Approach

Signs and symptoms

Patients with early disease are typically asymptomatic; thus, a majority of patients present in advanced stages of the disease when signs and symptoms appear.[2]

Signs and symptoms are typically vague/non-specific and gastrointestinal-related (e.g., abdominal bloating, nausea and emesis, early satiety, dyspepsia, increased abdominal girth, abdominal cramping, and change in bowel habit).[6][74] In one study, approximately 95% of patients reported vague gastrointestinal symptoms before their diagnosis of ovarian cancer, and approximately 75% of patients had these symptoms for at least 3 months.[74] In another study, the combination of bloating, increased abdominal girth, and urinary urgency or frequency was commonly reported in patients with ovarian cancer.[6]

Some patients with early-stage disease present with pelvic/abdominal pain or pressure due to ovarian torsion.[2] Patients may also have acute onset of lower abdominal pain with associated nausea and emesis. Ovarian cancer must be suspected with any of these signs or symptoms because there are no pathognomonic features associated with this cancer.[6][74]

History

Women with a personal and/or family history of certain cancers (e.g., breast cancer, ovarian cancer, colorectal cancer, endometrial cancer) are at increased risk of ovarian cancer; therefore, obtaining a detailed history is important.[15][16]​​​​[35][36][37]​​​​​​[75][76]

Genetic risk evaluation, including counselling and genetic testing, is recommended for women with a blood relative with a known pathogenic or likely pathogenic variant in a cancer susceptibility gene or a strong family history of:[16][17][64]​​​[77][78][79][80]

  • Breast and/or ovarian cancer (BRCA1, BRCA2, ATM, BRIP1, PALB2, RAD51C, RAD51D)

  • Colorectal, endometrial, and/or ovarian cancer (Lynch syndrome variants: MSH2, MLH1, MSH6, PMS2, EPCAM).

Physical examination

Patients with signs and symptoms suggestive of ovarian cancer should undergo a physical examination of the abdomen and pelvis.

Physical findings are varied and may include ascites, pleural effusion, palpable mass on pelvic examination, and abdominal distension that is dull to percussion. Patients may appear malnourished if they have significant gastrointestinal symptoms. Findings consistent with ascites (e.g., fluid wave, shifting dullness) or with a right-sided pleural effusion (e.g., diminished breath sounds or rales) can often be detected in patients with advanced-stage disease.

On pelvic examination, a mass might be detected in the adnexa (i.e., in the ovaries, fallopian tubes, or surrounding connective tissue) or recto-vaginal space. Referral to a gynaecological oncologist is recommended if a nodular or fixed pelvic mass is detected, or if a patient with an adnexal mass has additional physical examination findings that suggest metastatic disease (e.g., ascites and pleural effusion).[81]​​​

Imaging

Transvaginal pelvic ultrasound is the preferred method to evaluate a clinically suspected ovarian mass, providing both qualitative and quantitative information valuable in management.[82][83] Combined transvaginal and transabdominal ultrasound may be useful for assessing larger masses.[83]​​​​​

Ultrasound with Doppler imaging can characterise the mass (e.g., cystic, solid, complex), and in most cases can triage the mass into benign or malignant categories.[83]​​[Figure caption and citation for the preceding image starts]: Ovarian cyst with nodules on ultrasoundFrom the collection of Justin C. Chura, MD, Cancer Treatment Centers of America, Philadelphia, PA [Citation ends].com.bmj.content.model.Caption@4c6a229b[Figure caption and citation for the preceding image starts]: Ovarian cyst with normal Doppler flowFrom the collection of Justin C. Chura, MD, Cancer Treatment Centers of America, Philadelphia, PA [Citation ends].com.bmj.content.model.Caption@3ff63788 Suspicious masses on ultrasound are typically solid or complex (cystic and solid), septated, and multiloculated, and demonstrate a high blood flow (increased Doppler flow).[84] If suspicious findings are discovered on ultrasound, referral to a gynaecological oncologist is recommended.[81]​​

In circumstances where ultrasound cannot adequately characterise an ovarian mass, abdominal/pelvic magnetic resonance imaging (MRI) without and with gadolinium contrast may provide additional information (e.g., origin of a mass [uterine, ovarian, tubal]) and help determine if the mass is benign or malignant.[83]​​

