CARCINOEMBRYONIC IN RENAL
A. DUBIN,
TEST
CELL CARCINOMA
P. D. GUINAN, R. J. ABLIN,
ANTIGEN
M.D.
PH.D. M.S.
S. NOURKAYHAN, I. M. BUSH,
M.D.
M.D.
From the Sections of Urologic Oncology and Immunobiology, Division of Urology, Cook County Hospital, Chicago, Illinois
- CEA( carcinoembryonic antigen) determinations were performed on 203 blood and samples from 23 patients with renal cell carcinoma. Neither the blood nor the urine CEA test was able to confirm the diagnosis or predict the status of the disease in more than one half of these patients. As presently constituted, the CEA test is not accurate for the diagnosis or prognosis of renal
ABSTRACT urine
cell carcinoma.
Two hundred three CEA determinations on blood (91) and urine (112) samples were done (Table I). The patients were further evaluated as to whether their disease was “active” or “cured.” The assumption of active disease was made on the basis of standard clinical and surgical examinations, radiographic tests, and laboratory determinations. For this study to be considered in the cured group the patient had to be free of disease, on the basis of the foregoing evaluation, for at least six months following surgical treatment of the tumor. Using these criteria 9 patients were assumed to have been cured, and 14 patients were assumed to have active disease. Blood samples were collected in 22 of the 23 patients and urine in 15.
The CEA (carcinoembryonic antigen) test was originally developed by Gold and Freedman’ to detect a glycoprotein, with a molecular weight of 200,000, containing 14 amino acid residues and 6 carbohydrate constituents2 Although normally present in the first two trimesters of fetal life, it was initially believed to be present after birth only in individuals harboring an entodermally derived malignant disease. CEA has since been found in patients with nongastrointestinal cancer,3 with benign disease,4 and even in normal individualq5 albeit at low levels. CEA has been reported in patients with urologic cancer. 6*7Although the mesodermal origin of the kidney raises theoretical reasons why CEA may not be ofvalue in renal cancer, the hope for a convenient blood and urine test led us to investigate CEA in kidney cancer. This article is a report of the diagnostic and prognostic accuracy of the CEA test in renal cancer.
Disease Status
Material Twenty-three patients with a histologic diagnosis of renal cell carcinoma from the urologic oncology section of this hospital were evaluated.
UROLOGY
/ FEBRUARY
1975
/ VOLUME
V, NUMBER
I.
TABLE
Cured
8
Active
14
TOTAL
2
___ Patients
22
CEA determinations in patients with renal cancer Blood Determinations
Patients
43 48 91
5 10 15
Urine ____ Determinations 18 94 112
185
TABLE II. Disease Status Patients Cured Active TOTAL
Blood CEA determinations
INITIAL
10
Positive
Blood Samples Number Per Cent
8 I4
42 49
9 20
21 41
22
91
29
32
Method
Five cc. of blood were collected by venapuncture and frozen immediately at -4°C. if the determinations were not performed on the same day. Ten cc. of urine were collected from the first voided specimen in the morning of the same day and processed in a similar manner. The method with minor modifications was that of Hansen, Lance, and Krupey.s One cc. of sample was diluted with 0.9 per cent sodium chloride and the mixture extracted with perchloric acid. The perchloric acid was removed by dialysis. The neutralized extract was incubated with a mixture of CEA labeled with radioactive iodine-125 and monospecific goat anti-CEA antibody. The radioactivity of the bound fraction was counted in an automatic, multisample gamma ray spectrometer. Quantitation was carried out by referring to a standard curve prepared by plotting the per cent of CEA 1251bound versus known concentration of nonradioactive CEA standards, in accordance with established radioimmunoassay principles. A positive blood CEA was a sample with 2.5 ng. or more of CEA per cubic centimeter of blood. A positive urine CEA was a sample with 10 ng. or more of CEA per cubic centimeter of urine. The urine samples were not evaluated for infection.
