Tumor Markers - AFP, HCG, CA-125

Tumor markers are molecules occurring in blood or tissue that are associated with cancer and whose measurement or identification is useful in patient diagnosis or clinical management. The ideal marker would be a "blood test" for cancer in wich a positive result would occur only in patients with malignancy, one that would correlate with stage and response to treatment and that was easily and reproducibly measured. No tumor marker now available has met this ideal.

Tumor markers can be used for one of four purposes: (1) screening a healthy population or a high risk population for the presence of cancer; (2) making a diagnosis of cancer or of a specific type of cancer; (3) determining the prognosis in a patient; (4) monitoring the course in a patient in remission or while receiving surgery, radiation, or chemotherapy.

No test meets all of those requirements. Specifically, no marker has been established as a pratical cancer screening tool either in a general healthy population or in most high risk poulations. The reason for this is the relative lack of sensitivity and specificity of the available tests, given the low prevalence of cancers in most population groups. Given the low prevalence of cancer in general, even tests that are highly sensitive and specific may have low predictive values.

Tumor markers include many substances that are not readily systematically organized.Those discussed here are generally products or the cancer cell, although none is unique to cancer cells; they represent aberrant tumor production of a normal element. Some markers are produced by the organism in response to the cancer's presence.

Tumor Antigens
Include markers defined by both monoclonal antibodies and polyclonal antisera, often the so called oncofetal antigens. The oncofetal substances, present in embryo or fetus, diminish to low levels in the adult but reappear in the tumor.

Carcinoembryonic Antigen
Tumor marker, CEA: Carcinoembryonic antigen (CEA) is a protein found in many types of cells but associated with tumors and the developing fetus. CEA is tested in blood. The normal range is <2.5 ng/ml in an adult non-smoker and <5.0 ng/ml in a smoker. The CEA was one of the first oncofetal antigens to be described and exploited clinically. It is a complex glycoprotein of molecular weight 20,000, that is associated with the plasma membrane of tumor cells, from wich it may be released into the blood.

Although CEA was first indentified in colon cancer, an abnormal CEA blood level is specific neither for colon cancer nor for malignancy in general. Elevated CEA levels are found in a variety of cancers other than colonic, including pancreatic, gastric, lung, and breast. It is also detected in benign conditions including cirrhosis, inflamatory bowel disease, chronic lung disease, and pancreatitis. The CEA was found to be elevated in up to 19 percent of smokers and in 3 percent of a healthy control population. Thus, the test for CEA cannot substitute for a pathological diagnosis.

As a screening test, the CEA is also inadequate. Since cancer prevalence in a healthy population is low, an elevated CEA has an unacceptably low positive predictive value, with excess false positives. Also, since elevated CEA occurs in the advanced stage of incurable cancer but is low in the early, curable disease, the likelihood of a positive result affecting a patient's survival is diminished.

The CEA has been sugested as having prognostic value for patients with colon cancer. Preoperative CEA values have been positively correlated with stage and negatively correlated with disease free survival.

Although not satisfactory for screening a healthy population, CEA has been used to monitor recurrence. Early data suggested that CEA prededed clinical relapse by several months. Subsequently, several investigators have examined intensive, serial CEA monitoring as an indicator for second look surgery in the hope that relapse could be detected at a time when surgical ressection for cure was still possible. Criteria for reoperation included a significant rise of CEA above a base line level on serial determinations and absence of obvious unresectable disease on staging workup. Determinations of CEA should be done frequently: at a minimum of every 3 months and if possible every 1 month to 2 months. Elevations above baseline should be verified rapidly to exclude laboratory error.

The CEA is of some use as a monitor in treatment. Usually the CEA returns to normal within 1 to 2 months of surgery, but if it returns elevated persistent disease may be indicated. The test is not infallible in patients treated with radiotherapy and chemotherapy but can be useful in those whose tumor is not measurable.

The CEA is often positive in malignancies other than colonic. In cancer of the breast, lung, pancreas, stomach, and ovary the CEA may be elevated and can be used to monitor the progress of disease or response to treatement.

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

AFP is of importance in diagnosing hepatocellular carcinoma and may be useful in screening procedures. AFP elevation is more common in areas where hepatocellular carcinoma is endemic, such as Africa and in patients who are HBsAg positive.

