British Journal of Urology (19771, 49, 61-66 0

The Clinical Diagnostic Value of the Carcinoembryonic Antigen (CEA) in Haematuria A. G. TURNER,

s. CARTER, E. HIGGINS, R. w.

GLASHAN

and

A. MUNRO NEVILLE

Royal Marsden Hospital, Fulham Road, London: Institute of Cancer Research, Chester Beatty Research Institute, Fulham Road, London: and Huddersfield Royal Infirmary, Huddersfield

(Received 14 July 1976; accepted for publication 7 September 1976)

The carcinoembryonic antigen (CEA) is a glycoprotein first found in extracts of human colonic cancer and the colon of human foetuses during the first trimester of pregnancy by Gold and Freedman (1965a, b). Further studies by other workers have shown that CEA is present at trace levels in the plasma of normal subjects and may be raised in a wide variety of neoplastic and nonneoplastic conditions (see review by Neville and Cooper, 1976). Thomson el al. (1969) initially considered that plasma CEA elevations were found only in cases of endodermally-derived carcinomas. As the bladder is, in part, endodermally-derived, this led Hall ef al. (1972, 1973) to look for raised plasma and urine CEA levels in patients with urothelial carcinoma and to assess whether monitoring of plasma and/or urine CEA levels would be of value in the diagnosis and management of urothelial carcinoma. Plasma levels were found to have little relation to the presence or clinical stage of the tumour and they concluded that a raised plasma CEA was of no value in the detection of urothelial carcinoma (Hall ef al., 1973), a finding recently supported by Fraser et al. (1975). While CEA o r CEA-like substances were present in the urine of normal subjects (Neville et al., 1973), Hall ef al. ( I 972, 1973) found elevated urinary levels in 66 of patients with established overt urothelial carcinoma but not malignant tumours at other sites associated with raised plasma CEA levels, unless there was direct tumour invasion of the urothelium. In 2 subsequent studies, these data have been largely confirmed (Coombes ef a/., 1975; Fraser ef al., 1975). Unfortunately, some patients with urinary infections were found to have raised urinary CEA levels. In view of the above findings, a prospective study was initiated by the Medical Research Council and the Department of Health and Social Security to assess whether plasma and urinary CEA levels in patients presenting with haematuria would help to differentiate between benign and malignant conditions.

Patients and Methods The trial was composed of patients presenting with haematuria to the Urological Department of the Royal Marsden Hospital, London, and Huddersfield Royal Infirmary, over a period of 18 months. A total of 216 patients were admitted, 159 males and 57 females. Urothelial carcinoma was assessed according to the recommendations of the International Society of Urology on TNM Classification of Urological Tumours (UICC) I974 (Wallace, Chisholm and Hendry, 1975). Each patient, in addition to a full history and clinical examination, was investigated as follows: (i) mid-stream urine for bacteriological examination ; urinary infection was diagnosed if there were greater than 25 WBC per HPF and greater than 100,uoO organisms on urine culture; (ii) urine for cytology; (iii) intravenous pyelography ; (iv) cysto-urethroscopy and bimanual examination under general anaesthesia; 61

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Table I Diagnosis of Cases presenting with Haematuria No. of cases

Diagnosis I. Urinary tract infection with NO evidence of urothelial carcinoma 2. Urothelial carcinoma 3. Urological conditions with NO evidence of urinary infection Benign prostatic hypertrophy Infective* Calculous disease Non-urothelial malignant disease Extra-urinary tract disease involving the urinary tract Trauma Miscellaneous

82 (38 %I 22 36 7 4

2 1 10

* This is a group of patients in whom the haematuria occurred in association with the clinical symptomatology of a urinary infection but who were not referred to the Urological Unit until the infection had been treated and the haematuria ceased. Other investigations showed no abnormality to account for the haematuria. Table II Levels of Plasma and Urinary CEA in Patients presenting with Haematuria and Diverse Pathology Plasma CEA*

Urinary CEA*

Conditions

No. of patients

Normal

Raised

Normal

Raised

Infective Urothelial carcinoma

38 93

38 89

0

4

13 (34%) 14t (39%) 36t (63%)

25 (66%) 22t (61 %) 21$ (37%)

82

80

2

77 (94%)