Of the 91 blood CEA determinaDiagnosis. tions performed, 29 (32 per cent) were positive (Table II). Nine of 42 samples from patients in the cured group were positive (21 per cent), and 20 of 49 samples from patients in the active group were positive (41 per cent). Therefore, in these 91 blood samples, 33 samples from cured patients were negative, and 20 samples from patients with active disease were positive for an over-all accuracy rate of 59 per cent. Six patients had two or more Prognosis. blood CEA determinations performed during a six-month interval so that a correlation could be made between the serial CEA determinations
186
I
8 CEA ng/ml.
6 4 2
FIGURE 1. Change in serial CEA in 6 patients with renal cell carcinoma: 2 patients with active (A) disease: serial CEA rising in 1. patient and falling in the other; 4 patients cured (C) of disease: serial CEA rising in 2 patients and falling in 2.
and progress of the disease. Four patients had active disease, 2 had rising serial CEA, and 2 had falling serial CEA (Fig. 1). Two patients were cured of their disease: 1 patient had a rising serial CEA and the other a falling serial CEA. Therefore, there was an accuracy rate of 50 per cent. Urine
Of the 112 urine CEA determinaDiagnosis. tions performed on 15 of these patients, 7 (6 per cent) were positive (Table III). Five patients cured of disease had 15 urine CEA determinations, 2 of which were positive (13 per cent). Ten patients with active disease had 97 urine CEA determinations, 5 of which were positive (5 per cent). Therefore, in these 112 urine determinations 13 samples from cured patients were negative, and five samples from patients with active disease were positive for an over-all accuracy rate of 16 per cent. Serial urine CEA samples were Prognosis. collected in 10 patients (Table IV). In 8 patients the serial urine CEA neither rose nor fell; 1 cured
Results Blood
FOLLOW-UP
TABLE III. Disease Status Patients
Cured Active TOTAL
Urine CEA determinations Urine Samples
5
15 97
2
-5
13
10 15
112
7
6
TABLE IV. Disease Status Cured Active TOTAL
-Positive Number Percent
Rising
5
Serial urine CEA
Serial CEA Falling Unchanged
Total Patients
0 -0
2 -6
-1
3 7
0
8
2
10
1
UROLOGY / FEBRUARY1975 / VOLUMEV, NUMBER2
References
patient had a falling serial urine CEA, and 1 patient with active disease also had a falling serial urine CEA. No conclusion can be drawn from these data.
Demonstration of 1. GOLD, P., and FREEDMAN, S. 0.: tumor specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques, J. Exper. Med. 121:439 (1965).
Comment
2. TERRY, W. D., HENKART, P. A., COLIGAN, J. E., and TODD, C. W.: Structural studies of the major glycoprotein in preparations with carcinoembryonic antigen activity, ibid. 136: 200 (1972). 3. LAURENCE, D. J. R., et al. : Role of plasma carcinoembryonic antigen in diagnosis of gastrointestinal, mammary, and bronchial carcinoma, Br. Med. J. 3: 605 (1972).
