Vol. 115, January

Copyright © 1976 by The Williams & Wilkins Co.

Printed in U.S.A.



The 24-hour urinary carcinoembryonic antigen determinations were performed on 61 patients with different stages of bladder carcinoma. Elevated titers were found in 81 per cent of the patients with active tumors and falsely positive studies were found in 7 per cent. High stage lesions were found to have high carcinoembryonic antigen levels. Plasma carcinoembryonic antigen determinations were elevated in only 45 per cent of the patients with active tumors but further study may be warranted in advanced bladder cancer cases. The 24-hour urinary carcinoembryonic antigen measurements yield the highest percentage elevations in bladder carcinoma and further investigation is required to better define its clinical application. Carcinoembryonic antigen (CEA) was originally described by Gold and Freedman and so named because it was isolated from malignant tumors of the colon or endodermal tissues of fetuses between 2 and 6 months old. 1 It is detected by immunological methods, using antisera developed in heterologous hosts. 2 Initially, plasma CEA was considered to be specific for colon carcinoma• but investigations have found it to be present in numerous other malignancies• and in some benign diseases. 5 Hansen and associates have reported that heavy smoking also causes elevation of CEA. 6 In 30 to 50 per cent of the patients with urologic cancers the CEA plasma levels are abnormally high. 7 • 8 Urinary CEA-like antigen has been identified in patients with bladder carcinoma. •- 11 Most data on urinary CEA have been obtained on single randomly collected urine specimens. The CEA antigen appears to be excreted episodically during a 24-hour period and a single random urine specimen may not be able to detect all cases of bladder neoplasia. 12 Therefore, this is a report on the 24-hour urinary CEA antigen determination on bladder cancer patients in various stages of the disease. Plasma CEA levels were determined also in the majority of these cases. MATERIALS

Of the 61 patients investigated 44 were male and 17 were female subjects, ranging in age from 23 to 80 years. All patients had histologically diagnosed transitional cell carcinoma at some time in their clinical course. The patients were divided into 6 groups: group 1-patients free of recurrent bladder carcinoma, group 2-patients free of gross tumor after endoscopic resection, group 3-patients with superficial bladder carcinoma (0 to A), group 4-patients with deeply invasive bladder carcinoma (B to C), group 5-patients with metastatic bladder carcinoma (D 1 to D,) and group 6-patients who have undergone cystectomy with ileal conduits. For controls there were 44 normal individuals and 14 patients with non-malignant urological diseases (table 1). METHOD

The 24-hour urine specimens were collected and preserved with 3 to 4 ml. of toluene. They were immediately frozen before submitting to the Roche Cancer Diagnostic Laboratory. Ten ml. of blood were collected in a lavender-topped vacutainer Accepted for publication June 20, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. Supported in part by the Columbia University Urology Neoplasm Research Fund.

containing liquid ethylenediaminetetracetic acid and potassium sorbate. After centrifugation the plasma was stored in a polyethylene vial and forwarded to the Roche Cancer Diagnostic Research Laboratory. Urine and plasma samples were analyzed by the Z-gel method of Hansen.• CEA determinations are recorded in nanograms per milliliters (ng. per ml.). The bladder tumors were staged by the Jewett-Marshall classification, using accepted clinical means including complete blood count, SMA 12 , excretory urography, liver scanning, cystoscopy, biopsy and bimanual examinations. Urine cultures and sensitivity studies were performed on all patients, and to be positive a culture had to contain more than 10• organisms. The plasma CEA and the 24-hour urinary CEA were correlated with various stages of bladder carcinoma and with the presence or absence of infection. RESULTS

