Sections

Workup

Approach Considerations

The presence of advanced ovarian cancer is often suspected on clinical grounds but can be confirmed only pathologically by removal of the ovaries or, when disease is advanced, by sampling tissue or ascitic fluid.

Current guidelines from the Society of Gynecologic Oncology and the American Society of Clinical Oncology recommend that the primary clinical evaluation for ovarian cancer include a computed tomography (CT) scan of the abdomen and pelvis with oral and intravenous contrast, and chest imaging (CT preferred) to evaluate the extent of disease and the feasibility of surgical resection.^[44]National Comprehensive Cancer Network guidelines recommend ultrasound and/or abdominal/pelvic CT or magnetic resonance imaging (MRI), as clinically indicated, and chest CT or x-ray, as clinically indicated. Positron emission tomography (PET)/CT scan or MRI may be indicated for indeterminate lesions, if the results will alter management.^[45]

MRI can increase the specificity of imaging evaluation in cases where the ultrasound appearance of the lesion is indeterminate.^[8]MRI is not definitive, however. On MRI, endometriotic cysts with enhanced mural nodules are a hallmark of ovarian cancer, but they may also be a feature of benign neoplasms and even inflammatory diseases. Large contrast-enhanced nodules on large endometriotic cysts in an elderly patient are more likely to indicate malignancy.^[46]

When imaging studies demonstrate an adnexal mass, the decision whether to observe the patient with repeat imaging or to proceed to surgical evaluation must take into account not only the imaging characteristics but also the patient's medical history, physical examination results, and cancer antigen 125 (CA-125) level.^[47]Tumor markers such as CA-125 are not good discriminators of benign lesions from malignant lesions in premenopausal women but have better accuracy in postmenopausal women.

In patients with diffuse carcinomatosis and gastrointestinal (GI) symptoms, a GI tract workup may be indicated, including one of the following:

Upper and/or lower endoscopy
Barium enema
Upper GI series

Fine-needle aspiration (FNA) or percutaneous biopsy of an adnexal mass is not routinely recommended. In most cases, this approach may only serve to delay diagnosis and treatment of ovarian cancer. Instead, if a clinical suggestion of ovarian cancer is present, surgical evaluation for diagnosis and staging can be performed. An FNA, percutaneous biopsy, or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass, or in patients who will be treated with neoadjuvant chemotherapy.

Approximately 50% of epithelial ovarian cancers have homologous recombination deficiency (HRD)—that is, deleterious mutations in homologous recombination DNA repair genes, such as BRCA1/2. Because HRD status is a biomarker for sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors, testing for BRCA mutations is indicated for patients with ovarian cancer. Patients without a germline deleterious BRCA mutation should be assessed for a somatic BRCA mutation. In those without a BRCA mutation, next-generation sequencing can identify other HRD features (eg, genomic instability).^{[45, 48]}

Screening

Ovarian cancer does not lend itself to screening because it has a relatively low prevalence within the general population and no proven precursor lesion exists that can be detected and treated to prevent the cancer from occurring. No approved screening method is available for ovarian cancer.

The U.S. Preventive Services Task Force (USPSTF) recommends against screening for ovarian cancer in the general population. The USPSTF found fair evidence that although screening with serum CA-125 level or transvaginal ultrasonography can detect ovarian cancer at an earlier stage, earlier detection is likely to have a small effect, at best, on mortality from ovarian cancer. In addition, because of the low prevalence of ovarian cancer and the invasive nature of diagnostic testing, the USPSTF concluded that the potential harms outweigh the potential benefits.^[3]

A randomized trial in a US population found that simultaneous screening with ultrasonography and CA-125 did not reduce ovarian cancer mortality, and evaluation of false-positive results was associated with complications.^[49]

The US Food & Drug Administration (FDA) recommends against the use of tests marketed for ovarian cancer screening.^[4] The National Cancer Institute (NCI) cites evidence of lack of mortality benefit with screening, and potential harms relating to false-positive test results.^[5]

Studies are trying to improve the accuracy of screening for early-stage ovarian cancer. Most are targeting perimenopausal or postmenopausal women or those with a family history of epithelial ovarian cancer. Many studies are using a combination of ultrasound, serum CA125 testing, and other tumor markers. Large prospective trials include the United Kingdom Collaborative Trial of Ovarian Cancer Screening, a European trial of ovarian cancer screening in 202,638 women; and the National Institutes of Health Prostatic, Lung, Colorectal and Ovarian (NIH-PLCO) cancer study. The primary outcome measure of the latter study is mortality from ovarian and fallopian tube cancer on 10-year follow-up.^[50]

