When Is a Tumor Marker a Laboratory Test?

Transcription

1 ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 7, No. 1 Copyright 1977, Institute for Clinical Science When Is a Tumor Marker a Laboratory Test? ROBERT S. GALEN, M.D., M.P.H. Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY The editorial When Is a Tumor Marker Not a Tumor Marker? by Vaitukaitis9 contains a statement that cannot be supported by data from the recent literature on the subject. In the concluding paragraph, it was stated, By carefully defining the upper limits of normal for tumor markers indistinguishable from substances normally of placental and fetal tissue origin, one can effectively use the markers as screening procedures for high-risk persons. 9 Two tumor markers, CEA and AFP, can be evaluated by the predictive value (Bayesian) model for evaluating laboratory or other tests and procedures.4,8 The Predictive Value of Laboratory Diagnosis Sensitivity, specificity, predictive value and efficiency define a laboratory test s accuracy. Sensitivity indicates the frequency of positive test results in patients with a particular disease, whereas specificity indicates the frequency of negative test results in patients without that disease. The predictive value of a positive test result indicates the frequency of diseased patients in all patients with positive test results. The predictive value of a negative test result indicates the frequency of non-diseased patients in all patients with negative test results. The efficiency of a test indicates the percent correctly classified (disease and non-diseased) by the test (table I). In screening for disease, the predictive value of the positive result is that in which the physician is most interested. These results include patients who will be presumptive positives for a particular disease and undergo diagnostic workups. Of this group, those patients who turn out not to have the disease will be defined as false positives. In the discussion that follows, predictive value will be used to refer to the predictive value of the positive test result. A marked change in predictive value occurs when there is a change in the prevalence of the disease in the population under study. For example, it could be known from a test s sensitivity and specificity that it was positive in 95 percent of diseased patients and negative in 95 percent of nondiseased patients. In table II is demonstrated the change in predictive value that occurs for this test with changing prevalence of disease. It can readily be seen that a particular test has a higher predictive value when the disease occurs with a higher prevalence. This explains why a good diagnostic test frequently fails as a screening test, when the drop in prevalence is quite marked. When clinical judgment is used in ordering laboratory tests, the patient suspected of having 51

2 52 G A LEN TABLE I Predictive Value of Laboratory Diagnosis True Diagnosis Number Number With Without Test Result Disease Disease Positive Negative Total TP FN TP + FN FP TN FP + TN TP + FP FN + TN TP + FP + F N + TN TP = true positives: number of diseased patients correctly classified by the test. FP = false positives: number of non-diseased patients misclassified by the test. FN = false negatives: number of diseased patients misclassified by the t est. TN = true negatives: number of non-diseased patients correctly classified by the test. Sensitivity = positivity in disease (expressed as percent) = TP x 100 Specificity = negativity in health or absence of a particular disease (expressed as percent) x 100 FP + TN Predictive value of positive test = percent of patients with positive test results who are diseased - TP TP FP x 100 Efficiency of test = percent of patients correctly classified as diseased and non-diseased = TP + TN x 100 TP + FP + F N + TN a particular disease, is placed in a new population with a higher prevalence or probability of disease. Therefore, the test performs much better. In figure 1 is illustrated how sensitivity and specificity are altered by the selec- TABLE I I tion of an upper limit of normal for a particular test. If patients were studied who were admitted to the hospital for a tumor work-up, the population divided into cancer and other conditions based on biopsy findings, etc., and then the tumor marker concentrations expressed for each group as a frequency distribution, the classical overlapping distributions seen in figure 1 might be found. It is impossible to select a cut-off point or upper limit that would afford complete discrimination between the two groups. At any cut-off point, one must sacrifice sensitivity for specificity and vice versa. Herein lies the major flaw of laboratory diagnosis, in that the tests are not sensitive and specific at the same time. Looking at multiple laboratory tests improves the predictive value somewhat, but the trade off between sensitivity and specificity always remains. If a cut-off point were selected for the test illustrated in figure 1, any point in the overlapping region would be chosen. In table III are listed several cut-off points with the sensitivity, specificity and predictive value associated with each. Rather than use the word cut-off point or upper limit of normal, this point of reference is referred to as the referent value. For any laboratory test studied in any disease, the predictive value of the test in diagnosing the disease can be calculated at any referent value (table IV). TABLE I I I Predictive Value as a Function of Disease Prevalence For Laboratory Test with 95 S ensitivity and 95 Specificity Prevalence of Disease Predictive Value Tumor Marker Referent Value ng per ml Sensitivity ('Cut-off point) Specificity Predictive Value Disease prevalence = 50 percent. Referent values and associated predictive values for test illustrated in figure 1.

