Management of an adnexal mass is a common clinical scenario for obstetricians, gynecologists, and other providers in women’s health. Masses may be identified upon routine annual examinations, incidentally during imaging for other conditions, or when women present with pelvic and/or abdominal symptomatology. Many masses are ultimately found to be benign at time of surgery. Others, however, are malignant, and appropriate preoperative referral to a gynecologic oncologist for surgical management, staging, and determination of potential adjuvant therapy is critical to the outcome in these patients.
Epithelial ovarian cancer remains an aggressive disease. The American Cancer Society estimates that in 2019, 22,530 women will be diagnosed with ovarian cancer and 13,980 of them will die, ranking this malignancy the fifth most lethal behind lung, breast, colon and pancreas.1 Unfortunately, fewer than half of all women with ovarian cancer are cared for by a gynecologic oncologist, despite data supporting improved outcomes when a specialist is managing their care.2,3 These findings underscore the importance of appropriate and early referral.
Determining which women with adnexal masses will ultimately have cancer at time of surgery remains a clinical challenge. To assist in this risk stratification, initial evaluation of women with a pelvic mass has typically included ultrasound imaging and serum biomarker testing. To best care for patients most at risk, the American College of Obstetricians and Gynecologists (ACOG) recommends referral to a gynecologic oncologist for women who have a pelvic mass combined with elevated serum CA125, ascites, and/or evidence of metastatic disease.4 For women who have a mass but no ascites or imaging suggestive of metastatic disease, the accuracy of biomarkers for identification of those at highest risk of cancer is crucial to determine whether they would benefit from specialty referral. This review updates our current knowledge of preoperative biomarker utilization to optimize outcomes for women with a pelvic mass.
The serum biomarker CA125 has long been considered one of the primary evaluation tools in preoperative assessment of women with pelvic or adnexal masses. CA125 is a protein expressed in epithelial tissues, including the mesothelial lining of the pleura and peritoneum, and the Müllerian cells of the fallopian tube, endometrium, and endocervix.5
Surprisingly, CA125 is not typically expressed by the surface epithelium of benign ovaries. However, 90% of women with metastatic epithelial ovarian cancer have elevated serum levels, which has led to widespread adoption of this test in evaluation of potential malignancy. Unfortunately, the sensitivity and specificity of CA125 in predicting ovarian cancer remains low. Fifty percent of women with stage I ovarian cancers, where disease is confined to the ovaries, will have a normal preoperative CA125 level. In addition, several conditions will lead to serum elevations in CA125. These include both benign gynecologic processes, such as uterine fibroids, ovulation, menstruation, and endometriosis, and malignancies of other abdominal organs, such as gastric, colon, and pancreatic cancers.5 For these reasons, the US Food and Drug Administration (FDA) has not approved CA125 for preoperative use, but only for cancer surveillance after a diagnosis of ovarian cancer.
Over recent decades, limitations in the ability of CA125 to detect ovarian cancer have led investigators to evaluate additional serum proteins as potential candidates for biomarker utility, given the relative ease and reliable reproducibility of serum testing. Several initial studies in the early 2000s suggested combinations of serum markers, in contrast to CA125 alone, as a diagnostic tool in women with adnexal masses. These include the OvaSure serum test, which incorporated serum levels of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA125 into a diagnostic algorithm. The OvaCheck test similarly expanded this scale into proteomic profile analyses of thousands of serum proteins.6-8 Unfortunately, the lack of validation studies undermined the effectiveness of these modalities in clinical care.
The author reports no potential conflicts of interest with regard to this article.
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- Mercado C. Zingmond D, Karlan BY, et al. Quality of care in advanced ovarian cancer: the importance of provider specialty. Gynecol Oncol. 2010: 117(1): 18-22.
- Minig L, Padilla-Iserte P, Zorrero C. The relevance of gynecologic oncologists to provide high-quality of care to women with gynecological cancer. Frontiers Oncology. 2016;5:1-6.
- American College of Obstetricians and Gynecologists. Practice Bulletin No 174: Evaluation and management of adnexal masses. Obstet Gynecol. 2016; 128(5): e210-226.
- Bast RC, Xu FJ, Yu HY, Barnhill S, Zhang Z, Mills GB. CA-125: the past and the future. Int J Biol Markers. 1998;13(4):179-187.
- Visintin I, Feng Z, Longton G, et al. Diagnostic markers for early detection of ovarian cancer. Clin Cancer Res. 2008;14(4):1065-1072.
- Mor G, Visintin I, Lai Y, et al. Serum protein markers for early detection of ovarian cancer. Proc Natl Acad Sci USA. 2005;102(21):7677-7682.
- Petricoin EF, Ardekani Am, HItt BA, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet. 2002;359(9306):572-577.
- Hellstrom I, Raycraft J, Hayden-Ledbetter M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63(13):3695-3700.
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- Moore RG, McMeekin Ds, Brown AK, et al. A novel multiple marker bioassay utilizing He4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2009;112(1):40-46.
- Moore RG, Miller MC, Disilvestro P, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. 2011;118(2 pt 1):280-288.
- Ueland FR, Desimone CP, Seamon LG, et al. Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors. Obstet Gynecol. 2011;117(6):1289-1297.
- Ware Miller R, Smith A, DeSimone CP, et al. Performance of the American College of Obstetricians and Gynecologists’ ovarian tumor referral guidelines with a multivariate index assay. Obstet Gynecol. 2011;117(6):1298-1306.
- Coleman RL, Herzog TJ, Chan DW, et al. Validation of a second-generation multivariate index assay for malignancy risk of adnexal masses. Am J Obstet Gynecol. 2016;82:e1-e11.
- Urban RR, Pappas TC, Bullock RG, et al. Combined symptom index and second-generation multivariate biomarker test for prediction of ovarian cancer in patients with an adnexal mass. Gynecol Oncol. 2018;150:318-323.