AFP is a marker for hepatocellular and germ cell (nonseminoma) carcinoma.1 It is a glycoprotein produced in large amounts during fetal life and is homologous to albumin. In healthy adults, less than 10 µg/L of AFP is found in the circulation. AFP is elevated in normal pregnancy, benign liver disease (hepatitis, cirrhosis), as well as in cancer.

An elevated AFP has been termed by Sell "the single most discriminating laboratory test indicative of malignant disease now available." As such, it could be valuable in screening for hepatocellular carcinoma in high risk populations.

AFP is elevated in testicular germ cell tumors containing embryonal or endodermal sinus elements. A defenitive positive marker value is highly sensitive in indicating relapse or response to treatment.

The AFP is less frequently elevated in other malignancies such as pancreatic cancers, gastric cancers, colonic cancers, and bronchogenic cancers. This elevation was not necessarily associated with liver metastases.

The AFP is rarely elevated in healthy persons, and a rise is seen in only a few disease states. Elevation occurs in certain liver diseases, especially acute viral or drug induced hepatitis and conditions associated with hepatic regeneration. In general, the elevations are under 500 ng/ml and do not denote hepatocellular carcinoma. Is also elevated in ataxia-telangiectasia and in hereditary tyrosinosis.

Thus, AFP is a useful marker in hepatocellular carcinoma and germ cell tumors, the only conditions associated with extreme elevations greater than 500 ng/ml. In both tumors it has value in diagnosis and monitoring of therapy. In the former, wich is one of the most common tumors worldwide, AFP may be of use in screening.

CA 125
CA125 is an antigen present on 80 percent of nonmucinous ovarian carcinomas. It is defined by a monoclonal antibody ( OC125 ) that was generated by immunizing laboratory mice with a cell line established from human ovarian carcinoma. It circulates in the serum of patients with ovarian carcinoma and was therefore investigated for possible use as a marker.

CA125 is often elevated in patients with ovarian cancer, its level following the patient's clinical course. With surgical resection or chemotherapy, the level correlates with patient response. Thus, it is superior to other markers such as CEA.

The CA125 is elevated in other cancers including endometrial, pancreatic, lung, breast, and colon cancer, and in menstruation, pregnancy, endometriosis, and other gynecologic and non gynecologic conditions.

Because of the low prevalence of ovarian cancer, the test is not itself useful in screening.

CA19-9
CA19-9 is a monoclonal antibody generated against a colon carcinoma cell line to detect a monosialoganglioside found in patients with gastrointestinal adenocarcinoma. It is found it to be elevated in 21 to 42 percent of cases of gastric cancer, 20 to 40 percent of colon cancer, and 71 to 93 percent of pancreatic cancer, and has been proposed to differentiate benign from malignant pancreatic disease, but this capability remains to be established.

Prostate-Specific Antigen
The PSA screening test is a blood test that looks for a specific tumor marker. In general, tumor markers are produced by the tumor itself or by our body in response to the presence of cancer or non-cancerous conditions. If a tumor marker level is higher than normal, the patient is examined more closely to look for cancer or other conditions. The most commonly tested tumor marker for the prostate gland is prostate specific antigen. It is normally present in low levels in the blood of all adult men. The normal range is 0 to 4 ng/ml.

PSA is prostate-specific, not cancer-specific. A variety of conditions can raise PSA levels: prostatitis (prostate inflammation), benign prostatic hypertrophy (prostate enlargement), and prostate cancer. PSA levels can also be influenced by a number of other things. Some prostate glands normally produce more PSA than others. PSA levels tend to increase with age. And, PSA levels can vary with race: African Americans often have higher PSA levels; Asian men often have lower PSA levels.

PSA seems to have the capability of achieving at least one of the characteristics of an ideal tumor marker- tissue specificity; it is found in normal prostatic epithelium and secretions but not in other tissues. It is a glycoprotein, whose function may be to lyse the seminal clot.

PSA is highly sensitive for the pesence of prostatic cancer. The elevation correlated with stage and tumor volume. It is predictive of recurrence and response to treatment. Finally, the antigen has prognostic value in patients with very high values prior to surgery are likely to relapse.