Other urological conditions ~~

~~~~

5

(6%)

~

* Plasma CEA: normal 40 ng/ml. Urinary CEA: normal < 110 ng/ml (female). t Tumour and urinary infection present.

< 35 ng/ml (male);

$ Tumour and NO urinary infection present.

(v) urine and plasma for CEA, which was assayed as outlined by Hall ef al. (1972, 1973) and Laurence and

Neville (1972), respectively.

On the basis of our previous experience (Hall et al., 1972, 1973), urinary CEA values, 40 ng/ml abnormal (Hall et al., 1972, 1973; Laurence and Neville, 1972). For clinical diagnostic purposes, however, as only one reading is being studied, we have taken the cut-off point as

CLINICAL DIAGNOSTIC VALUE OF THE CARCINOEMBRYONIC ANTIGEN

63

Table 111 Plasma and Urinary CEA in Urothelial Carcinoma as a Function of the Tumour Stage Plasma CEA No. of

Stage

cases

Normal*

Raised*

TIS T1 T2 T3 T4 TX GO

3 29 13 24 6 11 7

3 28 13 21

0 1 0 3 0 0 0

6

11 7

Urinary CEAt ~~

Stage

No. of cases

TIS TI T2 T3 T4 TX GO

2 22 7 11 5 8 2

~

Normal*

Raised*

1 14 4 7 2

1 8 3 4 3 1 1

7 1

* For normal values, see Table 11.

t

Only cases with non-infected urines considered.

40 ng/ml. The grey area of 20-40 ng/ml is avoided in this way as such levels may be found in inflammatory disease alone.

Results A definitive diagnosis was made in 213 cases. Only 3 (less than 2%) of the cases presenting with haematuria remain undiagnosed even after repeated follow-up investigation. This percentage is lower than previous similar studies of haematuria (Burkholder et al., 1969; O’Reilly, 1974). Undiagnosed cases were excluded from the trial. The various diagnoses of the 213 patients are shown in Table I, and their plasma and urinary CEA levels in Table 11. Two cases without urothelial carcinoma were found to have a raised plasma CEA.One case was a carcinoma of cervix invading the urinary tract locally, while the other showed no evidence of malignant disease on investigation. The cause of the haematuria occurred synchronously with the symptoms of urinary infection and this was treated prior to referral to the Urological Unit. As may be seen, urinary infection frequently results in raised urinary CEA levels (Table 11). Of the 5 cases without evidence of either urothelial malignancy or infection, and a raised urinary CEA, the cause of the haematuria was considered to be infective in 4 cases. The patients experienced haematuria coincidentally with the clinical symptomatology of a urinary infection and this seemed to have been adequately treated prior to referral to the Urological Department. Urinary cytology in each of these cases showed no evidence of malignant cells. The fifth case was found to have a ureterocoele and again urinary cytology was normal. In all cases no other pathology was found after full investigation of the urinary tract. Urothelial carcinoma may be divided according to its stage and spread and the results are shown

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Table IV Results of Urinary Cytology as a Function of a Urinary Infection in Cases of Urothelial Carcinoma. Cytology No. of cases

Positive

Suspicious

Negative

32 53 85

24 36 60

2 2 4

6 15 21

Infected* Not infected? Totals

*

No cytology results on 4 cases. No cytology results on 4 cases.

Table V A Comparison of Urinary CEA and Urinary Cytology in Cases with NO Urinary Infection with Histologically Proved Urothelial Carcinoma. Urinary CEA

Cytology

No. of cases

Normal*

Raised

Positive Suspicious Negative Totals

35 2 15 53

20 0 11 31

16 2 4 22

~

*

~~

~

For normal values, see Table 11.

in Table 111. There appears to be little or no consistent correlation between the stage of the disease and the urinary CEA levels. Almost all of the patients, irrespective of stage, had normal plasma CEA levels. Cytological examination of the urine was performed on all patients. 3 patients who had urinary infections at the time of haematuria were found to have malignant cells in the urine, but despite repeated examination of the urinary tract, there is no clinical evidence of carcinoma of the urothelium. 