Carcinoembryonic Antigen in a Black Hospital Population Willie L. Ruff, PhD, Shirley D. Duhaney, MD, and Jong J. Kim, BS, MT Washington, DC
Sixteen normal individuals and 100 hospital patients, all black, were tested for abnormal carcinoembryonic antigen (CEA) levels. Male and female subjects (smokers and non-smokers) were tested. The results of the tests are discussed. For normal subjects, the CEA values ranged from 0.0 ng/ml to 2.6 ng/ml. Among hospital patients with neoplastic disease, male patients with lung disease showed elevated CEA titers but their female counterparts did not. On the other hand, female patients with breast cancer, in contrast to their male counterparts, had raised values of CEA. The clinical indices for laboratory tests of sensitivity, specificity, and predictive value were calculated and determined to be 71.5, 56, and 47.5 percent, respectively. Carcinoembryonic antigen (CEA), a complex glycoprotein with a molecular weight of about 200,000, is a tumorassociated antigen found in the plasma of patients with both malignant and non-malignant disease. 1-4 CEA was originally found by Gold and Freeman in 1965 in several fetal tissues during the first six months of gestation and in human cancerous colon, liver, and pancreas, but it was not found in normal human colonic tissue.5 A relatively low sensitivity of the CEA assay was the primary reason it was not found in the normal colon tissue. In 1969, Thomson et a16 developed a radioimmunoassay for CEA with greatly increased sensitivity and specificity. Using this method, CEA was detected in the sera of patients with adenocarcinoma of the colon. Subsequently, CEA was found in the sera of patients with other forms of cancer as well as in some patients with benign tumors and a variety of non-malignant disease 35 79 The literature is replete with examples of laboratory test values that show an age, sex, and race dependence. However, this situation does not pertain to CEA. Carcinoembryonic antiFrom the Department of Pathology, Howard University College of Medicine, and the Clinical Laboratories of Howard University Hospital, Washington, DC. Requests for reprints should be addressed to Dr. Willie L. Ruff, Clinical Laboratories, Howard University Hospital, Washington, DC 20060.
gen in fairly well defined populations has been reported by Pick et all' and Frost and Coates.7 There is a dearth of reports of CEA in ethnic groups. Accordingly, we measured the CEA levels in 16 normal healthy subjects and 100 black hospital patients for whom the CEA test had been performed in our laboratory at the request of their private physicians. We wanted to know the incidence of positive CEA results in the defined patient population and to correlate our results with those published from either heterogeneous racial groups or apparently homogeneous non-black racial groups. The results of this study are contained in this report.
Materials and Methods Carcinoembryonic antigen test kits were used (Roche, Hoffman-LaRoche, Nutley, NJ). In the Roche system, CEA is extracted from the patient's sample with 1.2 M cold perchloric acid and subsequently dialyzed to remove the acid. The perchloric acid extract is allowed to react with an excess quantity of anti-CEA. Then, CEA-1 125 iS added in excess. The free CEA-1'25 which does not bind to the anti-CEA is separated from the bound CEA-1125 by zirconyl phosphate gel. Quantitation was done by counting the bound antigen in a Beckman BioGamma II
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 10, 1979
counter (Beckman Instruments, Fullerton, California). The names of 100 hospitalized patients and 16 healthy subjects were selected at random from a CEA log book for the period June 1977December 1977, and entered on data sheets with the patients' identification numbers. The charts on the patients were pulled from either the wards or medical records and reviewed for pertinent medical information. The data retrieved from the charts for each patient included age, sex, CEA value(s), diagnosis, metastatic sites, treatment modality, and smoking status. All cancers were diagnosed by histological criteria unless otherwise indicated.
Results CEA levels in an apparently healthy black population are presented in Figure 1. The range of CEA values, from 0.0 ng/ml to 2.6 ng/ml, was the same in both sexes. Figure 2 illustrates the distribution by age and sex of patients with some form of neoplastic disease that results in a positive CEA test. Up to age 50 years, the number of patients with a positive CEA test is small and almost equally distributed according to sex. Between the fifth and sixth decades of life, the number of female patients was greater than male patients. After reaching the early 60s, the number of male patients exceeds that of females. The age and sex distribution of patients with a variety of nonneoplastic diseases is shown in Figure 3. At age 40 or less, near parity exists between the two sexes. The patients who were older than 40 but less than 61 were greater in number than the younger patients; however, neither sex had a large numerical advantage. After 60 years, the total number of patients increases with men holding a slight (insignificant) lead. 971
12
1
X
3.5
10
4
9U 3.0
8U 2.5
0)
6
3
40
5U
-~
EU z 4 3 0.