Although there are numerous reports of the value of the CEA test in the diagnosisg-” and prognosis12-l4 of malignant disease, there are relatively few reports dealing with urologic tumors15J6 and only one specifically evaluating the value of this test in renal cell carcinoma.” The latter article evaluated plasma CEA levels in 23 patients with advanced renal cell carcinoma; the authors did not evaluate urine CEA from these patients. They found plasma CEA levels elevated in 56 per cent of these patients and also found that serial CEA levels tended to correlate with the clinical status of the patient. They concluded that this test “is a valuable tool in the evaluation and follow-up of patients with renal cell carcinoma.” The results of our study indicate that in these 23 patients the over-all diagnostic accuracy of the blood CEA test in patients with active disease is 41 per cent; the accuracy of the urine CEA test in patients with active disease is 5 per cent. The serial blood CEA test in the small number of patients studied (6 patients with blood serial CEA) failed to reveal an accurate prognosis in more than one half of these patients. A diagnostic and prognostic accuracy which does not exceed at least 75 per cent is inadequate as a test for potential use in the management of patients with cancer. Theoretically, the diagnostic and prognostic inadequacy of the CEA test in renal cell carcinoma is not unexpected. The antisera used in this test were raised against tumor specific antigens extracted from colon carcinoma, an entodermally derived tumor. This explains the diagnostic accuracy of the CEA test in gastrointestinal tumor of 97 per cent” and prognostic accuracy of 95 per cent. l4 Since renal cell carcinoma arises from the proximal tubule, it is, therefore, a mesodermally derived tumor and embryologically would be expected to be dissimilar from gastrointestinal cancer. l8 The hope is (1) to extract a tumor specific antigen from renal cell carcinoma, (2) to radiolabel antisera raised against this antigen, and (3) to use these antisera for the diagnosis and prognosis of renal cell carcinoma. Section
UROLOGY
I
FEBRUARY
4. MOORE, T. L., KANTROWITZ, P. A., and ZAMCHECK, antigen (CEA) in inflammatory N. : Carcinoembryonic bowel disease, J.A.M.A. 222: 944 (1972). 5. CHU, T. W., REYNOSO, G., and HANSEN, H. J.: Demonstration of carcinoembryonic antigen in normal human plasma, Nature (Lond.) 238: 152 (1972). antigen in pa6. REYNOSO, G., et al. : Carcinoembryonic tients with different cancers, J.A.M.A. 220: 361(1972). 7. HALL, R. R., et al. : Carcinoembryonic antigen in the urine of patients with urothelial carcinoma, Br. Med. J. 3: 609 (1972). 8. HANSEN, H. J., LANCE, K. P., and KRUPEY, J.: Demonstration of an ion sensitive antigenic site on carcinoembryonic antigen using zirconyl phosphate gel. Clin. Res. 19: 143(1971). 9. MOORE, L., KUPCHIK, H. Z., MARCON, N., and ZAMCHECK, N. : Carcinoembryonic antigen assay in cancer of the colon and pancreas and other digestive tract disorders, Am. J. Digest. Dis. 16: 1 (1971). 10. DHAR, P., MOORE, T., ZAMCHECK, N., and KUPCHIK, H. Z.: Carcinoembryonic antigen (CEA) in colonic cancer: use in preoperative and postoperative diagnosis and prognosis, J.A.M.A. 221: 31 (1972). 11. THOMSON, D. M. P., KRUPEY, J., FREEDMAN, S. O., and GOLD, P.: The radioimmunoassay of circulating carcinoembryonic antigen of the human digestive system, Proc. Natl. Acad. Sci. 64: 161 (1969). 12. STEWARD, A. M. : Carcinoembryonic antigen in breast cancer patients: serum levels and disease progress, Cancer 33: 1246 (1974). antigen: clin13. SKAFUN,A. T., et al. : Carcinoembryonic ical correlation with chemotherapy for metastatic gastrointestinal. cancer, ibid. 33: 1239 (1974). 14. MOORE, T., DHAR, P., ZAMCHECK, N., and KUPCHIK, H. Z. : Carcinoembryonic antigen (CEA) in diagnosis of digestive tract cancer. Embryonic and Fetal Antigens in Cancer, Proceedings of the First Conference and Workshops on Embryonic and Fetal Antigens in Cancer, May 24-26, 1971, p. 393. 15. REYNOSO, G., CHU, T. W., GUINAN, P., and MURPHY, G. P.: Carcinoembryonic antigen in patients with tumor of the urogenital tract, Cancer 30: 1 (1972). antigen in pa16. GUINAN, P., et al. : Carcinoembryonic tients with urologic cancer, Urol. Res. 1: 101 (1973). 17. CHU, T. W., SKUKLA, S. K., MITTLEMAN, A. O., and MURPHY, G. P.: Plasma carcinoembryonic antigen in renal cell carcinoma patients, J. Urol. 111: 742 (1974). Embryology of the urogenital 18. CAMPBELL, M. F.: tract, in: Urology, Philadelphia, W. B. Saunders Co.. 1964, pp. 1516-1539.
of Urologic Oncology Chicago, Illinois 60612 (DR. GUINAN)
1975 i
VOLUME
V, NUMBER
2
187
A. DUBIN,
TEST
CELL CARCINOMA
P. D. GUINAN, R. J. ABLIN,
ANTIGEN
M.D.
