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Gynecologic Tumor Markers

What is tumor markers?

Tumor markers are substances, usually proteins, that are produced by the body in response to cancer growth or by the cancer tissue itself and that may be detected in blood, urine, or tissue samples. Some tumor markers are specific for a particular type of cancer, while others are seen in several cancer types. Most of the well-known markers may also be elevated in non-cancerous conditions. Consequently, tumor markers alone are not diagnostic for cancer. The goal is to be able to screen for and diagnose cancer early, when it is the most treatable and before it has had a chance to grow and spread.

Tumor markers indicate biological changes that signal the existence of malignancy in a host organism. Can usually be detected in elevated quantities in the blood, urine, or body tissues of patients with certain types. Tumor markers are produced by the tumor itself or by the body in response to the presence of cancer. Following the development of monoclonal antibodies, an array of new tumor markers has been discovered. Tumor markers can be used to;

1. Screen a healthy or high-risk population for the presence of cancer,

2. Assist in confirming a diagnosis of cancer or of a specific type of cancer,
   

3. Assist in determining a patient's prognosis, and
   

4. Monitor the disease course in a patient in remission or in a patient who is undergoing surgery, radiation, or chemotherapy.
   

5. Currently, tumor markers are primarily used to help assess tumor response to treatment and to check for recurrence.

Tumor markers are glycoproteins that are usually detected by monoclonal antibodies.

They are produced by the tumor itself or by the body in response to the presence of cancer or certain benign conditions.

The levels of tumor marker are not altered in all cancer patients, especially in early stage cancer. The level of some tumor markers can be elevated in patients with noncancerous conditions.

Some tumor markers can be used for screening, diagnosis, management, determining response, and recurrence. Some markers show promise as prognostic indicators.

How are tumor markers used in cancer care?

Tumor markers are used in the detection, diagnosis, and management of some types of cancer. Although an abnormal tumor marker level may suggest cancer, this alone is usually not enough to diagnose cancer. Therefore, measurements of tumor markers are usually combined with other tests, such as a biopsy, to diagnose cancer.
Tumor marker levels may be measured before treatment to help doctors plan appropriate therapy. In some types of cancer, tumor marker levels reflect the stage (extent) of the disease.

Tumor marker levels also may be used to check how a patient is responding to treatment. A decrease or return to a normal level may indicate that the cancer is responding to therapy, whereas an increase may indicate that the cancer is not responding. After treatment has ended, tumor marker levels may be used to check for recurrence (cancer that has returned).

Types of Gynecologic Tumors

Just being a woman puts you at risk for cancer. There are many cancers that affect only women. Gynecologic cancer is a group of cancers that affect the tissue and organs of the female reproductive system. Each type of cancer is named after the organ it originates. Types of gynecologic cancer include:

• Ovarian

• Cervical

• Uterine (endometrial)

• Vulvar

• Vaginal

• Fallopian tube

• Gynecologic sarcomas

• Gestational trophoblastic disease, a type of cancer that develops in the uterus

• Pre-invasive diseases of the lower genital tract

Types of gynecologic tumor markers

Ovarian cancer, uterine cervical cancer, endometrial cancer, and trophoblastic neoplasms are gynecologic malignancies for which tumor markers are in clinical use. The following are important gynecologic tumor markers:

• Cancer antigen 125 (CA-125)

• Beta human chorionic gonadotropin (beta-hCG)

• Urinary gonadotropin fragment

• Alpha-fetoprotein (AFP)

• Inhibin

• Estradiol

• Carcinoembryonic antigen (CEA)

• Squamous cell carcinoma (SCC) antigen

• Müllerian inhibiting substance (MIS)

• Topoisomerase II

• Carbohydrate antigen 19-9

• Cancer antigen 27-29

• Human telomerase reverse transcriptase (hTERT)

• Ferritin

Other potential gynecologic tumor markers include the following:

• Lysophosphatidic acid

• MIB1-determined tumor growth fraction

• L1 (CAM)

• Mesothelin[2]

• Human epididymis protein 4 (HE4)

• Osteopontin

• Vascular endothelial growth factor (VEGF)

• Interleukin 8 (IL-8)

• Macrophage colony-stimulating factor (M-CSF)

• Insulinlike growth factor–binding protein-3

• Tumor-associated trypsin inhibitor

• Cyclin E

• OVX1

MAKERS FOR RESPONSE TO THERAPY AND RELAPSE

The following tumor markers are helpful in assessing response to chemotherapy and in determining relapse when monitoring patients with complete remission.