2 further cases in whom the haematuria was associated with infection had suspicious cells on cytological examination but these also do not show any clinical evidence of carcinoma. The plasma and urinary CEA levels of these 2 patients are normal. All 5 cases remain under observation. Of the 93 cases of urothelial carcinoma, the results of cytological examination are shown in Table IV. A diagnostic accuracy of 70% was achieved. The usefulness of adding urinary CEA results to cytology in cases with non-infected urine is shown in Table 5. In only 6 cases out of 53 does CEA add significantly. Discussion The purpose of this prospective study was to ascertain whether estimation of the plasma or urinary CEA level in patients presenting with haematuria was of diagnostic or differential diagnostic value. Any further measurement that may be of value in the earlier diagnosis deserves evaluation and assessment, not only as a sole test, but also in conjunction with, and in relation to, already

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65

established and proven diagnostic methods. Hall et al. (1973) studied plasma CEA in relation to urothelial carcinoma and found only 2/73 patients had raised plasma CEA levels. Both patients had deeply invasive tumours. Later, Coombes et al. (1975) found that 13/76 (17%) and 11/33 (33 %) of patients with local or disseminated disease, respectively, had raised plasma CEA levels, while Fraser et al. (1975) found that 7/90 (8%) of patients with active disease had raised levels. Our present data agree with these findings, 4/93 (4 %) had raised levels and 3 had invasive tumours. The consensus, therefore, is that a single plasma CEA reading is of n o value in the diagnosis of urothelial carcinoma. However, if it is raised, it may indicate invasive tumour, or the presence of metastatic disease. The CEA assay for urine measures local CEA-like activity and chemical studies have revealed a variety of cross-reading components (Neville er al., 1973; Nery et al., 1974) which may reduce the accuracy of the urinary CEA value as measured by radioimmunoassay (Coombes et al., 1975). It has been shown that the level of urinary CEA and CEA-like materials are not related to plasma CEA levels (Karakousis, Holyoke and Chu, 1975) or the bacterial content of the urine (Hall et al., 1973). It is concluded, therefore, that the urinary CEA and CEA-like materials are released from the inflamed or malignant transitional epithelium, a conclusion which has been corroborated recently by the demonstration, by immunoperoxidase methods, of CEA in normal and malignant epithelium (Heyderman, 1976, personal communication). In this series, with proven urinary infection, and in the absence of urothelial malignancy, the urinary CEA levels were raised in 63 % of patients in accordance with previous reports (Hall et al., 1972; Coombes et al., 1975). 5 cases without evidence of infection or tumour were found to have raised urinary CEA levels but in 4 of these, a history strongly suggestive of urinary infection coincident with the episodes of haematuria was given. Evaluation of urinary CEA as a diagnostic parameter for urothelial carcinoma must be made in comparison to the established parameters, particularly urinary cytology, which alone has been shown to be positive in about 75% of cases (Foot et al., 1958; Schoonees et al., 1971; Coombes et al., 1975), a figure comparable to the present series (Tables IV and V). Urinary infection vitiates the use of urinary CEA as a diagnostic parameter. Thus, for a large number of cases (34 (39 %) in this series), the use of urinary CEA is negated and the clinician has to depend solely on urinary cytology and cysto-urethroscopy. A comparison of urinary cytology and urinary CEA can only be considered in the group without evidence of urinary infection. Of this group of 53 cases, 35 had a positive cytology. Of the 17 with negative cytology, 6 had raised urinary CEA levels. Hence, CEA adds'little to the initial diagnosisand also, when raised, seems to bear no relationship to the local clinical stage of invasion of the tumour. These results suggest that neither plasma nor urinary CEA are of value as diagnostic aids to complement established procedures in the detection or staging of urothelial carcinomas.

