Tumor Markers
A Review
A serum tumor marker is a substance produced by a tumor or produced by the host in response to a tumor that can be used to differentiate a tumor from normal tissue or to determine the presence of tumor based on measurement in the blood or secretions. Any cell product including enzymes, serum proteins, metabolites, receptors, and proteins encoded by genes can be used as tumor markers. These markers can be measured qualitatively or quantitatively by chemical, immunological, or molecular biological methods. Tumor markers can be directly identified within cells and tissues.
Although cancer results from the malignant transformation of a normal cell, there is little difference in phenotypic expression between a cancer cell and a normal cell. Mutations that result in malignant transformation do not seem to alter most of the genetic or phenotypic expressions of the cell except those related to cell growth regulation, in particular growth-promoting oncogenes and growth constraining tumor suppressor genes. Consequently, efforts spent to identify a tumor-specific marker or a tumor-specific epitope (antigenic determinant) have not been successful. Few markers are specific for a single individual tumor (tumor-specific markers) and most are found with different tumors of the same tissue type (tumor-associated markers).
The first tumor marker reported in 1847 was the Bence-Jones protein, a precipitation of protein seen in the urine of patients with multiple myeloma. More than 100 years after its discovery, the Bence-Jones protein was identified as the monoclonal light chain of immunoglobulin secreted by tumor plasma cells. The second phase in the evolution of tumor markers, from 1928 to 1963, included the discovery of hormones, enzymes, isoenzymes, and proteins and their application to the diagnosis of cancer and the use of the chromosomal analysis of tumors. Occasionally, such markers were useful in the diagnosis of individual tumors. The application of tumor markers for monitoring cancer patients began with discovery of alpha-fetoprotein (AFP) in 1963 and carcinoembryonic antigen (CEA) in 1965. The production of such markers in tumors, as well as during fetal development, led to the use of the term oncodevelopmental (carcinoembryonic) markers. The next phase in the evolution of tumor markers began in 1975 with the development of monoclonal antibodies and their use to detect oncofetal antigens and antigens derived from tumor cell lines. Examples include carbohydrate antigens, such as CA 19-9, CA 125, and CA 15-3. The specificity and sensitivity of currently used tumor markers have improved significantly over the last several decades. More recent advances in molecular techniques with the use of molecular probes and monoclonal antibodies to detect chromosome or protein alterations, including the study of oncogenes, suppressor genes, and genes involved in DNA repair have led to rapid understanding and use of tumor markers at the molecular level. Unlike earlier tumor markers, these newer markers can be linked to specific biological processes related to regulation of cell growth and tumor development including malignant transformation, proliferation, dedifferentiation, apoptotic cell death,
and metastasis.
The potential uses of serum tumor markers by oncologists and clinicians and tissue/cellular tumor markers by pathologists in the management of patients include screening, differential diagnosis in symptomatic patients, refinement of tissue diagnosis, staging, prognostic indicator for disease progression, monitoring effects of therapy, detection of disease recurrence and use as targets for localization and therapy.
With few exceptions, serum tumor markers are not recommended as a screening tool for the presence of malignancy, especially in an asymptomatic population. This is related to the lack of desired specificity and sensitivity of tumor markers in general as well as the low prevalence of cancer in the general population. The measurement of serum alpha-fetoprotein (AFP) in the screening 'for primary hepatoma in China and Alaska has proven to be useful particularly due to the high prevalence of liver cancer in that part of the world. Prostatic-specific antigen (PSA) has been used in combination with a digital rectal examination or transrectal ultrasound of the prostate for early detection of prostatic cancer. The benefit of screening with PSA is related to the tissue specificity of PSA and the relatively high prevalence of prostate cancer in men over 50 years of age. Because elevation of serum PSA can occur in benign prostatic hyperplasia, measurement of free PSA (fPSA) can help to distinguish between cancer and benign prostatic hyperplasia. Assuming the digital rectal exam is normal, men, whose total PSA test result falls between 4 and 10 ng/mL, still have a one in four chance of having prostate cancer. BPH is usually associated with a higher percentage of fPSA, while cancer is associated with a lower percentage.
The problems of both sensitivity and specificity associated with most serum tumor markers preclude their measurement for use in the diagnosis of cancer. The frequency of detecting elevated levels of tumor markers in nonmalignant conditions and the overlap observed between the normal concentrations and the concentrations of markers in patients with proven cancer discourages use in diagnosis. Serum tumor markers, however, have been used successfully as an adjunct test for cancer detection.
