Academy of Diagnostics & Laboratory Medicine - Scientific Short

What are the tumor markers that best identify the epithelial ovarian cancer?

José D. Santotoribio

The World Health Organization recognizes eight histological subtypes of epithelial ovarian tumors: serous, mucinous, endometrioid, clear cell, transitional cell, squamous cell, mixed epithelial and undifferentiated. Serous is the most frequent histological subtype of ovarian carcinoma and makes up 30-70% of all diagnoses; however, mucinous subtype is the most common form of ovarian carcinoma in patients under 40 years old.

Some guidelines on the recognition and initial management of ovarian cancer recommend that general practitioners should measure serum cancer antigen 125 (CA 125) in primary care in women with symptoms that suggest ovarian cancer. Also, a diagnostic approach based on the use of CA 125 in association with ultrasonography has been suggested for the early diagnosis of ovarian cancer. However, 20% of ovarian cancers do not express CA 125 and abnormal serum levels CA 125 may be found in patients with benign ovarian tumors. It is therefore necessary to combine CA 125 with other tumor markers that can provide better diagnostic accuracy.

Recently, another tumor marker for ovarian cancer has been proposed, serum human epididymis protein 4 (HE4), frequently overexpressed in ovarian cancers, especially in serous and endometrioid histology. HE4 improves the utility of CA 125 as a tumor marker in ovarian cancer, and using both markers simultaneously increases the tumor marker sensitivity. In addition, different studies propose the use of a Risk of Ovarian Malignancy Algorithm (ROMA) to improve the sensitivity and specificity of the combined use of both tumor markers in patients with abdominal masses. The combination of HE4 and CA 125 has the best diagnostic power in comparing benign tumors to epithelial ovarian cancer [1, 2]. However, serum HE4 concentration is low in patients with mucinous ovarian tumors and is not useful to predict whether a mucinous ovarian tumour is benign or malignant. The combination of CA 125 and HE4 shows low sensitivity in women under 40 years old who have higher incidence of mucinous ovarian cancer (MOC).

Serum cancer antigen 19.9 (CA 19.9) has low accuracy for diagnosis of serous ovarian cancer, but preoperative elevated CA 19.9 levels could be related to a higher probability of MOC. In my hospital, we have studied the tumor markers for diagnosis of MOC [3]. CA 19.9 and CA 125 showed similar sensitivity (50%) with high specificity. We performed a linear regression of a combination of CA 19.9 and CA 125 values. The regression formula was: CA 19.9+125 = 0.00102 x CA 19.9 + 0.00057 x CA 125. CA 19.9+125 exhibited 66.7% sensitivity and 95.1% specificity (cut-off value = 0.2327), increasing 16.7% sensitivity compared with using only CA 19.9 or CA 125 (table 1).

In conclusion, CA 125 and HE4 appear to be serum tumor markers that best identify epithelial ovarian cancer in patients over 40 years old and CA 19.9 in combination with CA 125 in women under 40 years old.


  1. Moore RG, McMeekin DS, Brown AK, DiSilvestro P, Miller MC, Allard WJ, et al. A novel multiple marker bioassay utilizing HE4 and CA 125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol 2009;112:40-6.
  2. Molina R, Escudero JM, Augé JM, Filella X, Foj L, Torné A, et al. HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumor Biol 2011;32:1087-95.
  3. Santotoribio JD, Cañavate-Solano C, García-de la Torre A, Arce-Matute F, Pérez-Ramos S. CA 19.9 and CA 125 for diagnosis of mucinous ovarian cancer. 2015 AACC Annual Meeting Abstracts S125:#A-351.

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Fellows of the Academy use the designation of FADLM. This designation is equivalent to FACB and FAACC, the previous designations used by fellows of the National Academy of Clinical Biochemistry and AACC Academy. Those groups were rebranded as Academy of Diagnostics & Laboratory Medicine in 2023.