effectiveness of haematuria clinics

British Journal of Urology (1993), 71,241-252 0 1993 British Journal of Urology

REVIEW

Effectiveness of Haematuria Clinics

J. P. BRlITON

Department of Urology, Guy’s Hospital, London

Haematuria is the most important symptom in urological practice because, so often, it heralds the presence of serious underlying disease, and in particular, urinary tract malignancy. Bleeding is also an emotive symptom because, to the patient, it equates with cancer. Because of the importance of haematuria as a symptom and because of the relatively routine nature of its investigation, the concept of “haematuria clinics” has become popu- lar over the last 10 to 15 years. With the introduction of resource management and the need to evaluate hospital services, however, the benefits of running such special clinics must be carefully examined.

The Size of the Problem

Bladder cancer is a disease of significant concern, with 9500 new cases diagnosed each year in England and Wales (Cancer Statistics, 1991) and approximately half of this number dying of the disease (Mortality Statistics, 1988). The majority of patients present with painless, gross haematuria, usually as the sole presenting symptom (Wallace and Harris, 1965; Gardner and Doyle, 1987), although in a review of 1500 bladder tumour patients, 15% gave no history of haematuria in any form (Miller et al., 1969). It can be predicted that up to 8000 cases of bladder cancer could be diagnosed in haematuria clinics in this country if all patients with haematuria were referred to such clinics.

About one-third of bladder cancers are low grade, non-invasive, papillary tumours (GlpTa) (Abel, 1988) which can be cured or controlled by trans- urethral surgery; in these cases, delay in diagnosis almost certainly does not affect the outcome as the risk of progression is so low (Abel et a/ . , 1988). A further third of patients have solid, infiltrating tumours at the time of initial diagnosis; at present,

Accepted for publication 24 December 1991

these patients have a poor prognosis irrespective of the treatment used. Finally, there are those patients with superficial tumours (usually pT1) whose disease follows a less predictable course; local recurrence in this group is common and up to 50% may show progression (Abel et al., 1988). Although several prognostic indices have been suggested to determine which patients will develop invasive disease (Abel, 1988), these are unreliable and this group of patients requires careful follow-up. If we assume that patients with infiltrating tumours at the time of initial diagnosis plus patients with superficial disease which progresses are the ones who may benefit from early diagnosis and treatment, then approximately half of those who attend haematuria clinics have the potential to benefit if their time to treatment can be reduced. In the remainder, delay in diagnosis and treatment is unlikely to influence survival because their tumours tend to follow a relatively benign course.

Visible urinary bleeding is a relatively specific symptom and its investigation will reveal urinary tract malignancy in up to one-third of cases, mostly bladder cancer (Gillatt and O’Reilly, 1987 ; Mariani et af., 1989). If we assume that 1 in 5 patients with haematuria will be found to have bladder cancer, then 40,000 patients would have to be seen in haematuria clinics to diagnose the 8000 cases of bladder cancer presenting with haematuria each year. This is equivalent to 150 patients per consultant urologist per year in England and Wales. Such computed figures are open to error but illustrate that these patients represent about 10% of a consultant’s new out-patient workload.

Patients with microhaematuria have not been included in these figures. In these patients the pick- up rate for bladder cancer is much less (Britton et al., 1989) and relatively few cases of bladder cancer present with microhaematuria as the prime presenting feature (Kaye and Lange, 1982). Since these patients represent only a small number of referrals

247

248 BRITISH JOURNAL OF UROLOGY

and since they tend to be selected cases, the author recommends full urological investigation of all men over the age of 40 years who are referred with microhaematuria. This is irrespective of the presence or absence of urinary symptoms and is still advised even if a repeat dipstick test for blood is negative because of the intermittent nature of microhaematuria.

With the increasing introduction of “well man” and “well woman” clinics, as well as private screening clinics, the number of patients with asymptomatic microhaematuria may well increase. The requirements of the 1990 terms of service for doctors in general practice are that a health check be carried out when a patient aged over 5 years registers with the practice for the first time and every 3 years thereafter in patients aged 16 to 74 who have not consulted their general practitioner (GP) during that period, implying that all patients consulting their GP should have a regular check- up (Mant and Fowler, 1990). This health check includes taking urine samples and analysing them for the presence of albumin and glucose, but does not include haematuria, although it is likely that many GPs will include this as part of the urine analysis. If testing for blood were to become routine, and all patients with microhaematuria were to be referred, the urological service in this country would become overburdened to the detri- ment of the rest of its service. It is essential that work is carried out to develop a soundly based policy for the investigation of microhaematuria in the future.

The Evidence “For”

The first suggestion that delay in treating bladder cancer may worsen prognosis came from Wallace and Harris in 1965. They showed that for tumours with evidence of infiltration at the time of treatment the crude survival rate was 60% at 3 years, provided treatment was given within a month of the onset of bleeding. If the delay exceeded 1 month, the survival rate fell to 25%. In the last 25 years, no studies have satisfactorily supported or refuted these figures.