PH.D. M.S.
S. NOURKAYHAN, I. M. BUSH,
M.D.
M.D.
From the Sections of Urologic Oncology and Immunobiology, Division of Urology, Cook County Hospital, Chicago, Illinois
- CEA( carcinoembryonic antigen) determinations were performed on 203 blood and samples from 23 patients with renal cell carcinoma. Neither the blood nor the urine CEA test was able to confirm the diagnosis or predict the status of the disease in more than one half of these patients. As presently constituted, the CEA test is not accurate for the diagnosis or prognosis of renal
ABSTRACT urine
cell carcinoma.
Two hundred three CEA determinations on blood (91) and urine (112) samples were done (Table I). The patients were further evaluated as to whether their disease was “active” or “cured.” The assumption of active disease was made on the basis of standard clinical and surgical examinations, radiographic tests, and laboratory determinations. For this study to be considered in the cured group the patient had to be free of disease, on the basis of the foregoing evaluation, for at least six months following surgical treatment of the tumor. Using these criteria 9 patients were assumed to have been cured, and 14 patients were assumed to have active disease. Blood samples were collected in 22 of the 23 patients and urine in 15.
The CEA (carcinoembryonic antigen) test was originally developed by Gold and Freedman’ to detect a glycoprotein, with a molecular weight of 200,000, containing 14 amino acid residues and 6 carbohydrate constituents2 Although normally present in the first two trimesters of fetal life, it was initially believed to be present after birth only in individuals harboring an entodermally derived malignant disease. CEA has since been found in patients with nongastrointestinal cancer,3 with benign disease,4 and even in normal individualq5 albeit at low levels. CEA has been reported in patients with urologic cancer. 6*7Although the mesodermal origin of the kidney raises theoretical reasons why CEA may not be ofvalue in renal cancer, the hope for a convenient blood and urine test led us to investigate CEA in kidney cancer. This article is a report of the diagnostic and prognostic accuracy of the CEA test in renal cancer.
Disease Status
Material Twenty-three patients with a histologic diagnosis of renal cell carcinoma from the urologic oncology section of this hospital were evaluated.
UROLOGY
/ FEBRUARY
1975
/ VOLUME
V, NUMBER
I.
TABLE
Cured
8
Active
14
TOTAL
2
___ Patients
22
CEA determinations in patients with renal cancer Blood Determinations
Patients
43 48 91
5 10 15
Urine ____ Determinations 18 94 112
185
TABLE II. Disease Status Patients Cured Active TOTAL
Blood CEA determinations
INITIAL
10
Positive
Blood Samples Number Per Cent
8 I4
42 49
9 20
21 41
22
91
29
32
Method
Five cc. of blood were collected by venapuncture and frozen immediately at -4°C. if the determinations were not performed on the same day. Ten cc. of urine were collected from the first voided specimen in the morning of the same day and processed in a similar manner. The method with minor modifications was that of Hansen, Lance, and Krupey.s One cc. of sample was diluted with 0.9 per cent sodium chloride and the mixture extracted with perchloric acid. The perchloric acid was removed by dialysis. The neutralized extract was incubated with a mixture of CEA labeled with radioactive iodine-125 and monospecific goat anti-CEA antibody. The radioactivity of the bound fraction was counted in an automatic, multisample gamma ray spectrometer. Quantitation was carried out by referring to a standard curve prepared by plotting the per cent of CEA 1251bound versus known concentration of nonradioactive CEA standards, in accordance with established radioimmunoassay principles. A positive blood CEA was a sample with 2.5 ng. or more of CEA per cubic centimeter of blood. A positive urine CEA was a sample with 10 ng. or more of CEA per cubic centimeter of urine. The urine samples were not evaluated for infection.