Computed tomography (CT) is less sensitive than ultrasound and MRI in evaluating pelvic organs; therefore, it is not considered part of the standard diagnostic work-up for a pelvic or adnexal mass.[83]​ CT imaging is mainly used for initial staging of ovarian cancer before initiation of treatment.[85] If suspected on examination, CT imaging of the abdomen, pelvis, or chest can be used to detect the presence of metastatic disease and may guide treatment.[85][86][Figure caption and citation for the preceding image starts]: Ovarian masses and ascites on coronal CTFrom the collection of Justin C. Chura, MD, Cancer Treatment Centers of America, Philadelphia, PA [Citation ends].com.bmj.content.model.Caption@f927af7

Positron emission tomography (PET), PET-CT, or PET/MRI can be useful for distinguishing between benign and malignant ovarian tumours, but they are not considered part of the standard diagnostic work-up for a pelvic or adnexal mass.[87][88][89]

Histopathology

If transvaginal ultrasound demonstrates suspicious findings, surgery (laparotomy or laparoscopy) is usually required for definitive histological diagnosis, staging, and tumour debulking (cytoreduction).[90]​​ Surgical staging guides further postoperative treatment, especially for early-stage disease.[19]​​[91]​​​​

For pre-menopausal patients with a suspicious ovarian mass detected on transvaginal ultrasound, surgery is frequently deferred for 2 to 3 menstrual cycles to establish if the mass is functional or physiological (i.e., not malignant).

Biopsy and fine-needle aspiration (FNA) are not routinely recommended for definitive diagnosis as these procedures can disseminate tumour cells into the peritoneal cavity.[19] They are also prone to sampling error, and may be non-diagnostic. However, for patients unsuitable for surgery, or those with bulky (advanced) disease who are unlikely to achieve complete cytoreduction or optimal (residual disease <1 cm) cytoreduction with surgery, a definitive histological diagnosis should be obtained by core biopsy (or FNA if biopsy is not possible) prior to initiating neoadjuvant chemotherapy.[19][92]​​

Laboratory evaluation

Serum CA-125 levels are elevated in >80% of women with advanced-stage disease.[93] However, this biomarker is not diagnostic because CA-125 levels can be elevated as a result of non-malignant conditions (e.g., endometriosis, uterine fibroids, pregnancy, pelvic inflammatory disease, appendicitis, and ovarian cysts) and other malignant conditions (e.g., pancreatic, breast, lung, gastric, and colon cancers).[66] Furthermore, normal CA-125 levels are observed in approximately 50% of patients with early-stage ovarian cancer.[93]

Despite its limitations, it is common practice for clinicians to routinely check CA-125 levels as part of the preoperative evaluation of an adnexal mass. An elevated CA-125 level is more predictive of malignancy in post-menopausal women than in pre-menopausal women.[94] In post-menopausal women, a CA-125 level greater than 65 units/mL is reported to have 98% specificity for diagnosing ovarian cancer. In pre-menopausal women CA-125 levels between 35 and 65 units/mL are associated with a 50% to 60% risk of cancer.[94] Consultation with a gynaecological oncologist is recommended for post-menopausal women with an elevated CA-125, and for pre-menopausal women with a very elevated CA-125.[81]​​

CA-125 levels are most useful postoperatively once a histological diagnosis of ovarian cancer has been confirmed, where it can be used to monitor treatment response and disease recurrence.[95][96] However, use of CA-125 alone for monitoring and detecting disease recurrence has not been found to improve survival.[97]

In the US, several biomarker tests (OVA1, OVERA, and the risk of ovarian malignancy algorithm [ROMA]) have been approved for determining risk of ovarian cancer in women with an ovarian adnexal mass for which surgery is planned. These tests are not to be used as ovarian cancer screening tools (i.e., prior to detection of an adnexal mass) or as stand-alone diagnostic tests.[19]

Testing for other tumour biomarkers (e.g. inhibin, alpha-fetoprotein, beta-human chorionic gonadotrophin, lactate dehydrogenase, carcinoembryonic antigen, CA 19-9, and HE4) may be useful in certain circumstances, including the preoperative work-up and monitoring of some less common ovarian cancers.[19]

Genetic risk evaluation and testing

Patients with a confirmed diagnosis of ovarian cancer should undergo genetic risk evaluation, and germline and somatic genetic testing (e.g., for BRCA1 and BRCA2 mutations, and other ovarian cancer susceptibility genes) if not previously done.[76][79][90]

Germline testing for a specific pathogenic variant can be carried out, if known; tailored multi-gene panel testing is recommended if the variant is unknown, based on personal and family history.[16][64]​​[76]​ BRCA1, BRCA2, and Lynch syndrome genes (MSH2, MLH1, MSH6, PMS2, EPCAM) are generally recommended in multi-gene panels for patients with ovarian cancer, with further genes added based on personal and family history.[76]​ Germline testing should be offered regardless of results from tumour testing.[76]

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