The utility of serum biomarkers
Cancer antigen 125 (CA-125) testing may be helpful – in combination with other findings – for decision-making regarding the likelihood of malignancy and the need to refer patients. CA-125 is like Doppler in that a normal CA-125 cannot eliminate the possibility of cancer, and an abnormal CA-125 does not in and of itself imply malignancy. It’s far from a perfect cancer screening test.
CA-125 is a protein associated with epithelial ovarian malignancies, the type of ovarian cancer most commonly seen in postmenopausal women with genetic predispositions. Its specificity and positive predictive value are much higher in postmenopausal women than in average-risk premenopausal women (those without a family history or a known mutation that predisposes them to ovarian cancer). Levels of the marker are elevated in association with many nonmalignant conditions in premenopausal women – endometriosis, fibroids, and various inflammatory conditions, for instance – so the marker’s utility in this population is limited.
For women who have a family history of ovarian cancer or a known breast cancer gene 1 (BRCA1) or BRCA2 mutation, there are some data that suggest that monitoring with CA-125 measurements and TVUS may be a good approach to following patients prior to the age at which risk-reducing surgery can best be performed.
In an adolescent girl or a woman of reproductive age, we think less about epithelial cancer and more about germ-cell and stromal tumors. When a solid mass is palpated or visualized on imaging, we therefore will utilize a different set of markers; alpha-fetoprotein, L-lactate dehydrogenase, and beta-HCG, for instance, have much higher specificity than CA-125 does for germ-cell tumors in this age group and may be helpful in the evaluation. Similarly, in cases of a very large mass resembling a mucinous tumor, a carcinoembryonic antigen may be helpful.
A number of proprietary profiling technologies have been developed to determine the risk of a diagnosed mass being malignant. For instance, the OVA1 assay looks at five serum markers and scores the results, and the Risk of Ovarian Malignancy Algorithm (ROMA) combines the results of three serum markers with menopausal status into a numerical score. Both have Food and Drug Administration approval for use in women in whom surgery has been deemed necessary. These panels can be fairly predictive of risk and may be helpful – especially in rural areas – in determining which women should be referred to a gynecologic oncologist for surgery.
It is important to appreciate that an ovarian cyst or mass should never be biopsied or aspirated lest a malignant tumor confined to one ovary be potentially spread to the peritoneum.
Referral to a gynecologic oncologist
Postmenopausal women with a CA-125 greater than 35 U/mL should be referred, as should postmenopausal women with ascites, those with a nodular or fixed pelvic mass, and those with suspected abdominal or distant metastases (per a CT scan, for instance).
In premenopausal women, ascites, a nodular or fixed mass, and evidence of metastases also are reasons for referral to a gynecologic oncologist. CA-125, again, is much more likely to be elevated for reasons other than malignancy and therefore is not as strong a driver for referral as in postmenopausal women. Patients with markedly elevated levels, however, should probably be referred – particularly when other clinical factors also suggest the need for consultation. While there is no evidence-based threshold for CA-125 in premenopausal women, a CA-125 greater than 200 U/mL is a good cutoff for referral.
For any patient, family history of breast and/or ovarian cancer – especially in a first-degree relative – raises the risk of malignancy and should figure prominently into decision-making regarding referral. Criteria for referral are among the points discussed in the ACOG 2016 Practice Bulletin on Evaluation and Management of Adnexal Masses.1
A note on BRCA mutations
As the American College of Obstetricians and Gynecologists says in its practice bulletin, the most important personal risk factor for ovarian cancer is a strong family history of breast or ovarian cancer. Women with such a family history can undergo genetic testing for BRCA mutations and have the opportunity to prevent ovarian cancers when mutations are detected. This simple blood test can save lives.
A modeling study we recently completed – not yet published – shows that it actually would be cost effective to do population screening with BRCA testing performed on every woman at age 30 years.
According to the National Cancer Institute website (last review: 2018), it is estimated that about 44% of women who inherit a BRCA1 mutation, and about 17% of those who inherit a BRAC2 mutation, will develop ovarian cancer by the age of 80 years. By identifying those mutations, women may undergo risk-reducing surgery at designated ages after childbearing is complete and bring their risk down to under 5%.
An international take on managing adnexal masses
- Pelvic ultrasound should include the transvaginal approach. Use Doppler imaging as indicated.
- Although simple ovarian cysts are not precursor lesions to a malignant ovarian cancer, perform a high-quality examination to make sure there are no solid/papillary structures before classifying a cyst as a simple cyst. The risk of progression to malignancy is extremely low, but some follow-up is prudent.
- The most accurate method of characterizing an ovarian mass currently is real-time pattern recognition sonography in the hands of an experienced imager.
- Pattern recognition sonography or a risk model such as the International Ovarian Tumor Analysis (IOTA) Simple Rules can be used to initially characterize an ovarian mass.
- When an ovarian lesion is classified as benign, the patient may be followed conservatively, or if indicated, surgery can be performed by a general gynecologist.
- Serial sonography can be beneficial, but there are limited prospective data to support an exact interval and duration.
- Fewer surgical interventions may result in an increase in sonographic surveillance.
- When an ovarian lesion is considered indeterminate on initial sonography, and after appropriate clinical evaluation, a “second-step” evaluation may include referral to an expert sonologist, serial sonography, application of established risk-prediction models, correlation with serum biomarkers, correlation with MRI, or referral to a gynecologic oncologist for further evaluation.
From the First International Consensus Report on Adnexal Masses: Management Recommendations
Source: Glanc P et al. J Ultrasound Med. 2017 May;36(5):849-63.
Dr. Brown reported that she had received an earlier grant from Aspira Labs, the company that developed the OVA1 assay. Dr. Miller reported that he has no relevant financial disclosures.
References
1. Obstet Gynecol. 2016 Nov. doi: 10.1097/AOG.0000000000001768.
2. Cancer. 2007 Jan 15. doi: 10.1002/cncr.22371.
3. Clin Obstet Gynecol. 2015 Mar. doi: 10.1097/GRF.0000000000000083.
4. Ultrasound Q. 2013 Mar. doi: 10.1097/RUQ.0b013e3182814d9b.
5. Ultrasound Obstet Gynecol. 2008 Jun. doi: 10.1002/uog.5365.