Summary Plasma and urinary CEA levels in patients presenting with haernaturia have been studied to assess whether they facilitate the differentiation between benign and malignant urothelial conditions. Plasma CEA is of no diagnostic value although, if raised, it may suggest an invasive tumour. Urinary CEA levels are only of value in the absence of urinary infection; even then, only 37% of the cases with overt urothelial tumours had raised titres. A knowledge of the urinary CEA level, therefore, would seem to contribute little to the diagnosis of patients presenting with haematuria and all patients must still be investigated by the conventional techniques of urinary bacteriology, cytology, intravenous pyelography and cystourethroscopy. We would like to express our gratitude to Dr P. Trott of the Royal Marsden Hospital and Mr A. Riley of 4911-E

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Huddersfield Royal Infirmary for their cytological studies, and to Mr Wallace, Mr Grant Williams and Mr Hendry for permission to study their cases. AGT was in receipt of a DHSS Fellowship.

References BURKHOLDER, G. V., DOTIN,L. N., THOMASON, W. B. and BEACH, P. D. (1969). Unexplained hematuria. Journal of the American Medical Association, 210, 1729-1733. D. J. R. and NEVILLE, A. M. (1975). Urinary carcinoembryonic antigen COOMBES, G. B., HALL,R. R., LAURENCE, (CEA)-like molecules and urothelial malignancy: a clinical appraisal. British Journal of Cancer, 31, 135-142. J. F. (1958). Exfoliative cytology of urinary FOOT,N. C., PAPANICOLAOU, G. N., HOLMQUIST, N. D . and SEYBOLT, sediments. Cancer, 11, 127-137. J. W. and Go, V. L. W. (1975). Clinical evaluation of urinary and serum FRASER, R. A., RAVRY, M. J., SEGURA, carcinoembryonic antigen in bladder cancer. Journal of Urology, 114,226-229. S. 0. (1965~).Demonstration of tumor-specific antigens in human colonic carcinomata GOLD,P. and FREEDMAN, by immunological tolerance and absorption techniques. Journal of Experimental Medicine, 121, 439-462. GOLD,P. and FREEDMAN, S. 0. (19656). Specific carcinoembryonic antigens of the human digestive system. Journal of Experimental Medicine, 122, 467-481. HALL,R. R., LAURENCE, D. J. R., DARCY, D., STEVENS, U., JAMES,R., ROBERTS, S. and NEVILLE, A. M. (1972). Carcinoembryonic antigen in the urine of patients with urothelial carcinoma. British Medical Journal, 3,609-611. HALL,R. R., LAURENCE, D. J. R., NEVILLE, A. M. and WALLACE, D. M. (1973). Carcinoembryonic antigen and urothelial carcinoma. British Journal of Urology, 45, 88-92. E. (1976). Personal communication. HEYDERMAN, E. D. and CHU,T. M. (1975). Simultaneous determination of plasma and urinary KARAKOUSIS, C. P., HOLYOKE, carcinoembryonic antigen levels. Journal of Surgical Oncology, 7 , 77-80. LAURENCE, D. J. R. and NEVILLE, A. M. (1972). Foetal antigens and their role in the diagnosis and clinical management of human neoplasms-a review. British Journal of Cancer, 26,335-355. NERY,R., BARSOUM, A. L., BULLMAN, H. and NEVILLE, A. M. (1974). Carcinoembryonic antigen-like substances of human urothelial carcinomas. Biochemical Journal, 139, 43 1-440. NEVILLE, A. M. and COOPER, E. H.(1976). Biochemical monitoring of cancer. Annals of CIinical Biochemistry, 13, 283-305. NEVILLE, A. M., NERY,R., HALL,R. R., TURBERVILLE, C. and LAURENCE, D. J. R. (1973). Aspects of the structure and clinical role of the carcinoembryonic antigen (CEA) and related macromolecules with particular reference to urothelial carcinoma. British Journal of Cancer, 28, Suppl. I, 198-207. O'REILLY,P. H. (1974). Hematuria of unknown origin. Postgraduate Medical Journal, 50, 746-749. G. P. (1971). The diagnostic value of urinary SCHOONEES, R., GAMARRA, M. G., MOORE,R. H. and MURPHY, cytology in patients with bladder carcinoma. Journal of Urology, 106,693-696. D. M. P., KRUPEY,J., FREEDMAN, S. 0. and GOLD,P. (1969). The radioimmunoassay of circulating THOMSON, carcinoembryonic antigen of the human digestive system. Proceedings of the National Academy of Science, USA, 64, 161-167. WALLACE, D. M., CHISHOLM, G. D. and HENDRY, W. F. (1975). TNM classification for urological tumours (UICC), 1974. British Journal of Urology, 47, 1-12.

The Authors A. G. Turner, FRCS, Lecturer in Urology, Institute of Cancer Research and Hon. Senior Registrar, Royal Marsden Hospital. S. Carter, Technician, Institute of Cancer Research. E. Higgins, DObstRCOG, Clinical Assistant, Huddersfield Royal Infirmary. R. W. Glashan, FRCSEd, FRCSGlas, Consultant Urologist, Huddersfield Royal Infirmary. A. Munro Neville, MRCPath, Professor of Experimental Pathology, Institute of Cancer Research and Hon. Consultant Pathologist, Royal Marsden Hospital.