Primary analysis of data from the United Kingdom Collaborative Trial of Ovarian Cancer Screening found no significant difference in ovarian cancer mortality in women who underwent annual multimodal screening (MMS) with serum CA-125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound, or no screening. When prevalent cases were excluded, however, a significant mortality reduction with MMS was noted, with evidence of a mortality reduction in years 7-14. The authors conclude that "further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening."^[50]

Considerable interest has developed in the characterization of computer-analyzed protein patterns in the blood as a way of improving screening for ovarian cancer. Such methods are currently undergoing intensive research and clinical validation, and they may hold hope for the future.

Lachance et al tested a nomogram for estimating the probability of ovarian cancer. The model had a sensitivity of 90% and a specificity of 73%, which may provide a further tool to aid in ensuring referral.^[51]

In a study by van Nagell et al, asymptomatic women who underwent annual sonographic screening achieved increased detection of early stage ovarian cancer, with an increase in 5-year disease-specific survival.^[52]

Tumor Markers

Tumor markers are glycoproteins that are usually detected by monoclonal antibodies. Each tumor marker has a variable profile of usefulness for screening, determining diagnosis and prognosis, assessing response to therapy, and monitoring for cancer recurrence. They are produced by tumor cells in response to cancer or certain benign conditions and indicate biological changes that signal the existence of malignancy. These soluble molecules can usually be detected in elevated quantities in the blood, urine, or body tissues of patients with certain types of cancer.

The levels of tumor marker are not altered in all cancer patients, especially in early-stage cancer. The level of some tumor markers can be elevated in patients with noncancerous conditions. Following the development of monoclonal antibodies, many new tumor markers have been discovered during the past 2 decades. Some tumor markers can be used for screening, diagnosis, management, determining response, and recurrence. Some markers show promise as prognostic indicators.

Due to the location of ovarian tumors within the abdominal cavity, making a preoperative pathological diagnosis of cancer is difficult without laparotomy. From this point of view, the use of tumor markers that consist of carbohydrate antigens, such as CA-125, in addition to diagnostic imaging, is useful in the diagnosis of ovarian cancer.

CA-125 is a glycoprotein antigen detected by using mouse monoclonal antibody OC125 raised from an ovarian cancer cell line. CA-125 is not specific for epithelial ovarian cancer and is elevated in other benign and malignant conditions, including menstruation; endometriosis; pelvic inflammation; liver, renal, and lung disease; and cancer of the endometrium, breast, colon, pancreas, lung, stomach, and liver. It is also elevated in 6% of women who do not have epithelial ovarian cancer. Although CA-125 is elevated in 83% of women with epithelial ovarian cancer, it is elevated in only 50% of those with stage I disease.

A monoclonal antibody-based immunoassay for CA-125 has been used to monitor the treatment of epithelial ovarian carcinomas. Persistent elevation of CA-125 in serum has generally reflected persistence of disease at second-look surveillance procedures. However, CA-125 levels can return to within normal limits and residual disease can be found at laparoscopy or laparotomy.

CA-125 is not useful when used alone as a single one-time test for ovarian cancer screening, but it may have increased value when serial measurements are performed over time and if it is incorporated into a risk of ovarian cancer algorithm. CA-125 shows promise for distinguishing benign from malignant pelvic masses. Several trials are ongoing to determine the potential of CA125 in combination with other markers to increase earlier detection of occult ovarian cancer.^[39]

A study by Hirai et al found that stage IA ovarian cancers in women with normal CA125 levels are usually smaller, have slightly different histopathologic type distribution, and have less solid components than cancers with elevated CA-125 levels.^[53]

A study by Buys et al found that among women in the general US population, screening simultaneously with CA-125 and transvaginal ultrasonography did not reduce ovarian cancer mortality compared with usual care. False-positive results occurred in 9.6% of women, resulting in 6.2% undergoing surgery.^[54]