3 W H E N IS A TUM OR M ARKER A LABORATORY TEST? 53 TABLE IV S ensitivity of Carcinoembryonic Antigen Test Disease Sensitivity Positive Colon cancer 72 Lung cancer 74 Pancreatic cancer 91 Stomach cancer 61 Breast cancer 47 Other cancers 49 TUMOR M A RKER, ng/ml Ingelfinger has stated that decision analysis may prove more useful to those who make plans affecting an entire population, or large segments thereof, than to the practitioner taking care of a specific individual. 6 It is suspected that practitioners agree and that this may be a factor responsible for the proliferation of laboratory tests and profiles, many of which are redundant and unnecessary. It is essential that practitioners ordering laboratory tests be able to use the predictive value model. It is hoped that the application of this model in the following section will demonstrate that the information necessary to construct a decision matrix is readily available in the clinical literature and that the mathematics involved are simple and straight forward. Carcinoembryonic Antigen To Test or Not to Test? Currently, physicians are deluged with brochures recommending the wise and careful use of the carcinoembryonic antigen (CEA) test in selected cases. Recent data enable us to evaluate the sensitivity, specificity and predictive value of the CEA test.5the sensitivity of CEA for carcinoma, when the test is considered positive at a CEA level greater than 2.5 ng per ml, is variable. These data indicate serious difficulties since the sensitivity in biopsy proven cases of colon carcinoma is only 72 percent. This number includes patients with all stages of the disease. F i g u r e 1. Hypothetical frequency distribution. Selection of an upper limit of normal based on the sensitivity and specificity of a laboratory test. Prevalence of cancer = 50 percent. Mean tumor marker concentration, cancer = 97 ng per ml. Mean tumor marker concentration, other conditions (noi)- cancerous) = 27 ng per ml. Upper limit of normal = 20, sensitivity = 100 percent, specificity = 60 percent. Upper limit of normal = 100, sensitivity = 50 percent, specificity = 100 percent. Using the same cut-off point of 2.5 ng per ml, the CEA test s specificity, or its negativity in the absence of cancer can be defined as shown in table V. It is not negative enough in patients free of cancer. It can be seen that non-cancerousstates, such as alcoholic cirrhosis which is not at all uncommon, have the same percentage of positive results as patients with colon carcinoma. In order to use the test reliably, patients should be free of the conditions stated in table V. Unfortunately, most patients suspected of having colon cancer will rarely be free of one or more of the conditions. Many of the non-malignant conditions, furthermore, are a lot more common than cancer in the general population. Under ideal conditions, the CEA test has a sensitivity of 72 percent for colon carcinoma, and a specificity of 97 percent when the patient is a healthy non-smoker. The CEA test performance is examined, keeping in mind a cancer prevalence of 10 percent for colon carcinoma. In table VI are detailed the predictive values of this test as applied to 1,000 healthy non-smokers.

4 54 G A LEN TABLE V S p e cificity of Carcinoembryonic Antigen Test in Absence of Cancer Condition Specificity Negative Emphysema 43 Alcoholic cirrhosis 30 Alcoholism, no cirrhosis 35 Ulcerative colitis 69 Gastric ulcer 55 Rectal polyps 81 Diverticulitis 73 Osteoarthr itis 70 Bronchitis 67 Obesity 69 Hernia 77 Diabetes 62 Heart disease 61 Hypertension 72 Hepatitis, viral 70 Hemorrhoids 67 Choielithiasis 82 Pneumonia 54 Miscellaneous conditions 67 Smoking 81 The test missed 28 percent of the cancers. The predictive value of the positive CEA test is only 73 percent, since only 72 of the 99 positive CEA test results occurred in subjects with cancer. As a diagnostic test, CEA may not be used under TABLE V I Carcinoembryonic Antigen: CEA (2.5 ng per ml) Total 100 A Diagnostic Test? Colonic Cancer Other Total Prevalence of colonic cancer - 10 percent Sensitivity = 72/100 = 72 percent Specificity = 873/900 = 97 percent Predictive value = 72/99 = 73 percent False positive rate = 27/99 = 27 percent ,000 such ideal conditions. It will be applied to patients at risk who are suspected of having cancer. Nearly all of these patients will have one or more of the conditions listed in table V. Thus, the actual specificity of the test is not 97 percent but probably 80 percent. Let us see what happens when there is a test with 72 percent sensitivity and 80 percent specificity. In table VI is demonstrated that 180 of 252 positive results are false. The predictive value of a positive test result is only 29 percent (72/252). With lower disease prevalence, the results will be far worse. The data presented demonstrate the limited usefulness of CEA as a diagnostic test.3 AIpha-F etoprotein Recent articles on serum alphafetoprotein (AFP) can be evaluated in a similar fashion. Kohn and Weaver reported on a sensitivity countercurrent immunoelectrophoretic technique for detecting serum AFP. The authors indicated that A.F.P. detection and assay correctly performed and interpreted is a valuable, sensitive, and specific serological marker of hepatocellular carcinoma. 7 The authors data are presented in the predictive value model in table VII. Kohn and Weaver suggested that an AFP screening test be done in conditions known to be associated with a high risk of TABLE V I I Diagnosis o f Hepatoma Colonic Cancer Other Total CEA (2.5 ng per ml) Total ,000 Prevalence of colonic cancer = 10 percent Sensitivity = 72/100 = 72 percent Specificity = 720/900 = 80 percent Predictive value 72/252 «29 percent False positive rate * 180/ percent Hepatoma Other Total Alpha fetoprotein {Immunoelectrophoresis) 17 2,079 2,096 Total 107 2,118 2,225 Prevalence of hepatoma = 107/2225 = 4.8 percent Sensitivity = 90/107 = 84 percent Specificity = 2079/2118 = 98.2 percent Predictive value = 90/129 = 70 percent False positive rate = 39/129 = 30 percent

