Ovarian cancer

In the US, ovarian cancer is the second most common gynecologic cancer and has the highest mortality rate of any gynecologic cancer. Incidence increases with age (peak incidence at 55–64 years of age). Genetic risk factors include mutations in the BRCA1/BRCA2 and/or mismatch repair (MMR) gene. The most common type of ovarian cancer is epithelial cell carcinoma. Symptoms of ovarian cancer are usually nonspecific (e.g., abdominal pain and distention), and over half of individuals with ovarian cancer have metastatic disease at the time of diagnosis. Transvaginal ultrasound (TVUS) 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 patients with 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 TVUS 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 gynecologic cancer (after endometrial cancer)
  • Incidence increases with age.
• Lifetime risk
  • General population: ∼ 1% ^[2][3]
  • Individuals with genetic predisposition, e.g.:
    • BRCA1-positive: 25–65% ^[2]
    • BRCA2-positive: 10–30% ^[2]
    • MMR gene mutation: 10% ^[2]
• Age
  • Peak incidence: 55–64 years of age ^[4]
  • Women with genetic mutations are typically diagnosed at a younger age.
• Mortality: highest mortality rate of any gynecologic cancer in the US ^[1]

Epidemiological data refers to the US, unless otherwise specified.

Risk factors ^[5]

• General
  • Increasing age
  • Cigarette smoking
  • Asbestos exposure ^[6]
• Genetic predisposition
  • BRCA gene mutation
  • MMR gene mutation associated with HNPCC syndrome
  • Positive family history
  • Ashkenazi Jewish descent ^[7]
• Hormonal factors
  • Elevated number of ovulatory cycles: early menarche and/or late menopause
  • Nulliparity
  • Endometriosis
  • Hormone replacement therapy ^[8]
  • Polycystic ovarian syndrome (PCOS) ^[9]

Protective factors ^[5]

• Surgery
  • Risk-reducing bilateral salpingo-oophorectomy (rrBSO) for high risk patients ^[10]
  • Tubal ligation
  • Hysterectomy
• Hormonal factors
  • Oral contraceptives ^[11]
  • Breastfeeding
  • Parity

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

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
  • Nongestational 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. ^[12]

• Krukenberg tumor: secondary ovarian tumor that most commonly arises from metastatic spread of gastric carcinoma ; ^[13]
  • 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. ^[2][8]

Abdominal and pelvic symptoms ^[2][8]

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

Advanced disease ^[2][8]

Over half of those with ovarian cancer have metastatic disease at the time of diagnosis. ^[2]

• 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 ^[2][17]

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

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

General principles

• Clinical evaluation includes abdominal, pelvic, and lymph node examination. ^[18]
• Obtain TVUS and CA-125 levels in individuals with risk factors and clinical features concerning for ovarian cancer.
• Refer the following patients to a gynecologic oncologist for diagnostic confirmation:
  • Postmenopausal patients with elevated CA-125 (> 35 U/mL) levels
  • All patients with either:
    • Malignant features on imaging (e.g., ascites or a fixed pelvic mass)
    • ↑ CA-125 levels disproportionate to the clinical context
• Biopsy or fluid cytology is required to confirm the diagnosis.

Imaging

Ultrasound ^[2][19]

• TVUS: first-line for evaluating suspected ovarian cancer
• Abdominal ultrasound: alternative if TVUS cannot be performed or additional study if there are patient-related factors that limit its accuracy (e.g., postsurgical adhesions, masses extending beyond the pelvis)

Other modalities ^[19]

Cross-sectional imaging is not routinely recommended for the initial evaluation of adnexal masses.

• CT scan of the chest, abdomen, and pelvis: for staging
• MRI pelvis: to evaluate the feasibility of surgical resection and assess the origin of nonovarian pelvic masses

Omental caking (thickening) is a radiologic finding on cross-sectional imaging that is consistent with advanced peritoneal ovarian cancer and is due to tumor infiltration of the greater omentum.

Tumor markers

• CA-125 levels are elevated in ∼ 80% of malignant epithelial ovarian tumors (and in certain germ cell tumors). ^[2][19]
  • Premenopausal women: Elevated CA-125 may indicate a benign process (e.g., endometriosis, pregnancy, pelvic inflammatory disease). ^[18]
  • Postmenopausal women: Elevated CA-125 (> 35 U/mL) raises concern for malignancy. ^[19]
• Additional tumor markers: Consider in consultation with a specialist based on clinical suspicion.
  • Germ cell tumor markers: β-hCG, AFP, LDH
  • Granulosa cell tumor: inhibin
  • See “Overview of ovarian tumors” for details.