Tests that use multiple markers have been devised. The OVA1 test includes five markers: transthyretin, apolipoprotein A1, transferrin, beta-2 macroglobulin, and CA-125. The Ovasure test includes six markers: leptin, prolactin, osteopontin, insulinlike growth factor II, macrophage inhibitory factor, and CA-125. The National Comprehensive Cancer Network (NCCN) does not endorse either of those for ovarian cancer screening.^[45]

Other markers that have been investigated include lysophosphatidic acid, tumor-associated glycoprotein 72 (TAG 72), OVX1, and macrophage colony-stimulating factor (M-CSF). Newer experimental markers have been identified through various laboratory techniques. These markers include mesothelin, human epididymis protein 4, kallikrein, and haptoglobin-alpha. A study by No et al found that p-4EBP1 expression was associated with poor prognostic factors and that overexpression may be a prognostic biomarker.^[55]Tapia et al report that p-trkA may be a potential new tumor marker and that nerve growth factor may act as a direct angiogenic factor.^[56]

A study by Lin et al found that the adjusted hazard ratio for ovarian cancer in women with pelvic inflammatory disorder was 1.92. This suggests that pelvic inflammatory disorder may be a useful marker for ovarian cancer.^[57]

No marker is completely specific; therefore, diagnostic immunohistochemistry testing must be used in conjunction with morphologic and clinical findings.

Please go to the main article on Gynecologic Tumor Markers for more information.

Imaging in Ovarian Cancer

Imaging studies used in ovarian cancer include ultrasonography, chest radiography, computed tomography (CT), and magnetic resonance imaging (MRI). Positron emission tomography (PET) scanning does not have an established role in the diagnosis of primary ovarian malignancy.

Ultrasonography is the most useful initial investigation in a patient found to have a pelvic mass. This may define the morphology of the pelvic tumor. In addition, it can determine whether large masses are present in other parts of the abdomen, including in the liver.

Chest radiography or CT is performed routinely, as it is useful in helping exclude pleural effusions or pulmonary spread of malignant diseases of the ovary.

The primary advantage of using MRI in the evaluation of ovarian masses is the ability to employ this modality in the characterization of tissue. The presence of fat, hemorrhage, mucin, fluid, and solid tissue within an ovarian mass can be determined with the aid of MRI. The ability to characterize tissue in this way is most useful in determining whether a mass is definitely benign.

In many cases, CT is complementary to surgical staging. CT can identify possible sites of unsuspected disease such as the pelvic peritoneum, paraaortic nodes, diaphragm, and chest.^[58]

For more information, see Malignant Ovarian Tumor Imaging.

GI Tract Workup

In patients with diffuse carcinomatosis and GI symptoms, a GI tract workup may be indicated, including one of the following:

Upper and/or lower endoscopy
Barium enema
Upper GI series

Carcinoembryonic antigen (CEA) levels may also be measured.

Biopsy

FNA, percutaneous biopsy, or diagnostic paracentesis should be performed in patients with diffuse carcinomatosis or ascites without an obvious ovarian mass, and in patients who will be treated with neoadjuvant chemotherapy

Mammography

The preoperative workup also should include mammography for women older than 40 years who have not had a recent mammogram. This is especially important in women with estrogen-producing tumors because these may increase the risk of breast malignancies.

Additionally, breast cancers can metastasize to the ovaries, often bilaterally. Mammography can help rule out the possibility of a nongynecologic primary neoplasm in the breast.

Workup of Tumors of Low Malignant Potential

All histologic subtypes of endothelial ovarian cancer have serous, mucinous, endometrioid, clear cell, and Brenner low malignant potential (LMP) variants, with the essential feature being that no invasion occurs. Mucinous and serous types are most common (see the image below). Invasion is difficult to interpret in mucinous tumors, and the requisite microscopic feature is epithelial stratification exceeding 3 cell layers with associated nuclear atypia. Ovarian tumors require very careful pathologic examination, with sufficient numbers of sections taken to ensure adequate assessment. Particular care must be taken with frozen section interpretation of large mucinous tumors at the time of surgery.

Inside of a large, smooth-surfaced tumor replacing the ovary. Final histologic studies indicated the tumor was a mucinous carcinoma of low malignant potential. Note the multiple cysts with thick septa between. This tumor was extensively sectioned and was a mucinous carcinoma of low malignant potential.

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Serous LMP tumors usually are unilocular, more often bilateral than mucinous LMP tumors, and filled with clear serous fluid. The external surface normally is smooth, but excrescences on the outside surface and papillary projections on the inside may be observed. Mucinous LMP tumors are multicystic with a smooth outer surface. Both types may be large.