-
___
__
2
_
30
31-40
51-60
41-50
61-70
70
Age (years) Female
Male
Figure 1. CEA levels in normal subjects
Female * patients
0 Male patients Table 1 groups a number of patients with neoplasia according to the organ system with the primary neoplasm. The table also includes the percentage of patients in each group who developed metastases. Colorectal cancer patients constituted the largest group of patients. Approximately 55 percent of patients with colonic cancer had metastases and a CEA level sometimes exceeding 25 nglml. The next largest group of patients had breast cancer with a 30 percent incidence of metastases and a CEA maximum slightly greater than one half of that shown by colorectal cancer victims. Of the other patients, only those with carcinoma of the anus, stomach, and bladder showed any metastases. The distribution of patients with non-neoplastic disease according to the primary organ system dysfunction is correlated with the CEA ranges in Table 2. Of the 56 patients, the majority had either cardiovascular or hepatic disease. The highest limits of CEA were seen in patients with gastroenterological, endocrinological, and hematological disese. Among all of the patients, the lowest CEA levels were found in patients with cardiovascular disease. The clinical usefulness of the CEA test in this hospital population is assessed in Table 3. Subtotals of cancer and non-cancer patients are given plus the calculated sensitivity of 71.5 percent, specificity of 56 percent, and predictive value of 47.5 percent. 972
Figure 2. Distribution by age and sex of patients with both neoplastic disease and positive CEA test 11
10 9
8 7 0
5
z
4
3 2
0 30
31-40
51-60
41-50
61-70
70
Age (years)
Male Figure 3. Distribution by age and sex of patients with non-neoplastic disease and positive CEA test LIFemale
For patients with neoplastic disease, Figure 4 correlates the CEA values with the primary neoplastic organ according to sex. Depending on the organ system, male patients have either lower or higher CEA values than the females, although the upper limit is about the same. Malignancies of the breast showed a unimodal distribution with an upper limit for CEA of 15.0 ng/ml for females. By way of contrast, lung cancer
was present only in men. The CEA range for men with lung cancer had a lower range than for men with colonic cancer. Figure 5 reflects the distribution patterns by sex, disease, and CEA values of patients with non-neoplastic diesase. The range for CEA in men with hematopoietic disease is much broader than it is for women at both ends of the spectrum.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 10, 1979
Table 1. Distribution of Patients According to Organ With the Primary Neoplasm
Number
Organ System Involved
of Patients
Colon Breast Lung Rectum Cervix Mouth Anus Stomach Bladder
11 10
Number with Metastases
%
CEA Range (ng/mI)
6 3 0 0 0 0 2 2 1
54.5 30 0 0 0 0 100 100 50
0.8-25 2.3-13.4 3.9-25 0.5- 7.8 3.4-25 5.8- 9.6 1.6-11.4 2.4-10.0 9.2-12.6
5 3 2 2 2 2 2
Table 2. Patients With Non-Neoplastic Disease
Organ System Involved
Number of Patients
CEA Range (ng/ml)
Cardiovascular Hematopoeitic Hepatic Renal/urethral Pulmonary Brain Skeleton GI Endocrine Skin
10 5 10 3 6 3 1 7 5 2
1.1-11.2 3.1-23 2.2-11.4 3.4- 5.6 3.0-12.2 4.3- 7.0 4.3- 6.4 1.6-25 3.0-25 2.6-10.4
Table 3. Sensitivity, Specificity, and Predictive Value of the CEA Test
No. of Cancer Patients 44 No. of Non-Cancer Patients 56 Total 100 All Patients
A schematic illustration of the distribution of patients with malignant GI disease- is given in Figures 5 and 6. There were 20 such patients without any accompanying disease. Of the 20, 13 had metastases and seven did not. Colorectal carcinoma was present in 11 of the 13 patients who had metastases and carcinoma of the stomach was found in the other two. Of the patients with colorectal metastatic carcinoma, nine were females and two were males.
True Positives
True Negatives
False Positives
False Negatives
40
0
0
4
0 40
56 56
44 44
12 16
Sensitivity 71.5%
Specificity 56%
Predictive Value 47.5%
Six of the female patients in this group had primary disease and three were classified in the recurrent category. The two male patients in this group were equally distributed in the primary and recurrent disease groups. There were four patients with colorectal cancer/neoplasia without metastases. Three of the patients were female and one was male. Two thirds of the female patients in this group, as in the case of the patients with metas-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 10, 1979
tases, had primary disease. One male patient with colorectal carcinoma had primary disease and one had recurrent disease. In Figure 6, the classification of seven patients with malignant GI disease with accompanying conditions is given. Five of these patients had colorectal disease; one each had anal and esophageal disease. Of the five with colorectal malignancy, three were asymptomatic and two were symp973
s*x.