There were 44 control individuals clinically free of disease who underwent urinary CEA determinations and 98 per cent of them had urinary CEA titers less than 2.5 ng. per ml. Hansen and associates have reported that 97 per cent of healthy, non-smoking subjects had plasma CEA values in the normal range of O to 2.5 ng. per ml.• Of the 14 patients with non-malignant urological diseases who underwent urinary CEA determination 4 had elevations greater than 2.5 ng. per ml. Of these 4 cases 2 had active urinary tract infections and the other 2 had urinary tract calculi. In group 1, which represents patients who have no clinical evidence of recurrent bladder carcinoma, there was only 1 patient with a markedly elevated urinary CEA (19.6 ng. per ml.) and 1 patient with a slight elevation (3.7 ng. per ml.) (table 2). The plasma CEA was moderately elevated in 4 patients (table 3). Group 2 included patients on whom transurethral resections of bladder tumors were performed and no evidence of residual gross tumor was noted by the surgeon. Urinary CEA values after the procedure were elevated in 38 per cent of the patients (5 of 13) and plasma CEA was elevated in 50 per cent (4 of 8) (tables 2 and 3). Of the patients in group 3 with superficial bladder carcinoma (0 to A) the urinary CEA levels were elevated in 80 per cent of the cases (8 of 10) and 57 per cent (4 of 7) had elevations in the plasma. Group 4 patients with deeply invasive carcinoma (B to C) showed 87 per cent (7 of 8) and group 5 patients with 46



metastatic disease showed 75 per cent (6 of 8) elevation in urinary CEA. The plasma CEA was elevated in 12 per cent of patients in group 4 and in 60 per cent of those in group 5 (tables 2 and 3). All patients with ilea! conduits (group 6) had elevated urinary CEA while 60 per cent of the cases studied had elevated plasma CEA titers (tables 2 and 3). The over-all incidence of elevated urinary CEA in patients with active bladder cancer was 81 per cent, with 45 per cent elevation of plasma CEA. There were 14 patients who had urine and plasma CEA elevations (table 4). The mean values of urinary CEA increase with the extent of the disease (table 5) and a similar finding is true with plasma CEA except for group 4. Sixty-three per cent of the ua,.1,;in" with elevated plasma CEA were smokers. Excluding had Three infected had no gross tumor present but had increased ievels of while 3 had a concomita:1t tumor plus infection with elevated urinary CEA. There was 1 patient with an infection but no tumor who had a normal urinary CEA. In the group of with non-malignant urological disease (14 cases) there were 2 patients with tract infection who also had eievated urinary CEA titers.


1. Plasma and urine samples



Normal controls Non-malignant urological disease 1-no recurrent carcinoma 2-free of carcinoma after transurethral resection 3-superficial carcinoma ( 0-A) 4-deeply invasive carcinoma (B-C) 5-metastatic carcinoma (D,-D 2 ) 6-cystectomy with ilea! conduit Totals



44 14 15 13

lO 8



8 8 9




2. CEA levels in urine (ng. per ml.) ----

Group 1-no recurrent cancer 2-free of tumor after transurethral resert ion 3-stages 0-A 4-stal(eS B-C 5-stages D,-D2 6-ileal conduit


1-no recurrent cancer 2-free of tumor after transurethral resection 3-stages 0-A 4-stages B-C 5-stages D 1 -D 2

6-ileal conduit

1:l 8


2 2

0 1 0




8 6 6 8

80 87 75 100

2. .5-5.0


6 4

4 12





:l 6 :2 2


0 0 2



(ng. per ml.) Group



3-stages 0-A 4-stages B-C 5-stages D,-D 2 6-ileal conduit

2.96 1.49 6.12 3.20

1.5.6 28.3 48.:J



A review of the control group (non-malignant urologic disease) and the patients free of tumor indicated that there is a false elevation of CEA in subjects with urinary tract infections. Other that bacteria per se do not cause elevation but irifections will cause false elevations in infected cases are excluded a 7 per cent rate of is noted. CEA levels from ilea] conduit urine were uniformly This correlates with other studies 10 and elevation reflects interference with intestinal proteins. Therefore, CEA determinations are not of value in patients with ilea! conduits. In group 2, 38 per cent of the patients (5 of 13) had an elevated urinary CEA after gross removal of the tumor transurethral resection. This finding may represent incomplete removal of the carcinoma or may be a manifestation of cellular repair. For in a short after resection '2 in this elevated group were found to have recurrent disease. Further fo!lowup in this category will be of extreme clinical interest. There seems to be a correlation between the stage of the tumor and the urine CEA in that patients with stages B to C and D1 to D2 tumors had the highest mean values of CEA (table 5).