A study from Denmark (Mommsen et al., 1983) showed that shorter delay tended to give better survival in T1-2 tumours, but the numbers in the study were too small to allow any conclusions. The length of delay did not appear to influence the crude survival rate in patients with T3-4 tumours.

Several studies have looked at regional differences in survival and suggested that these differ-

encesmay reflect regional variation in the detection, diagnosis and management of cancers. However, many other variable factors could be influencing the data (particularly methods of cancer registration) and conclusions from such figures must be interpreted with caution (Silman and Evans, 1981).

The Evidence “Against”

If we were to accept 2 simple concepts-first, that cancers progress slowly from pre-malignancy to superficial non-invasive localised disease, to inva- sion and then finally metastasise, and second, that all tumours present with bleeding at an early stage in the disease, then a straight line graph could be drawn between iength of symptoms and survival. Both of these statements, however, are untrue. Bleeding for the first time occurs at very variable stages of the disease and simple clinical observation shows that ordered cancer progression does not occur. With respect to bladder cancer, most invasive tumours appear to arise de nouo and not from papillary tumours (Brawn, 1982; Kaye and Lang, 1982). Indeed, it has been suggested that there are probably 2 distinct pathways in bladder neoplasia : the papillary and the non-papillary (Koss, 1979).

If early diagnosis were able to improve prognosis. programmes aimed at screening for asymptomatic disease should show better survival. Screening of the urine of workers exposed to the hazard of occupational tumours of the urinary tract has been carried out in the United Kingdom since 1952 and the results from a number of such programmes have been reported in the literature, but few have analysed the benefits of screening. Cartwright el 01. (1981) studied all male cases of bladder cancer originating in the workforce of a factory which offered a screening programme and compared those: receiving monthly cytological screening with those who had not availed themselves of the screening service. A matched set of hospital cases acted as controls. The results showed that cancers diagnosed by urine cytology were detected at an earlier stage than those in the factory and hospital unscreened groups. The patients also survived longer, although the small numbers meant that a statistically significant result was unlikely to be achieved. However, much of the gain in survival could be explained by lead time, the time by which screen- detected cancer is diagnosed earlier than it would have been if awaiting symptomatic presentation, and selection bias, introduced because screening is dependent on volunteer populations who exhibit

EFFECTIVENESS OF HAEMATURIA CLINICS 249

different risk factors and cancer incidence. One feature of note was that the unscreened factory group fared worse than the hospital group, suggest- ing that the factory patients had a basically more aggressive disease. This may partly explain the failure to demonstrate a significant benefit from screening such workers and may also explain the different survival rates of bladder cancer patients in areas close to such industries (Cartwright et al., 1980).

A recent retrospective report (Gulliford et al., 1991) studied the survival of 609 men registered as new cases of bladder cancer in 1982 in the South East and South West Thames Health Regions and compared this with the length of delay before treatment, speciality and grade of the surgeon, and the use made of different treatment modalities. It was shown that case severity was the most important influence on survival and, after adjusting for this, the authors concluded that “there was little evidence to suggest that the prognosis deteriorated with increasing delay” However, from the data presented, this statement is misleading because, to effect an analysis, the authors combined data from patients with superficial and invasive disease ; any association that may have been present between prognosis and delay in patients with invasive disease would have been diluted. Because of the small numbers, analysis of patients with pT2 or > disease alone (90 patients) would also have failed to show any significant difference unless the influence of delay on prognosis was very considerable. When comparing different methods of management, about 1000 patients are required to show a 10% improvement in 2-year survival.

Where is the Delay?

1.

2.

3.

4.

5.

6 .

7.

The delay between onset of symptoms and treatment is made up of a number of factors :

Onset of haematuria and consultation with GP. Initial consultation with GP and hospital referral. Hospital referral and attendance at clinic. Attendance at clinic and investigations. Investigations and their review in clinic. Waiting list time for diagnostic cystoscopy . Waiting list time for definitive treatment.

With so many factors it is easy to see how delay may be considerable. If one factor stands out as causing significant delay, then the incentive to minimise delay through the rest of the process is lost.

Patients report haematuria to their GP quickly. Stower (1988) reported that the median delay was 1 week. Much of the delay in treatment appears to be the responsibility of the hospital (Wallace and Harris, 1965; Stower, 1988). The aims of a haematuria clinic are (1) to offer easy access for the referring GP, so encouraging immediate referral, and (2) to offer early investigation, preferably during a single hospital visit. Once the diagnosis is made, there is no point in then placing the patient on a long hospital waiting list for definitive treatment, but initial investigation should identify many of the patients who may benefit from early treatment, i.e. those with the more aggressive type of disease. They can then be given priority over those with apparent low grade, non-invasive, papillary tumours.

