Tumor markers are proteins, antigens, or biologically active substances abnormally expressed or produced reactively by tumor cells. These markers can be detected in tissues, blood, bodily fluids, or excretions of cancer patients. They provide certain insights into the existence and growth of tumors and aid in diagnosis, differential diagnosis, treatment monitoring, and prognosis evaluation.
Tumor-Associated Antigens and Proteins
Carbohydrate Antigen 125 (CA125)
Detection Methods and Reference Values
The detection of CA125 (carbohydrate antigen 125) commonly utilizes radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA) with standardized kits. The typical reference range for serum detection is <35 U/mL.
Clinical Significance
CA125 is a high-molecular-weight glycoprotein associated with Müllerian-derived epithelial tissues. It shows positive expression in the epithelium of embryonic coelomic cavities and amniotic membranes and, in adults, is distributed in the endometrium, fallopian tube mucosa, cervical mucosa, peritoneum, pleura, and pericardium. It is expressed positively in most serous ovarian adenocarcinomas, with an accuracy rate exceeding 80%. CA125 is currently the most widely used tumor marker for epithelial ovarian cancer. It is frequently utilized in the clinical setting for the differential diagnosis of pelvic masses.
In postmenopausal women presenting with adnexal masses and elevated CA125 levels (>200 U/mL), the positive predictive value for diagnosing malignant ovarian tumors reaches 96%. However, specificity is lower for premenopausal patients. CA125 also plays an important role in monitoring disease progression and prognosis after tumor treatment and is particularly sensitive for evaluating therapeutic efficacy. CA125 levels in the blood decrease significantly after effective surgical resection or successful chemotherapy. Sustained elevation of CA125 suggests the possibility of residual lesions, recurrence, or progression. For patients whose CA125 levels remain elevated after treatment or briefly return to normal but subsequently rise again, there is a significantly increased likelihood of recurrence and metastasis. Persistent elevation of CA125 is thought to indicate a risk of tumor recurrence within 2-4 months, with a recurrence rate of up to 92.3%, even when no tumor is detected during secondary investigations. In such cases, metastases may have already occurred in retroperitoneal or inguinal lymph nodes.
CA125 also demonstrates some sensitivity for diagnosing endocervical adenocarcinoma and endometrial carcinoma. For primary adenocarcinomas, sensitivity ranges from 40% to 60%, while sensitivity for detecting recurrence is approximately 60% to 80%. Elevated CA125 levels can also be observed in benign gynecological conditions such as endometriosis and chronic pelvic inflammatory disease, but levels rarely exceed 200 U/mL.
Human Epididymis Protein 4 (HE4)
Detection Methods and Reference Values
The detection of HE4 (human epididymis protein 4) is performed using standardized kits. The normal reference range is <150 pmol/L.
Clinical Significance
HE4 has emerged as a highly recognized marker for epithelial ovarian carcinoma, following CA125. HE4 is not expressed in normal ovarian surface epithelium but is overexpressed in serous ovarian carcinomas and endometrioid carcinomas. Studies indicate that 93% of serous ovarian carcinomas and 100% of endometrioid ovarian carcinomas express HE4. Compared to CA125, HE4 is superior in distinguishing between benign and malignant ovarian tumors.
The combined use of HE4 and CA125 demonstrates significant clinical value in early diagnosis, disease monitoring, postoperative recurrence surveillance, and differentiating malignant from benign ovarian tumors. The Risk of Ovarian Malignancy Algorithm (ROMA) integrates CA125, HE4, and menopausal status to calculate a risk index (RI) for ovarian cancer. ROMA's sensitivity and specificity for diagnosing epithelial ovarian cancer in premenopausal women are 100% and 74.2%, respectively. For women of any age, ROMA achieves a sensitivity of 93.8%, a specificity of 74.9%, and a negative predictive value of 99%.
HE4 also has diagnostic utility for endometrial carcinoma. Its detected levels are strongly associated with clinical staging, degree of differentiation, and other pathological characteristics of endometrial carcinoma.