LMP tumors can metastasize throughout the abdominal cavity and elsewhere. Metastases can be differentiated microscopically as those without invasion and those with invasion.

Workup of Malignant Germ Cell Tumors

If a malignant germ cell tumor (GCT) is suspected at presentation, blood should be examined for tumor markers, including beta human human chorionic gonadotropin (beta-hCG), alpha-fetoprotein, and lactate dehydrogenase. In premenarchal girls found to have an adnexal mass, perform karyotyping to determine the status of the sex chromosomes.

Other investigations include chest x-ray for lung metastases and ultrasound to help define the morphology of the pelvic tumor, to help evaluate the kidneys for evidence of ureteric obstruction, and to help detect ascites and the presence of metastases in the liver and retroperitoneum. Preoperative CT scan or MRI may document intra-abdominal disease, including liver or lymph node metastases that are deemed undetectable on ultrasound imaging.

Patients with immature teratomas will not have elevated levels of tumor markers unless the tumor contains elements of other GCTs. The cardinal histologic feature is immature elements, mostly of neural tissue.

Staging

Ovarian cancer is typically staged using the system formulated and updated by the International Federation of Obstetrics and Gynecology (FIGO),^[59]as listed below.

Stage I

In stage I, growth is limited to the ovaries. Substages are as follows:

Stage IA - Tumor limited to 1 ovary, capsule intact, no tumor on external surface
Stage IB - Tumor involves both ovaries, capsule intact, no tumor on external surface
Stage IC - Tumor either stage IA or IB, plus surgical spill (IC1), capsule rupture before surgery or tumor on ovarian surface (IC2), or malignant cells in the ascites or peritoneal washings (IC3)

Stage II

In stage II, tumor involves one or both ovaries, with pelvic extension (below the pelvic brim) or primary peritoneal cancer. Substages are as follows:

Stage IIA - Extension to and/or implants on the uterus or fallopian tubes
Stage IIB - Extension to other pelvic intraperitoneal tissues

Stage III

In stage III, tumor involves one or both ovaries, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis, and/or metastasis to the retroperitoneal lymph nodes. Substages are as follows:

Stage IIIA - Positive retroperitoneal lymph nodes and/or microscopic metastasis beyond the pelvis
Stage IIIA1 - Positive retroperitoneal lymph nodes only (IIIA1), metastasis ≤10 mm (IIIA1[ii]), or metastasis >10 mm (IIIA1[ii])
Stage IIIA2 - Microscopic, extrapelvic (above the brim) peritoneal involvement ± positive retroperitoneal lymph nodes
Stage IIIB - Macroscopic, extrapelvic, peritoneal metastasis ≤2 cm ± positive retroperitoneal lymph nodes; includes extension to capsule of liver/spleen
Stage IIIC - Macroscopic, extrapelvic, peritoneal metastasis >2 cm ± positive retroperitoneal lymph nodes; includes extension to capsule of liver/spleen

Stage IV

Stage IV comprises distant metastasis, excluding peritoneal metastasis. Substages are as follows:

Stage IVA - Pleural effusion with positive cytology
Stage IVB - Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)

Other recommendations

Additional major recommendations from FIGO include the following:

Histologic type, including grading, should be designated at staging
The primary site (ovary, fallopian tube, or peritoneum) should be designated if possible
Tumors that may otherwise qualify for stage I but are involved with dense adhesions justify upgrading to stage II if tumor cells are histologically demonstrated in the adhesions

Treatment & Management

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Media Gallery

An enlarged ovary with a papillary serous carcinoma on the surface.
Metastases from epithelial ovarian carcinoma involving the omentum.
Inside of a large, smooth-surfaced tumor replacing the ovary. Final histologic studies indicated the tumor was a mucinous carcinoma of low malignant potential. Note the multiple cysts with thick septa between. This tumor was extensively sectioned and was a mucinous carcinoma of low malignant potential.
Granulosa cell tumor excised from a woman aged 44 years. Note the yellowish tumor that has eroded through, onto the surface of the ovary.
This photo shows a granulosa cell tumor, with the cut surface showing classic features of a hemorrhagic cyst and yellowish solid component.
Mature cystic teratoma of the ovary exhibiting multiple tissue types.
Mature cystic teratoma of the ovary with hair, sebaceous material, and thyroid tissue.
Dr. Oliver Zivanovic, MD, PhD, discusses the role of hyperthermic intraperitoneal chemotherapy in ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.
Dr. Oliver Zivanovic, MD, PhD, demonstrates hyperthermic intraperitoneal chemotherapy for ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.