5 W H E N IS A TUM OR M ARKER A LABORATORY TEST? 55 hepatocellular carcinoma. Their own data, however, raise serious questions about the test s diagnostic accuracy and, therefore, its value in this setting.2 Would a radioimmunoassay for AFP provide a more accurate diagnosis? Bloomer and co-workers concluded their study on alpha-fetoprotein in nonneoplastic hepatic disorders by stating, Thus, the use of radioimmunoassay to measure serum alpha-fetoprotein levels in patients with hepatoma should provide more information than is available with methods in current use, although some specificity for the diagnosis of hepatoma will be lost. 1 According to their own data, however, so much specificity is lost, that the test is rendered useless for most diagnostic purposes. The application of this test in two classes of patients who are at increased risk of developing hepatoma is shown in tables V III and IX using the authors results. These tables demonstrate an intolerable false-positive rate that could only complicate the diagnostic process. Furthermore, the efficiency of this test (overall percent total correct diagnosis) is low. The results would be far worse with lower prevalence rates of hepatoma. Discussion No matter how carefully the upper limits of normal are defined for these TABLE V I I I Diagnosis of Hepatoma in Patients with Chronic Active H epatitis Hepatoma Other Total Alpha-fetoprotein (40 ng per ml) Total ,000 Prevalence of hepatoma = 200/1000 =: 20 percent Sensitivity = 138/200 = 69 percent Specificity = 504/800 = 63 percent Predictive value = 138/434 = 32 percent False positive rate = 296/434 = 68 percent Efficiency of test = 642/ percent TABLE IX Diagnosis of Hepatoma in Patients with Alcoholic H epatitis Hepatoma Other Total Alpha-fetoprotein {40 ng per ml) Total ,000 Prevalence of hepatoma = 200/1000 = 20 percent Sensitivity 138/200 = 69 percent Specificity = 680/800 «85 percent Predictive value = 138/258 = 53 percent False positive rate = 120/258 = 47 percent Efficiency of test = 818/1000 = 82 percent tumor markers, the overlapping frequency distribution of results in patients with cancer and patients with high-risk conditions prohibits the use of these markers as useful screening procedures as suggested by Vaitukaitis.9 In clinical settings, when these tests can be of greatest value (ulcerative colitis, cirrhosis, etc.), it has been found by us that the false-positive rate is unacceptably high. Certainly at the present time, the tumor markers CEA and AFP have no role in cancer screening and have an extremely limited role in cancer diagnosis. Their usefulness in the management of patients under treatment for known cancer has not been considered in this review. Hopefully, as research proceeds in the area of tumor markers, more specific antigens will be identified so that the resulting assays will have high predictive values and low false-positive rates. The specificity of tumor markers must be improved if they are to be used effectively as laboratory screening or diagnostic tests. References 1. B l o o m e r, J. R W a l d m a n n, T. A., M c I n t ir e, K. R., and Kl a t s k in, G.: Alpha fetoprotein in nonneoplastic hepatic disorders. J. Amer. Med. Assoc. 233:38-41, G a l e n, R S.: False-positives. Lancet!/: 1081, 1974.

6 56 G A LEN 3. G a l e n, R. S. and G a m b in o, S. R.: Carcinoembryonic antigen. Human Pathol. 6: , G a l e n, R. S. and G a m b i n o, S. R.: Beyond Normality The Predictive Value and Efficiency of Medical Diagnoses. John Wiley and Sons, New York, H a n s e n, H. J., M i l l e r, E., M i l l e r, O. N., and B u r n s, J. J.: Carcinoembryonic antigen (CEA) assay. A laboratory adjunct in the diagnosis and management of cancer. Human Pathol. 5: , IN G E L F IN G E R, F. J.: Decision in medicine. New Eng. J. Med. 293: , K o h n, J. and W e a v e r, P. C.: Serum-alphar fetoprotein in hepatocellular carcinoma. Lancet 17: , M c N e i l, B. J., Ke e l e r, E., and A d e l s t e in, S. J.: Primer on certain elements of medical decision making. New Eng. J. Med. 293: , V A lt U K A m S, J. L.: When is a tumor marker not a tumor marker? New Eng. J. Med. 293: , 1975.