BlueCross BlueShield of Tennessee Medical Policy Manual

Ovarian Cancer Tumor Markers


A variety of substances, including enzymes, hormones, antigens, and proteins, can be detected in higher-than-normal amounts in the blood, urine, or body tissues of some individuals with certain types of cancer. These tumor markers may be produced by a tumor itself or by the body's response to the presence of cancer. The detection of tumor markers may be used to determine a diagnosis, disease progression, or response to treatment; however, these markers may also be elevated in individuals with benign conditions. The use of tumor markers for diagnosing ovarian cancer is insufficient in the absence of a comprehensive evaluation that includes abdominal/pelvic examination.

The most extensively studied serum marker is cancer antigen 125 (CA-125), which is a protein associated with epithelial ovarian malignancies. Elevation of CA-125 levels may occur in endometriosis, pregnancy, pelvic inflammatory disease and in other types of cancer. CA-125 appears to be most useful in identifying nonmucinous epithelial cancer.  Other tumor markers (e.g., alpha fetoprotein, beta human chorionic gonadotropin, carcinoembryonic antigen, CA 19-9, Inhibin and lactate dehydrogenase) can be elevated in less common ovarian histopathologies (e.g., carcinosarcomas, clear cell carcinoma, mucinous carcinoma, low-grade [grade 1] serous/endometrioid epithelial carcinoma, borderline epithelial tumors, malignant sex cord-stromal tumors and malignant germ cell tumor).

Human epididymis protein 4 (HE4) is a novel biomarker proposed as a replacement for or a complement to CA-125 for screening asymptomatic women and evaluating women with ovarian masses and monitoring ovarian cancer progression and recurrence. Data show that HE4 does not increase early enough to be useful in the detection of early-stage ovarian cancer.  There are also limited data on the diagnostic test performance of the HE4 test used to monitor disease progression and recurrence in women after initial treatment for epithelial ovarian cancer.





There is insufficient evidence to support the measurement of tumor markers not referenced within the medical appropriateness criteria and for testing asymptomatic, average risk individuals. 


American Cancer Society. (2020). Ovarian cancer. Retrieved May 15, 2020 from

American College of Obstetricians and Gynecologists. (2016, November). Practice Bulletin #174.Evaluation and management of adnexal masses. Retrieved May 22, 2020 from

American College of Obstetricians and Gynecologists. (2017, September; reaffirmed 2019). Committee opinion #716. The role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer in women at average risk. Retrieved March 15, 2021 from

BlueCross BlueShield Association. Evidence Positioning System. (1:2021). Serum biomarker human epididymis protein 4 (2.04.66). Retrieved March 12, 2021 from (26 articles and / or guidelines reviewed)

Buys, S., Partridge, E., Black, A., Johnson, C., Camerato, L., Isaacs, C. et al. (2011). Effect of screening on ovarian cancer mortality. The prostate, lung, colorectal and ovarian (PLCO) cancer screening randomized controlled trial. Journal of American Medical Association, 305 (22), 2295-2303. (Level 1 evidence)

Centers for Medicare & Medicaid Services. NCD for tumor antigen by immunoassay – CA 125 (190.28). Retrieved February 12, 2016 from

Dong, X., Men, X., Zhang, W., Lei, P. (2014).  Advances in tumor markers of ovarian cancer for early diagnosis. Indian Journal of Cancer, 51 Suppl 3, e72-e76. (Level 2 evidence)

Gentry-Maharah, A., Burnell, M., Dilley, J., Ryan, A., Karpinskyj, C., Gunu, R., et al. (2019). Serum HE4 and diagnosis of ovarian cancer in postmenopausal women with adnexal masses. American Journal of Obstetrics and Gynecology, 222(1), 56.e1-56.e17. (Level 2 evidence)

Giuliani, M., Gui, B., Valentini, A., Giovanni, S., Miccò, M., Rodolfino, E. (2017). Early detection of recurrence or progression disease in patients with ovarian cancer after primary debulking surgery: a diagnostic challenge still unresolved. Correlation between CT findings and CA 125 levels. Minerva Ginecologic, doi: 10.23736/S0026-4784.17.04062-X. Abstract retrieved July 7, 2017 from PubMed database.

National Cancer Institute. (2020, December). Ovarian, fallopian tube, and primary peritoneal cancer screening. Retrieved March 15, 2021 from     

National Comprehensive Cancer Network. (2021, February). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. Retrieved March 12, 2021 from the National Comprehensive Cancer Network.

National Institute for Health and Clinical Excellence. (2011, April). Ovarian cancer: the recognition and initial management of ovarian cancer. Retrieved May 30, 2012 from

Scaletta, G., Plotti, F., Luvero, D., Capriglione, S., Montera, R., Miranda, A., et al. (2017). The role of novel biomarker HE4 in the diagnosis, prognosis and follow-up of ovarian cancer: a systematic review. Expert Review of Anticancer Therapy, 17 (9), 827-839. Abstract retrieved August 14, 2017 from PubMed database.

Society of Gynecologic Oncologists. (2017, March). An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Retrieved June 20, 2018 from

Sölètormos, G., Duffy, M., Hassan, S., Verheijen, R., Tholander, B., Bast, R., et al. (2016). Clinical use of cancer biomarkers in epithelial ovarian cancer. International Journal of Gynecological Cancer, 26 (1), 43-51. (Level 1 evidence)

United States Preventive Services Task Force. (2018). Ovarian cancer screening. Retrieved May 30, 2019 from




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