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Author

Andrew E Green, MD Consulting Staff, Northeast Georgia Medical Center

Andrew E Green, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, Society of Gynecologic Oncology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Coauthor(s)

Agustin A Garcia, MD Associate Professor of Medicine, University of Southern California Keck School of Medicine

Agustin A Garcia, MD is a member of the following medical societies: European Society for Medical Oncology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Samina Ahmed, MD Fellow, Division of Oncology, Department of Medicine, University of Southern California, Keck School of Medicine

Samina Ahmed, MD is a member of the following medical societies: American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Chief Editor

Yukio Sonoda, MD Associate Professor, Weill Cornell Medical College; Associate Attending Surgeon, Gynecology Service, Department of Surgery, Memorial Hospital for Cancer and Allied Diseases; Associate Member, Memorial Sloan-Kettering Cancer Center

Yukio Sonoda, MD is a member of the following medical societies: AAGL, American College of Obstetricians and Gynecologists, American College of Surgeons, American Medical Association, American Society of Clinical Oncology, International Gynecologic Cancer Society, Japanese Medical Society of America, Korean American Medical Assocation, Society of Gynecologic Oncology, Society of Laparoscopic and Robotic Surgeons

Disclosure: Nothing to disclose.

Acknowledgements

Robert P Edwards, MD Professor, Department of Obstetrics, Gynecology, and Reproductive Science, University of Pittsburgh; Vice-Chair, Clinical Affairs, Director, Ovarian Cancer Center of Excellence, Magee-Womens Hospital of University of Pittsburgh

Robert P Edwards, MD is a member of the following medical societies: American Association for Cancer Research, American College of Obstetricians and Gynecologists, American College of Surgeons, American Medical Association, and Society for Gynecologic Investigation

Disclosure: Nothing to disclose.

C William Helm, MB, BCh, MA, FRCS(Edin), FRCS Professor, Division of Gynecologic Oncology, Saint Louis University School of Medicine

C William Helm, MB, BCh, MA, FRCS(Edin), FRCS is a member of the following medical societies: American College of Obstetricians and Gynecologists, European Society of Gynaecologic Oncology, and International Gynecologic Cancer Society

Disclosure: ThermaSolutions, Inc Grant/research funds Research Registry of patients treated with hyperthemic intraperitoneal chemotherapy; Sanofi-Aventis, Inc Grant/research funds Support for and investigator initiated research study of HIPEC for consolidation in ovarian cancer; ThermaSolutions, Inc Honoraria Speaking and teaching; UpToDate Royalty Online Text Book Chapters; Genzyme, Inc Honoraria Speaking and teaching

Warner K Huh, MD Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Senior Scientist, Comprehensive Cancer Center, University of Alabama School of Medicine

Warner K Huh, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American College of Surgeons, American Society of Clinical Oncology, Massachusetts Medical Society, and Society of Gynecologist Oncologists

Disclosure: MERCK Consulting fee Consulting; ROCHE PHARMA/DIAGNOSTICS Consulting fee Consulting; INTUITIVE SURGICAL Proctor Fee Consulting; Qiagen Consulting fee Consulting

Karen Loeb Lifford, MD Director of General Gynecology, Associate Program Director, Department of Obstetrics and Gynecology, Instructor, Brigham and Women's Hospital, Harvard Medical School

Karen Loeb Lifford, MD is a member of the following medical societies: Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Michel E Rivlin, MD Professor, Department of Obstetrics and Gynecology, University of Mississippi School of Medicine

Michel E Rivlin, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Mississippi State Medical Association, and Royal College of Surgeons of Edinburgh

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ovarian Cancer Workup

Approach Considerations

Screening

Tumor Markers

Imaging in Ovarian Cancer

GI Tract Workup

Biopsy

Mammography

Workup of Tumors of Low Malignant Potential

Workup of Malignant Germ Cell Tumors

Staging

Stage I

Stage II

Stage III

Stage IV

Other recommendations

References

Tables

Contributor Information and Disclosures

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