Tumor markers are a group of proteins, hormones, enzymes, receptors, and other cellular products that are overexpressed (produced in higher than normal amounts) by malignant cells. Tumor markers are usually normal cellular constituents that are present at normal or very low levels in the blood of healthy persons. If the substance in question is produced by the tumor, its levels will be increased either in the blood or in the tissue of origin.
The majority of tumor markers are used to monitor patients for recurrence of tumors following treatment. In addition, some markers are associated with a more aggressive course and higher relapse rate and have value in staging and prognosis of the cancer. Most tumor markers are not useful for screening because levels found in early malignancy overlap the range of levels found in healthy persons. The levels of most tumor markers are elevated in conditions other than malignancy, and are therefore not useful in establishing a diagnosis.
Tumor markers are sometimes elevated in nonmalignant conditions. Not every tumor will cause a rise in the level of its associated marker, especially in the early stages of some cancers. When a marker is used for cancer screening or diagnosis, the physician must confirm a positive test result by using imaging studies, tissue biopsies, and other procedures. False positive results may occur in laboratory tests when the patient has cross-reacting antibodies that interfere with the test.
Physicians use changes in tumor marker levels to follow the course of a patient's disease, to measure the effect of treatment, and to check for recurrence of certain cancers. Tumor markers have been identified in several types of cancer, including malignant melanoma; multiple myeloma; and bone, breast, colon, gastric, liver, lung, ovarian, pancreatic, prostate, renal, and uterine cancers. Serial measurements of a tumor marker are often an effective means to monitor the course of therapy. Some tumor markers can provide physicians with information used in staging cancers, and some help predict the response to treatment. A decrease in the levels of the tumor marker during treatment indicates that the therapy is having a positive effect on the cancer, while an increase indicates that the cancer is growing and not responding to the therapy.
There are five basic types of tumor markers.
ENZYMES. Many enzymes that occur in certain tissues are found in blood plasma at higher levels when the cancer involves that tissue. Enzymes are usually measured by determining the rate at which they convert a substrate to an end product, while most tumor markers of other types are measured by a test called an immunoassay. Some examples of enzymes whose levels rise in cases of malignant diseases are acid phosphatase, alkaline phosphatase, amylase, creatine kinase, gamma glutamyl transferase, lactate dehydrogenase, and terminal deoxynucleotidyl transferase.
TISSUE RECEPTORS. Tissue receptors, which are proteins associated with the cell membrane, are another type of tumor marker. These substances bind to hormones and growth factors, and therefore affect the rate of tumor growth. Some tissue receptors must be measured in tissue samples removed for a biopsy, while others are secreted into the extracellular fluid (fluid outside the cells) and may be measured in the blood. Some important receptor tumor markers are estrogen receptor, progesterone receptor, interleukin-2 receptor, and epidermal growth factor receptor.
ANTIGENS. Oncofetal antigens are proteins made by genes that are very active during fetal development but function at a very low level after birth. The genes become activated when a malignant tumor arises and produce large amounts of protein. Antigens comprise the largest class of tumor marker and include the tumor-associated glycoprotein antigens. Important tumor markers in this class are alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), prostate specific antigen (PSA), cathespin-D, HER-2/neu, CA-125, CA-19-9, CA-15-3, nuclear matrix protein, and bladder tumor-associated antigen.
ONCOGENES. Some tumor markers are the product of oncogenes, which are genes that are active in fetal development and trigger the growth of tumors when they are activated in mature cells. Some important oncogenes are BRAC-1, myc, p53, RB (retinoblastoma) gene (RB), and Ph 1 (Philadelphia chromosome).
HORMONES. The fifth type of tumor marker consists of hormones. This group includes hormones that are normally secreted by the tissue in which the malignancy arises as well as those produced by tissues that do not normally make the hormone (ectopic production). Some hormones associated with malignancy are adrenal corticotropic hormone (ACTH), calcitonin, catecholamines, gastrin, human chorionic gonadogropin (hCG), and prolactin.
Currently, there are over 60 analytes that are used as tumor markers. All of the enzymes and hormones mentioned above have been approved as tumor markers by the Food and Drug Administration (FDA), but most of the others are not; they have been designated for investigation purposes only. The following list describes the most commonly used tumor markers approved by the FDA for screening, diagnosis, or monitoring of cancer.
Determination of the circulating level of tumor markers requires a blood test performed by a laboratory scientist. A nurse or phlebotomist usually draws the patient's blood; he or she ties a tourniquet above the patient's elbow, locates a vein near the inner elbow, cleanses the skin overlying the vein with an antiseptic solution, and inserts a sterile needle into that vein. The blood is drawn through the needle into an attached vacuum tube. Collection of a blood sample takes only a few minutes.
Tissue samples are collected by a physician at the time of surgical or needle biopsy. A urine sample is collected by the patient, using the midstream void technique.
Aftercare following a blood test consists of routine care of the area around the puncture site. Pressure is applied for a few seconds and the wound is covered with a bandage. If a bruise or swelling develops around the puncture site, the area is treated with a moist warm compress.
The risks associated with drawing blood include dizziness, bruising, swelling, or excessive bleeding from the puncture site. As previously mentioned, the results of blood tests should be interpreted with caution. A single test result may not yield clinically useful information. Several laboratory reports over a period of months may be needed to evaluate treatment and identify recurrence. Positive results must be interpreted cautiously because some tumor markers are increased in nonmalignant diseases and in a small number of apparently healthy persons. In addition false negative results may occur because the tumor does not produce the marker, and because levels seen in healthy persons may overlap those seen in the early stages of cancer. A false positive result occurs when the value is elevated even though cancer is not present. A false negative result occurs when the value is normal but cancer is present.
Reference ranges for tumor markers will vary from one laboratory to another because different antibodies and calibrators are used by various test systems. The values below are representative of normal values or cutoffs for commonly measured tumor markers.
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Victoria E. DeMoranville Mark A. Best