Tumor markers measured directly in tissues and cells have become an important tool of the surgical pathologist. Traditionally, the role of the surgical pathologist in the diagnosis and prognostic evaluation of tumors has been through the use of light microscopy in assessing the morphologic features of tumors. In recent years, immunohistochemistry (IHC) and molecular-based methods such as flow cytometric immunophenotypic analysis for evaluation of tissue and cytologic specimens have greatly enhanced the ability to precisely define the lines of differentiation of tumors and provide additional prognostic and therapy-related information. Immunohistochemistry (IHC) involves the application of antibody-mediated stains that can demonstrate the presence of antigenic determinants in cells and tissue components. The ever-increasing number of commercially available monoclonal antibodies is expanding the resolution capabilities of the IHC assay. Everything from surface receptors to intercellular matrix components to hormones can now be determined with relative ease and used to pinpoint the cell type, the degree of immunophenotypic differentiation, and even the functional state of the cell. IHC has greatly reduced the number of undifferentiated or unclassified tumors of unknown primary site. Pathologic staging of tumors has become more precise when the involvement of lymph nodes is established using IHC to detect small number of tumor cells. Important prognostic and therapeutic information for breast cancer including estrogen and progesterone receptor status and Her2/neu expression are determined with IHC. The use of IHC for the identification of surface lymphoid determinants has become essential in the precise diagnosis and classification of malignant lymphomas.
Most tumor markers values used to monitor treatment and progression of cancer correlate with the effectiveness of treatment and response to therapy. In general, marker values usually increase with progressive disease, decrease with remission, and do not change significantly with stable disease. Monitoring tumor markers for the detection of recurrence following surgical removal of a tumor is a very useful application of tumor markers.
The assessment of tumor aggressiveness and the prognosis for the outcome of a cancer patient has been enhanced in recent years with the use of certain tumor markers. Most risk factors associated with the process of tumor metastasis such as proteases and adhesion molecules are usually better markers for predicting prognosis. These markers are generally measured in tumor tissues. In solid tumors, such as breast carcinomas, IHC is becoming a required complement of predictive clinical value, determining estrogen and progesterone receptor status, and, more recently with the advent of antibody-based anti Her-2/neu therapy, assessing the expression pattern of this tyrosine-based receptor.
Antibodies to tumor markers labeled with a radioactive tag are used to localize tumor masses (radioimmunoscintigraphy) or to provide direction for labeled antibodies to attack the tumor site.
The evolution of molecular diagnostic techniques continues to expand the knowledge of the basic pathogenesis of tumors and has led to the discovery and application of molecular tumor markers. Diagnosis and prognosis have been enhanced by the use of these molecular markers. Molecular markers have played a role in the selection of specific therapeutic interventions (i.e. overexpression of the gene product associated with the Her-2/neu oncogene in breast cancer and the use of the chemotherapeutic agent Trastuzumab (Herceptin), a monoclonal antibody specifically targeted to the gene product) and in the risk assessment for the development of cancer (i.e. detection of mutations in BRCA 1 and 2 in somatic cells of individuals in breast cancer families who carry the mutated gene). These molecular techniques will eventually provide a complete understanding of the molecular biology of specific tumor types which will lead to the development of specific therapies and the rational selection of therapeutic modalities for a specific patient. Molecular markers will provide greater accuracy in the assessment of response to therapy and modification of therapy and will increase the ability to detect inherited and acquired risks which may lead to improved monitoring of cancer prevention.
References:
1. Chan, D., Sell, S.: Tumor Markers. In: Tietz Textbook of Clinical Chemistry. 3rd ed.
C.A. Burtis, E. R. Ashwood, Eds. W. B. Saunders Company, 1999, pp. 722-749.
2. Costa, J., Cordon-Cardo, C.: Cancer Diagnosis: Molecular Pathology. In: Cancer:
Principles and Practice of Oncology. 6th ed. V.T. DeVita, S. Hellman,
S.A. Rosenberg, Eds. Lippincott Williams and Wilkins, 2001, pp. 641-657.
3. Wu, J.: Diagnosis and Management of Cancer Using Serologic Tumor Markers.
In: Clinical Diagnosis and Management by Laboratory Methods. 20th ed.
J. B. Henry, Ed. W. B. Saunders Company, 2001, pp. 1028-1042.
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