Carbohydrate Antigen 19-9 (CA19-9)
Detection Methods and Reference Values
CA19-9 (carbohydrate antigen 19-9) is commonly measured using single-antibody or double-antibody radioimmunoassay (RIA). The normal reference range in serum is <37 U/mL.
Clinical Significance
CA19-9 is a carbohydrate antigen detectable by monoclonal antibodies produced against tumor cells. In addition to serving as a marker for gastrointestinal tumors such as pancreatic cancer, colorectal cancer, gastric cancer, and liver cancer, approximately 50% of epithelial ovarian tumors also show CA19-9 positivity. The positivity rate is as high as 76% in mucinous ovarian carcinomas and 27% in serous tumors. Furthermore, positive CA19-9 expression can also be observed in ovarian mature teratomas, endometrial carcinomas, and cervical adenocarcinomas.
Alpha-Fetoprotein (AFP)
Detection Methods and Reference Values
AFP (alpha-fetoprotein) is a glycoprotein produced by fetal hepatocytes and the yolk sac. Its measurement is typically performed using RIA or ELISA. The normal reference range for serum AFP is ≤20 µg/L.
Clinical Significance
AFP is a protein product produced during the embryonic stage, with extremely low levels in adult serum. However, AFP synthesis can be reactivated in certain malignancies, such as liver cancer and ovarian germ cell tumors. Among ovarian germ cell tumors, certain subtypes exhibit significantly elevated AFP levels. For example, yolk sac tumors (endodermal sinus tumors)—formed by the differentiation of primitive germ cells toward the yolk sac—often exhibit serum AFP levels >1,000 µg/L. Embryonal carcinomas and immature teratomas of the ovary may also have elevated AFP levels, with some cases exceeding 1,000 µg/L.
Following surgery and chemotherapy, AFP levels generally return to baseline or become undetectable. A sustained negative AFP level for one year post-treatment is often associated with no recurrence during long-term clinical follow-up. Conversely, an increase in AFP levels, even in asymptomatic patients, may indicate occult relapse or metastasis, necessitating close monitoring and prompt intervention. AFP is particularly valuable for the diagnosis and monitoring of ovarian malignant germ cell tumors, especially yolk sac tumors. Notably, AFP levels do not typically rise in dysgerminomas.
Carcinoembryonic Antigen (CEA)
Detection Methods and Reference Values
CEA (carcinoembryonic antigen) is primarily measured using RIA or ELISA. The normal threshold for plasma CEA levels varies depending on the detection method but is generally ≤2.5 µg/L. A normal curve should be established for each method, with levels >5 µg/L often considered abnormal.
Clinical Significance
CEA is a tumor-associated embryonic antigen and glycoprotein. Fetal gastrointestinal tissues, pancreas, and liver have the capacity to synthesize CEA, but its levels in adult plasma are negligible. CEA serves as a broad-spectrum tumor marker, with elevated levels found in cancers such as colorectal cancer, breast cancer, gastric cancer, lung cancer, pancreatic cancer, and others. In gynecological malignancies, including cervical cancer, endometrial cancer, epithelial ovarian cancer, vaginal cancer, and vulvar cancer, CEA levels can also be elevated.
Among gynecological cancers, mucinous ovarian adenocarcinomas exhibit the highest rate of CEA positivity, followed by Brenner tumors, endometrioid carcinomas, and clear cell carcinomas. Serous tumors show relatively lower CEA positivity rates. Variations in CEA positivity are linked to tumor malignancy. For benign mucinous ovarian tumors, the positivity rate is around 15%. This increases to 80% for borderline tumors and 100% for malignant mucinous ovarian tumors. Approximately 50% of ovarian cancer patients demonstrate persistently elevated serum CEA levels, with poorly differentiated mucinous carcinomas showing the most significant elevations. CEA measurements play an important role in the dynamic monitoring of gynecological tumor progression and assessing treatment efficacy.
Lactate Dehydrogenase (LDH)
Detection Methods and Reference Values
LDH (lactate dehydrogenase) is commonly measured using forward or reverse reaction methods. The normal reference range for adult serum is 120–250 U/L.