Of the 91 blood CEA determinaDiagnosis. tions performed, 29 (32 per cent) were positive (Table II). Nine of 42 samples from patients in the cured group were positive (21 per cent), and 20 of 49 samples from patients in the active group were positive (41 per cent). Therefore, in these 91 blood samples, 33 samples from cured patients were negative, and 20 samples from patients with active disease were positive for an over-all accuracy rate of 59 per cent. Six patients had two or more Prognosis. blood CEA determinations performed during a six-month interval so that a correlation could be made between the serial CEA determinations
186
I
8 CEA ng/ml.
6 4 2
FIGURE 1. Change in serial CEA in 6 patients with renal cell carcinoma: 2 patients with active (A) disease: serial CEA rising in 1. patient and falling in the other; 4 patients cured (C) of disease: serial CEA rising in 2 patients and falling in 2.
and progress of the disease. Four patients had active disease, 2 had rising serial CEA, and 2 had falling serial CEA (Fig. 1). Two patients were cured of their disease: 1 patient had a rising serial CEA and the other a falling serial CEA. Therefore, there was an accuracy rate of 50 per cent. Urine
Of the 112 urine CEA determinaDiagnosis. tions performed on 15 of these patients, 7 (6 per cent) were positive (Table III). Five patients cured of disease had 15 urine CEA determinations, 2 of which were positive (13 per cent). Ten patients with active disease had 97 urine CEA determinations, 5 of which were positive (5 per cent). Therefore, in these 112 urine determinations 13 samples from cured patients were negative, and five samples from patients with active disease were positive for an over-all accuracy rate of 16 per cent. Serial urine CEA samples were Prognosis. collected in 10 patients (Table IV). In 8 patients the serial urine CEA neither rose nor fell; 1 cured
Results Blood
FOLLOW-UP
TABLE III. Disease Status Patients
Cured Active TOTAL
Urine CEA determinations Urine Samples
5
15 97
2
-5
13
10 15
112
7
6
TABLE IV. Disease Status Cured Active TOTAL
-Positive Number Percent
Rising
5
Serial urine CEA
Serial CEA Falling Unchanged
Total Patients
0 -0
2 -6
-1
3 7
0
8
2
10
1
UROLOGY / FEBRUARY1975 / VOLUMEV, NUMBER2
References
patient had a falling serial urine CEA, and 1 patient with active disease also had a falling serial urine CEA. No conclusion can be drawn from these data.
Demonstration of 1. GOLD, P., and FREEDMAN, S. 0.: tumor specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques, J. Exper. Med. 121:439 (1965).
Comment
2. TERRY, W. D., HENKART, P. A., COLIGAN, J. E., and TODD, C. W.: Structural studies of the major glycoprotein in preparations with carcinoembryonic antigen activity, ibid. 136: 200 (1972). 3. LAURENCE, D. J. R., et al. : Role of plasma carcinoembryonic antigen in diagnosis of gastrointestinal, mammary, and bronchial carcinoma, Br. Med. J. 3: 605 (1972).