I
I
25.00 25.0
22.5 E
20.0
4: w
17.5
C-,
15.0 12.5 10.0 7.5
5.0
J
2.5
7
Colon
Rectum
Lung
Breast
I
Male L Female Figure 4. Correlation of CEA values with the organ having the primary neoplasm
6-,-I>, No Metastasis
Metastasis r,
11
1
Colorectal
Stomach
/9F Primary
2
Mouth 2
2
iF
2M Recurrent
1M
1F
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1
Recurrent
Primary
7
6F
Surgery
1iM No Surgery
AJ-75F
adenocma colon colon
BS-57F
adenocza cecu m BF-69F colon adenocEa colon DB-32F adenocEa colon DC-28F adenocza rectu m JM-65F adenocEa colon poorly cdifferentiated RJ-82M adenoczal colon
1M
Recurrent
SC-66M squamous cell mouth AT-58F squamous cell mouth
BC-56F adenoca colon OM-68F
~~~adenoca
cecum
~~~~adenoca
rectum
4
SJ-69M adenoca colon TS-75F
Anus
iM
Colorectal
3F-lM
Primary
Recurrent
Primary
~~~~~~JL-57
3 2F
iM
Recurrent
\
\
aqut
amous cell ca
Mg
Surgery/No Surgery
Surgery OF 1M EW-46M
adenoca colon
No Sugrery
2F, 0-M RG adenoca colon poorly differentiated
MS-71aF adenoca colo n
AJ-58F adenoca colon
Figure 5. Symptomatic malignant GI diseases (only) with
974
no
accompanying disease
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 10, 1979
7 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~1
1'--
Anus 1
No Metastasis
Esophagus 1
Metastasis
Primary
Primary
Recurrent
Symptomatic
No Metastasis
Recurrent
Primary Symptomatic
Symptomatic
/ \No Surgery
Metastasis
Surgery No Surgery BP-61F alcoholic cirrhosis
Surgery
No Metastasis
Primary Recurrent Recurrent Symptomatic
Asymptomatic
Surgery
Colorectal 5
Asymptomatic
Surgery
No Surgery
VB-56F adenoca colon
No Surgery
AM-36F squamous cell ca anus
Primary
Metastasis
Primary
Recurrent
Recurrent
Symptomatic Asymptomatic Asymptomatic Surgery No Surgery Symptomatic MW-65F adenoca colon
TF-67M adenoca colon JQ-69M adenoca rectum RB-59F adenoca colon
Figure 6. Symptomatic malignant GI diseases with accompanying conditions
tomatic. The patients with anal and esophageal malignancies were both symptomatic. All seven patients described in this figure had primary disease. Figure 7 depicts ten patients with pulmonary neoplasia. In this group of patients, four had metastases and six did not. All ten patients were symptomatic. However, eight of the ten patients did not have surgery while two did. Figure 8 shows the 13 patients with breast cancer. Seven of these patients had metastases but six did not. Of the patients without metastases, all six had primary disease. But only four of the seven patients with metastases had primary disease. The other three had recurrent disease. Nine of the 13 patients with breast cancer were symptomatic.
Discussion Carcinoembryonic antigen is found in the plasma of patients with both entodermal (colon, pancreas, lung, and stomach) and non-entodermal-derived carcinomas.2'5 The results of the present study are consistent with these reports. High concentrations of CEA were found in a variety of malignant and nonmalignant diseases. High CEA titers were most pronounced in the case of patients with neoplastic disease.
Patients with non-neoplastic disease often had CEA levels which were above normal, but they were not as high as those seen in neoplasia.'7' In our patient population, the frequency of elevated CEA titers is highest beginning with the sixth decade of life. Hansen et a19 reported similar findings. It is not surprising that the incidence of elevated CEA values appears to be age dependent. With advancing years, CEA levels rise as does morbidity.9 Prior to age 60, there was an asymmetric distribution by sex of high CEA values. The actual number of female patients with an elevated plasma CEA was greater than the number of male patients. This situation pertained in both neoplasia and non-neoplasia. After age 60, the number of male patients with abnormally high CEA values exceeded the number of female patients. The number of patients less than 50 years of age is small. Hence, it is doubtful that the patient distribution by sex is significant. CEA values were high in female patients with breast cancer, with a bias toward those with metastatic disease. In this study there were no male patients with breast cancer. The study revealed the converse sexual pattern for patients with bronchogenic carcinoma. Male patients had raised CEA levels. There were no female patients with the disease. The asymmetric distribution by sex of hypercarcinoembryonic antiginemia in patients with
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 10, 1979
bronchogenic carcinoma may be attributed in part to cigarette smoking. Most of the male patients in this study with lung cancer smoked many cigarettes each day. A more precise correlation of bronchogenic carcinoma with cigarette smoking in patients in the study is not practical due to the absence of smoking status in some patient records. Thus, the exact relationship of carcinoma to cigarette smoking in these patients is obscure. Among these patients, the sensitivity of the CEA test was 71.5 percent and the specificity and predictive values were 56 and 47.5 percent, respectively. The sensitivity agrees with the expected value given by Gambino and Galen.51' However, specificity differs from that of Gambino and Galen. The discordance between these results and those of Gambino and Galen may be due to the small sample used or to problems of sample spectrum and bias.