Squamous cell carcinoma antigen

The squamous cell carcinoma antigen level can be increased in patients with epidermoid carcinoma of the cervix, benign tumors of epithelial origin, and benign skin disorders.

Carcinoembryonic antigen

Most sweat gland tumors of the vulva stain positively for CEA. In most instances, the reaction for CEA occurs in cells that line cysts, form glands, or are arranged around a lumen. The reaction for CEA does not differentiate eccrine from apocrine adnexal tumors. In patients with vaginal adenosis, both surface columnar epithelium and glands may show focal cytoplasmic membrane staining for CEA. As the columnar cells are gradually replaced by the process of squamous metaplasia, CEA positivity may be observed in the cytoplasm of metaplastic cells. Malignant vulvar tumors of sweat gland origin stain positively for CEA. Both in situ and invasive adenocarcinomas underlying extramammary Paget disease of the anogenital area express CEA. CEA is also demonstrable in Paget cells in metastatic sites such as lymph nodes. CEA is present in most urothelial adenocarcinomas of the female urethra.

CEA levels are elevated in up to 35% of patients with endometrial cancer. CEA immunohistochemistry cannot distinguish between benign and malignant glandular proliferations of the uterine cervix; therefore, CEA staining is of no value in the differential diagnosis of endocervical and endometrial adenocarcinomas.
Most epithelial neoplasms of the ovary also express CEA. The neoplasms include, with decreasing intensity and frequency, Brenner, endometrioid, clear cell, and serous tumors. CEA is frequently present in patients with cancer that has metastasized to the ovary because the primary cancer is generally mammary or gastrointestinal in origin and these tumors frequently contain CEA.

Alpha-fetoprotein

AFP is a normal fetal serum protein synthesized by the liver, yolk sac, and gastrointestinal tract that shares sequence homology with albumin. AFP is a major component of fetal plasma, reaching a peak concentration of 3 mg/mL at 12 weeks of gestation. Following birth, AFP rapidly clears from the circulation because its half-life is 3.5 days. AFP concentration in adult serum is less than 20 ng/mL.

Most endodermal sinus tumors of the ovary express AFP. AFP is present within the cytoplasm of tumor cells and in the characteristic hyalin globules observed in the endodermal sinus tumor. AFP is also expressed by ovarian embryonal cell carcinoma, immature teratomas, and polyembryomas.

Lysophosphatidic acid

Lysophosphatidic acid stimulates cancer cell proliferation, intracellular calcium release, and tyrosine phosphorylation, including mitogen-activated protein kinase activation. Lysophosphatidic acid has been shown to be a multifunctional signaling molecule in fibroblasts and other cells. It has been found in the ascitic fluid of patients with ovarian cancer and is associated with ovarian cancer cell proliferation. Further studies are needed to determine the role of these markers.

Pros and cons of gynecologic tumor markers.

The use of a tumor marker not only depends upon its sensitivity and specificity, but also upon its ability to influence decisions between alternative plans for patient management. Use of beta human chorionic gonadotropin (hCG) for monitoring gestational trophoblastic neoplasia has set the standard to which other assays must be compared. Beta hCG and alphafetoprotein have provided useful markers for ovarian germ cell tumors. Recently, a monoclonal antibody-based immunoassay for CA 125 antigen has been used to monitor the treatment of epithelial ovarian carcinomas. Persistent elevation of CA 125 in serum has generally reflected persistence of disease at second look surveillance procedures. CA 125 levels can, however, return to within normal limits and residual disease can be found at laparoscopy or laparotomy. CA 125 shows promise for distinguishing benign from malignant pelvic masses. Trials are currently underway to evaluate the potential of CA 125 in combination with other markers to facilitate earlier detection of occult ovarian cancer.