Although there are numerous reports of the value of the CEA test in the diagnosisg-” and prognosis12-l4 of malignant disease, there are relatively few reports dealing with urologic tumors15J6 and only one specifically evaluating the value of this test in renal cell carcinoma.” The latter article evaluated plasma CEA levels in 23 patients with advanced renal cell carcinoma; the authors did not evaluate urine CEA from these patients. They found plasma CEA levels elevated in 56 per cent of these patients and also found that serial CEA levels tended to correlate with the clinical status of the patient. They concluded that this test “is a valuable tool in the evaluation and follow-up of patients with renal cell carcinoma.” The results of our study indicate that in these 23 patients the over-all diagnostic accuracy of the blood CEA test in patients with active disease is 41 per cent; the accuracy of the urine CEA test in patients with active disease is 5 per cent. The serial blood CEA test in the small number of patients studied (6 patients with blood serial CEA) failed to reveal an accurate prognosis in more than one half of these patients. A diagnostic and prognostic accuracy which does not exceed at least 75 per cent is inadequate as a test for potential use in the management of patients with cancer. Theoretically, the diagnostic and prognostic inadequacy of the CEA test in renal cell carcinoma is not unexpected. The antisera used in this test were raised against tumor specific antigens extracted from colon carcinoma, an entodermally derived tumor. This explains the diagnostic accuracy of the CEA test in gastrointestinal tumor of 97 per cent” and prognostic accuracy of 95 per cent. l4 Since renal cell carcinoma arises from the proximal tubule, it is, therefore, a mesodermally derived tumor and embryologically would be expected to be dissimilar from gastrointestinal cancer. l8 The hope is (1) to extract a tumor specific antigen from renal cell carcinoma, (2) to radiolabel antisera raised against this antigen, and (3) to use these antisera for the diagnosis and prognosis of renal cell carcinoma. Section
UROLOGY
I
FEBRUARY
4. MOORE, T. L., KANTROWITZ, P. A., and ZAMCHECK, antigen (CEA) in inflammatory N. : Carcinoembryonic bowel disease, J.A.M.A. 222: 944 (1972). 5. CHU, T. W., REYNOSO, G., and HANSEN, H. J.: Demonstration of carcinoembryonic antigen in normal human plasma, Nature (Lond.) 238: 152 (1972). antigen in pa6. REYNOSO, G., et al. : Carcinoembryonic tients with different cancers, J.A.M.A. 220: 361(1972). 7. HALL, R. R., et al. : Carcinoembryonic antigen in the urine of patients with urothelial carcinoma, Br. Med. J. 3: 609 (1972). 8. HANSEN, H. J., LANCE, K. P., and KRUPEY, J.: Demonstration of an ion sensitive antigenic site on carcinoembryonic antigen using zirconyl phosphate gel. Clin. Res. 19: 143(1971). 9. MOORE, L., KUPCHIK, H. Z., MARCON, N., and ZAMCHECK, N. : Carcinoembryonic antigen assay in cancer of the colon and pancreas and other digestive tract disorders, Am. J. Digest. Dis. 16: 1 (1971). 10. DHAR, P., MOORE, T., ZAMCHECK, N., and KUPCHIK, H. Z.: Carcinoembryonic antigen (CEA) in colonic cancer: use in preoperative and postoperative diagnosis and prognosis, J.A.M.A. 221: 31 (1972). 11. THOMSON, D. M. P., KRUPEY, J., FREEDMAN, S. O., and GOLD, P.: The radioimmunoassay of circulating carcinoembryonic antigen of the human digestive system, Proc. Natl. Acad. Sci. 64: 161 (1969). 12. STEWARD, A. M. : Carcinoembryonic antigen in breast cancer patients: serum levels and disease progress, Cancer 33: 1246 (1974). antigen: clin13. SKAFUN,A. T., et al. : Carcinoembryonic ical correlation with chemotherapy for metastatic gastrointestinal. cancer, ibid. 33: 1239 (1974). 14. MOORE, T., DHAR, P., ZAMCHECK, N., and KUPCHIK, H. Z. : Carcinoembryonic antigen (CEA) in diagnosis of digestive tract cancer. Embryonic and Fetal Antigens in Cancer, Proceedings of the First Conference and Workshops on Embryonic and Fetal Antigens in Cancer, May 24-26, 1971, p. 393. 15. REYNOSO, G., CHU, T. W., GUINAN, P., and MURPHY, G. P.: Carcinoembryonic antigen in patients with tumor of the urogenital tract, Cancer 30: 1 (1972). antigen in pa16. GUINAN, P., et al. : Carcinoembryonic tients with urologic cancer, Urol. Res. 1: 101 (1973). 17. CHU, T. W., SKUKLA, S. K., MITTLEMAN, A. O., and MURPHY, G. P.: Plasma carcinoembryonic antigen in renal cell carcinoma patients, J. Urol. 111: 742 (1974). Embryology of the urogenital 18. CAMPBELL, M. F.: tract, in: Urology, Philadelphia, W. B. Saunders Co.. 1964, pp. 1516-1539.
of Urologic Oncology Chicago, Illinois 60612 (DR. GUINAN)
1975 i
VOLUME
V, NUMBER
2
187