Literature Cited 1. Chu TM: Current status of carcinoembryonic antigen assay. Semin Nucl Med 5(3):255-262, 1975 2. Del Vecchio P: A Presentation on CEA. Nutley, NJ, Hoffman-LaRoche, 1975 3. Lo Gerfo P, Krupey J, Hansen HJ:
975
10
~~~~~~~~~~~~~~~~4
6 No Metastasis
Metasasis
Recurrent
Primary
Recurrent
Primary
~~~~~~~~~~~~~~~~~4
1 6
Asymptomatic
Symptomatic, SymptomaticmptomticyAsyptomati Asymptomatic
\
t
/
Symptomatic 4
Asymptomatic
Symptomatic 6
2
2/11,11,44
Surgery
o
4
Surgery Surgery
\.
/ Surgery
RS-54M(19.2,20.2) squamous cell ca
No Surgery RD-57F(4.0, 1.8) anaplastic large cell ca JL-64M bronchogenic ca TS-72M(5.2)
No Sre Surgery \ Surgery No Surgery No Surgery / VH-56M(25) anaplastic ca
Surgery No Surgery No Surgery ur
AR-67M(10.4) metastasis
TS-65M(15.4) bronchogenic
epidermoid ca
ca
LW-64M(3.9) bronchogenic ca
CT-72M(22) undifferentiated ca
Asymptomatic
Symptomatic
No
Figure 7. Carcinoma of lung Surgery
No Surgery
Surgery Surgery
13
7
.6
Metastasis
No Metastasis
Symptom
660
Symptomatic Asymptomatic
Recurrent
Primary 4
Recurrent
Primary
Asymptomatic Symptomatic
3
AsymptomaticSymptomatic
Asymptomatic
Surgery No Surgery
Surgery
No Surgery
(23.4) (2.3,5.0)
BC-74F
MT-53F (5.6)
No Surgery
Surgery
AB-61 F
l
RL-82F
(4.0) (5.4)
RW-62F
r:;.ge
Surgery
Surgery JB-77F
(12.8,9.2) CF-46F (16,9.6 4.)(4.6,25) LF-61 F (11.4) (5.4) AW-42F
169648)VC-24F
No Surgery
'12.6'
(26
NP-54F (3.0, 9.0)
Figure 8. Schematic illustration of patients with breast carcinoma. The numbered alphabets are the ages and sex of the patients. The numbers in parentheses are the CEA values N
Demonstration of an antigen common to several varieties of neoplasia. N Engi J Med 285:138-141, 1971 4. Moore TL, Kupchik HZ, Marcon N, et al: Carcinoembryonic antigen assay in cancer of the colon and pancreas and other digestive tract disorders. Am J Dig Dis 16:1-7, 1971 5. Gold P, Freedman SO: Specific carcinoembryonic antigens of the human digestive system. J Exp Med 122:467-481, 1965 6. Thompson DMP, Krupey J, Freedman 976
SO, et al: The radioimmunoassay of circulating carcinoembryonic antigen of the human digestive system. Proc NatI Acad Sci 64:161-167, 1969 7. Frost MA, Coates AS: Plasma CEA in an Australian hospital population. Med J Australia 1(26):950-953, 1976 8. Gardner RC, Feinerman AE, Kantrowitz PA, et al: Serial carcinoembryonic antigen (CEA) blood levels in patients with ulcerative colitis. Am J Dig Dis 23(2):129-133, 1978
9. Hansen HJ, Snyder JJ, Miller E, et al: Carcinoembryonic antigen (CEA) assay. Hum Pathol 5:139-147, 1974 10. Pick AL, Shoenfeld Y, Zelikovski A, et al: Diagnostic significance of carcinoembryonic antigen concentrations. Am J Proctology 28(3):37-43, 1977 11. Gambino SR, Galen RS: Beyond Normality: The Predictive Value and Efficiency of Medical Diagnoses. New York, John Wiley, 1975, pp 9-14
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