Unfortunately, PSA is detectable in normal men and often is elevated in benign prostatic hypertrophy, which may limit its value as a screening tool for prostate cancer. A recent study has shown that PSA combined with rectal exam is a better method of detecting prostate cancer than rectal exam alone.

Age-Specific Reference for Serum PSA (Reference Range [ng/ml])

Age Range (Years) Black Caucasians Japanese 40 - 49 0.0 - 2.0 0.0 - 2.5 0.0 - 2.0 50 - 59 0.0 - 4.0 0.0 - 3.5 0.0 - 3.0 60 - 69 0.0 - 4.5 0.0 - 4.5 0.0 - 4.0 70 - 79 0.0 - 5.5 0.0 - 6.5 0.0 - 5.0

Hormones:
Hormones are produced by many tumors. The hormone may be a natural product of its associated organ or represent abnormal synthesis reflecting unregulated cancer cell metabolism. Examples include insulin production by islet cell tumor, calcitonin by medullary thyroid carcinoma, and catecholamines by pheochromocytoma. Or it may be that the hormone is not a natural product of its associated organ, in which case is designated "ectopic". Examples include the production of ACTH and ADH by lung cancers.

In this section, discussion is limited to human chorionic gonadotropin. Other hormones will be discussed in another review.

Human Chorionic Gonadotropin
HCG is a glycoprotein consisting of subunits a e b, which are nonconvalently linked. The hormone is normally produced by the syncytiotrophoblastic cells of the placenta and is elevated in pregnancy. Its most important uses as a tumor marker are in gestational trophoblastic disease and germ cell tumors.

All gestational trophoblastic tumors produce HCG, and it is a valuable marker in these tumors, screening reliably in all cases and indicating poor responses to treatment. The level correlates with tumor mass and thus has prognostic value. HCG is extremely sensitive, being elevated in women with minute amounts of tumor. The patient is followed weekly during treatment, and at the completion of treatment indefinite follow up is advised to detect recurrence. HCG is essential in managing trophoblastic neoplasms.

The level of HCG is occasionally elevated in other cancers including those of breast, lung, and gastrointestinal tract, but in these diseases it has found little clinical application.

Enzymes
Investigators observe either enzymes that are native to normal tissue or those that could be associated with changes in metabolism that are unique to cancer tissue.

Acid Phosphatase
This enzyme is found in high concentraitions in the normal prostate as well as in primary and metastatic prostate cancers. Acid Phosphatase may also originate from other tissues.

The more sensitive immunological test (RIA or counterimmunoelectrophoresis for prostatic acid phosphatase, wich are specific for the enzyme of prostate tissue) often gives positive results in the early stages of disease.

Because of the reliability of acid phosphatase as a marker in early disease, it was hoped that the test could be used as a screening tool. However, it may also be elevated in up to 6 percent of cases of benign prostatic hypertrophy and other conditions. Thus, its predictive value is low on theoretical grounds. So, acid phosphatase is useful in following patients with advanced disease.

Neuron Specific Enolase
Neuron specific enolase is an isozyme of the glycolytic pathway that is found only in brain and neuroendocrine tissue. Its an immunohistochemical marker for tumors of the central nervous system, neuroblastomas, and APUD tumors.

Use of NSE has been evaluated in lung cancer and neuroblastoma.

Galactosyl Transferase II
Galactosyl Transferase II, an isozyme of galactosyl transferase, has been shown to be elevated in a variety of malignancies, predominantly gastrointestinal. In colon cancer its level correlated with the extent of disease and disease progression; in pancreatic cancer it was more sensitive and specific in distinguishing benign from malignant disease than CEA and other tests.

Immunoglobulins
Production of a monoclonal immunoglobulin molecule is characteristic of multiple myeloma. These paraproteins are usually complete antibody molecules but may be isolated light chains or, rarely, heavy chains. They may be lambda or kappa light chains and of any immunoglobulin subtype.

Immunoglobulins are valuable in the staging and treatment of myeloma, the amount of paraprotein serving as an index of tumor volume. Response to treatment is indicated by a fall in paraprotein production, whereas a rise points to relapse.