The over-all incidence of elevated 24-hour urinary CEA titers in patients with active tumors was 81 per cent. Previous reports using have indicated 66 to 70 per cent elevations. 9 • 10 Plasma CEA was elevated in 43 per cent of the patients with active bladder carcinoma. 2 patients had markedly elevated levels (more than 5.0 ng. per ml.) and both had metastatic disease. Plasma CEA does not appear to be of help in bladder carcinoma but adequate numbers of patients with metastatic disease have not been studied. Dr. ,J. P. Vandevoorde, Roche Cancer Diagnostic Research Laboratory, provided the CEA determinations. REFERENCES


14 60 160


1. Gold, P. and Freedman, S. 0.: Demonstration of tumor-specific

2. 3.

4. Patients with elevated urine and plasma CEA No.

1-no recurrent carcinoma 2-free of carcinoma after transurethral resection 3-stages 0-A 4-stages B-C

2 :i

D,-D 2




conduit Totals



5. Mean urinary and plasma CEA in bladder cancer

3. Plasma CEA levels (nl{. per ml.)





;3 1 :1 2 lt

Plasma No. (e,;;-,) 10 8



Fi ;)



antigens in human colonic carcinomata by immunological tolerance and absorption techniques. ,J. Exp. '.Vled .. 121: 439. 1965. Gold, P. and Freedman. S. 0.: Specific carcinoembryonic antigens of the human digestive svstem. J. Exp. Med., 122: 46,. 196fi. Thomson, D. M. P., ,J., Freedman, S. 0. and Gold, P.: The radioimmunoassav circulating carcinoembryonic antigen of the human digestive system. Proc. Nat. Acad. Sci., 64: 161, 1969. Reynoso, G., Chu. T. lVl.. Holyoke, D., Cohen. E., '.\'emoto. T .. Wang, J-,L Chuang, ,J., Guinan, P. and Murphy, G. P.: Carcinoembryonic antigen in patients with different cancers. J.A.M.A., 220: :,61, 1972. Rule, A. H., Straus, E., Vandevoorde, J. and ,Janowitz, H. D.: Tumor-associated (CEA-reacting) antigen in patients with inHammatorv bowel disease. J,;ew Engl. ,J. Med., 287: 2cl, 1972. Hansen, I-l. ,J.. Snyder. ,J. J., Miller. E.. Vandevoorde, .,J, P .. Miller, 0. N , Hin2~.:;" L. R. 2.nd Burns, . rJ : Carcinoembryonic anrigen


8. 9.

10. 11. 12.


Bush, I. M.: Carcinoembryonic antigen in patients with urologic cancers. Urol. Res., 1: 101, 1973. Reynoso, G., Chu, T. M., Guinan, P. and Murphy, G. P.: Carcinoembryonic antigen in patients with tumors of the urogenital tract. Cancer, 30: 1, 1972. Hall, R. R., Laurence, D. J. R., Darcy, D., Stevens, U., James, R., Roberts, S. and Neville, A. M.: Carcinoembryonic antigen in the urine of patients with urothelial carcinoma. Brit. Med. J., 3: 609, 1972. Hall, R.R., Laurence, D. J. R., Neville, A. M. and Wallace, D. M.: Carcinoembryonic antigen and urothelial carcinoma. Brit. J. Urol., 45: 88, 1973. Guinan, P., John, T., Sadoughi, N., Ablin, R. J. and Bush, I.: Urinary carcinoembryonic-like antigen levels in patients with bladder carcinoma. J. Urol., 111: 350, 1974. Unpublished data.

COMMENT Evidence of microheterogeneity between CEAs derived from different tumors' raises the possibility that a bladder specific CEA may exist. Detection and estimation of such an antigen would further augment the significance of studies such as this one. T.R.H.

1. Reisfeld, R. A., David, G. S., Wang, R., Chino, T. and Sevier, E. D.:

New approaches for the isolation of carcinoembryonic antigens (CEA) and their utilization as immunodiagnostic reagents. Symposium Monograph: Cellular Membrane and Tumor Cell Behavior. Published by University of Texas, in press.

Carcinoembryonic antigen and bladder carcinoma.

The 24-hour urinary carcinoembryonic antigen determinations were performed on 61 patients with different stages of bladder carcinoma. Elevated titers ...
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