The positive predictive value and specificity of CA-125 for malignancy are higher in postmenopausal women.

Tissue diagnosis ^[19]

• Surgical biopsy
  • Recommended for definitive diagnosis of ovarian cancer ^[8]
  • Should be performed in patients with clinical, radiographic, and/or laboratory findings that suggest ovarian cancer
  • Laparoscopic removal is the preferred surgical procedure.
• Other studies
  • Needle biopsy: generally avoided because of the risk of tumor seeding, which can advance the stage of disease
  • Fluid cytology of ascites or pleural effusion

Fine-needle aspiration is absolutely contraindicated in potentially resectable ovarian tumors because it can directly spread tumor cells to the peritoneum.

Nongynecologic ^[19]

• Benign causes
  • Appendiceal abscess
  • Pelvic kidney
  • Complicated diverticulitis
  • Bladder diverticulum
• Malignant causes
  • Retroperitoneal sarcoma
  • Gastrointestinal cancer
  • Metastatic cancer (e.g., breast, gastric, colorectal) ^[13]

Gynecologic ^[19]

• 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) ^[13]

During pregnancy

• Additional conditions to consider in pregnant individuals:
  • Pregnancy luteoma ^[21]
    • 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 is based on the International Federation of Gynecology and Obstetrics (FIGO) and the Tumor, Node, Metastasis (TNM) classification systems.

General principles

• Refer all patients to a gynecologic oncologist for ongoing management.
• Surgical staging: performed to obtain pathological specimens and evaluate the extent of cancer spread
• Surgical debulking improves long-term outcomes. ^[23]
• Most patients should receive adjuvant chemotherapy.
• CA-125 levels may be used to monitor disease progression and/or recurrence after treatment. ^[8]

Surgery ^[8][24][25]

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

• Surgical staging
  • Hysterectomy with bilateral salpingo-oophorectomy
  • Pelvic and paraaortic lymph node dissection
  • Omentectomy
  • Peritoneal cytology
• Surgical debulking ^[23]
  • Optimal debulking is defined as < 1 cm of residual tumor. ^[27]
  • Used in disease stages I–III and, occasionally, stage IV

Surgical resection alone may be curative in patients with early-stage disease. ^[27]

Chemotherapy ^[8]

• Patients with ovarian cancer should receive adjuvant chemotherapy, except for those with low-grade, stage I disease.
• Common regimen: platinum-based agent (e.g., carboplatin) PLUS taxane (e.g., paclitaxel) ± bevacizumab ^[28]
• Adjuvant intraperitoneal chemotherapy combined with intravenous chemotherapy results in a higher survival rate than intravenous chemotherapy alone. ^[29]
• Neoadjuvant chemotherapy followed by interval debulking surgery can be considered in patients with advanced-stage disease and high perioperative risk. ^[29]

Targeted molecular therapy

• Indications
  • BRCA-positive disease ^[30]
  • Maintenance therapy after surgical debulking and chemotherapy ^[31]
• Targeted agents: oral poly (ADP-ribose) polymerase inhibitors (PARP inhibitors)
  • Olaparib: first-generation oral PARP inhibitor ^[32]
  • Niraparib: highly selective PARP1/PARP2 inhibitor ^[33]
  • Rucaparib: inhibits PARP1, PARP2, and PARP3 ^[34]

Management of recurrence ^[35]

• Relapse within 6 months of completing chemotherapy is classified as platinum-resistant disease and can be managed with either:
  • A different chemotherapy regimen
  • Inclusion in clinical trials
  • A focus on palliative therapy over curative therapy
• If relapse occurs > 6 months after completing initial chemotherapy:
  • Treat with platinum-containing combination chemotherapy and bevacizumab or PARP inhibitors if indicated.
  • Consider secondary cytoreductive surgery.

• 5-year survival rates after initial diagnosis vary by disease stage. ^[3]
  • Overall (all stages): ∼ 51%
  • Localized disease (no spread): ∼ 92%
  • Regional disease (spread to lymph nodes): ∼ 72%
  • Distant disease (metastatic): ∼ 31%
• The lifetime risk of relapse is > 80% for patients with stage III or IV disease. ^[35]

Ovarian cancer screening ^[36][37]

• Indications
  • Routine screening with CA-125 or transvaginal ultrasound is not recommended in individuals with an average risk of ovarian cancer. ^[38][39]
  • In individuals at high risk, 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. ; ^[40]
    • 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. ^[41]
    • 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. ^[42]
      • Periodic screening for ovarian cancer (e.g., annual transvaginal ultrasound, pelvic exam, and CA-125 levels) is an alternative to rrBSO ^[43]
• 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.