Clinical Significance
LDH is a widely utilized oxidation-reduction enzyme involved in anaerobic glycolysis and gluconeogenesis. Increased LDH levels can occur in ovarian germ cell tumors. In dysgerminomas, LDH levels tend to correlate with tumor size, with elevated levels associated with more extensive disease and poorer prognosis. Elevated LDH levels may also be observed in embryonal carcinomas and yolk sac tumors in some patients.
Neuron Specific Enolase (NSE)
Detection Methods and Reference Values
NSE (neuron specific enolase) is measured using ECLIA or ELISA methods. The normal reference range for serum NSE is <13 µg/L (as measured by ELISA).
Clinical Significance
NSE is an acidic enzyme involved in glycolysis. Enhanced glycolysis in cancerous tissues and accelerated cell proliferation cycles can lead to an increased release of NSE from cells into the bloodstream, resulting in elevated serum levels. In addition to being associated with pheochromocytomas, pancreatic islet cell tumors, medullary thyroid cancer, and melanomas, abnormal NSE expression can also be observed in immature ovarian teratomas, ovarian dysgerminomas, and cervical neuroendocrine carcinomas.
Squamous Cell Carcinoma Antigen (SCCA)
Detection Methods and Reference Values
SCCA (squamous cell carcinoma antigen) is commonly measured using RIA or ELISA methods. Chemiluminescent assays may also be employed to improve sensitivity. The normal reference range for serum SCCA is ≤1.5 µg/L.
Clinical Significance
SCCA is a tumor-associated glycoprotein antigen isolated from cervical squamous epithelial cell carcinoma, with a molecular weight of 48,000 kD. It is highly specific for diagnosing most squamous epithelial cell carcinomas. Elevated SCCA levels are detected in over 70% of patients with cervical squamous cell carcinoma, whereas only approximately 15% of cervical adenocarcinoma cases show elevated SCCA levels. For vulvar and vaginal squamous epithelial cell carcinomas, diagnostic sensitivity ranges from 40% to 50%. SCCA levels are closely associated with disease progression and clinical staging in cervical squamous cell carcinoma patients, with significant increases observed when lymph nodes are affected. Following successful treatment, SCCA levels decline over time.
SCCA is also valuable for evaluating therapeutic responses in cervical cancer patients. Persistently rising levels after chemotherapy suggest insensitivity to the current treatment regimen, warranting adjustments or alternative approaches. SCCA demonstrates sensitivity rates of 65%–85% for predicting tumor recurrence and begins to rise approximately three months before abnormalities are detected via imaging. As such, SCCA provides useful insights into prognosis prediction and disease monitoring in tumor patients.
Estrogen Receptor (ER) and Progesterone Receptor (PR)
Detection Methods and Reference Values
ER (estrogen receptor) and PR (progesterone receptor) are typically measured using monoclonal antibody-based immunohistochemical staining methods. Positive staining is localized to the cell nucleus.
Clinical Significance
ER and PR bind to their respective hormones to produce specific physiological or pathological effects. Hormone-receptor binding is characterized by strong specificity, high affinity, and low binding capacity. ER and PR are mainly distributed in target organs such as the uterus, vagina, and breasts. Studies suggest that ER and PR, under the influence of sex hormones, can play a role in the occurrence and progression of gynecological tumors. Intratumoral steroid hormone receptor levels can serve as predictors for endocrine treatment outcomes and prognostic evaluations.
Estrogen is known to stimulate ER and PR synthesis, while progesterone inhibits ER synthesis and indirectly suppresses PR synthesis. Type I endometrial cancer, which is associated with excessive estrogen stimulation, frequently demonstrates positive ER and PR expression, particularly in lower-grade endometrioid adenocarcinomas. In contrast, serous carcinoma typically shows no or weak ER/PR expression. Furthermore, poorly differentiated endometrioid adenocarcinomas may exhibit negative or weakly positive ER/PR expression due to their low degree of differentiation. ER and PR assessments also provide significant value in evaluating conservative treatment outcomes for endometrial cancer.
In addition to their diagnostic utility, combined use of ER, PR, and other immunohistochemical markers such as PAX8, CDX2, and SATB2 can aid in distinguishing between primary ovarian tumors and metastatic tumors.