%

Ovarian cancer screening ^[31][32]

• Indications
  • Routine screening with CA-125 or transvaginal ultrasound is not recommended in individuals with an average risk of ovarian cancer. ^[33][34]
  • 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. ^[35]
    • 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. ^[36]
      • Periodic screening for ovarian cancer (e.g., annual transvaginal ultrasound, pelvic exam, and CA-125 levels) is an alternative to rrBSO ^[37]
• Potential benefits
  • Reduction in mortality
  • Diagnosis of ovarian cancer at an earlier stage
• 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.