Experience with Haematuria Clinics

Perhaps the simplest method of reducing delay in diagnosis is to organise pre-clinic investigations. In 1 series, however, this only reduced time from receipt of the GP’s referral letter to diagnosis from 85 to 67 days (Jones et al., 1988). An alternative is to offer a “haematuria diagnostic service” with immediate access and then return to the next clinic for the results of investigations ; this successfully reduced delay further (Turner et al., 1977; Talbot et al., 1984). Hendry et al. (1981) reported that 74% of patients underwent cystoscopy within 5 weeks of referral, but a comparison of tumours diagnosed through this “haematuria diagnostic service” with those diagnosed before its introduction showed only a small shift in the proportion of T3 to T2 - -

Patient tumours. delay GP

The ideal system, which has been described more recently (Lynch, personal communication), is to institute an “open access haematuria clinic” where referral is by telephone and all investigations, including urine microscopy, urine cytology, intravenous urography and flexible cystoscopy, are performed at one visit. A leaflet is sent to the patient to explain the format of the clinic. In the first series of 250 patients, 7% with microscopic haematuria and 17% with gross haematuria had a urological malignancy. The system has proved satisfactory, both for the referring GP and the patient, although radiological services were the

~ Hospital delay


limiting factor with respect to the number of patients who could be seen.

Methods of Investigation

The standard investigations considered most useful for evaluating haematuria are microscopy and culture, urine cytology, intravenous urography and cystoscopy .

Urine microscopy and culture. Both visible and occult haematuria are intermittent and failure to detect red cells, either on repeat dipstick testing or microscopy, should not preclude the need for investigation. Urine culture may be requested, but if leucocyte esterase, nitrite, blood and protein are all negative on dipstick testing, then a positive culture is unlikely. Although recent studies have suggested that Coulter Counter analysis of mean corpuscular red cell volume may help to identify the source of haematuria (Banks et al., 1989), the results provide only supportive information and should not preclude the need for cystoscopy in any patient over the age of 40 years presenting with haematuria.

Urine cytology. Even if the patient is going to undergo cystoscopy, cytological examination of the urine is a useful additional investigation. A positive cytology result identifies most of the patients with higher grade tumours; these are the ones who may benefit from a reduced delay in treatment. Urine cytology may also be used in combination with upper tract ultrasonography as a means of identifying upper tract urothelial tumours; this will be discussed further below. It provides a key method of identifying non-papillary carcinoma in situ and, lastly, it identifies the small number of patients with haematuria who should have further follow- UP.

Intravenous urography. The traditional starting point in the evaluation of haematuria has been intravenous urography, although ultrasonography, combined with a single plain abdominal radio- graph, may provide an alternative.

Spencer et al. (1990) concluded that ultrasonography was better than intravenous urography in investigating patients with haematuria. However, their conclusion was based on the improved detection of bladder tumours; if all patients had undergone cystoscopy, this would not have been relevant (Stonelake and Wallace, 1990). They further concluded that patients with negative

ultrasonography and cystoscopy (i.e. the majority) should proceed to intravenous urography ; this would then almost double the cost of patient investigation.

As urologists, we accept the limitations of radiological investigations in detecting tumours in the bladder (Juul et al., 1986; Malone et al., 1986; Vallancien et al., 1986) and are well aware of the need for cystoscopy. But what are the pros and cons of intravenous urography and ultrasonography in visualising the upper tracts?

Ultrasonography is a simple, safe and quick investigation and it is superior to urography in detecting renal carcinoma (Paivansalo et al., 1983 ; Warshauer et al., 1988). The addition of urine cytology may aid the detection of some upper tract urothelial tumours, but ultrasound will certainly miss some ureteric and renal pelvis tumours, fortunately, these are both uncommon causes of haematuria. Ultrasonography, even with plain abdominal radiography, will also fail to identify all urinary tract stones.

Intravenous urography will detect most, but not all, upper tract urothelial tumours and most radio- opaque stones, but will miss some mass lesions of the kidney (Loosemore et al., 1991). The investigation exposes the patient to a small amount of ionising radiation, equivalent to a 0.1% incidence of radiation-induced cancer (Mariani et al., 1989) and contrast-induced renal failure has been reported in 0.8% of patients without pre-existing renal disease (Teruel et al., 198 1). Life-threatening anaphylactic contrast medium reactions have been reported in 0.03% (Hartman et al., 1982).

The author believes that either mode of investigation is suitable for examining the upper tract, as long as the clinician accepts the limitations of each study. Ultrasonography is probably preferable in the elderly. Should the patient present with a second episode of bleeding, when no cause was found during the course of initial investigations, the patient should be reinvestigated by the alternative upper tract study not used in the initial evaluation.

Follow-up

In a large number of patients no cause for the bleeding will be identified. What is the recom- mended follow-up for these patients?

Late follow-up of patients with haematuria has shown that few, if any, develop genitourinary malignancies (Appleton et al., 1986). Regular follow-up of patients with haematuria can introduce complacency on the part of the patient and is an

EFFECTIVENESS OF HAEMATURIA CLINICS 25 1

inefficient use of hospital services. However, if no follow-up is arranged, patients should be able to return easily and quickly if they get further bleeding. The patients who should be followed up are the few with atypical urine cytology but no apparent cause. These patients have a high chance of developing urothelial cancer at a later stage (Heney er al., 1977).

Cost Effectiveness

The total cost of a haematuria evaluation is about &200 when using flexible cystoscopy. Assuming each consultant had to see 150 patients with haematuria each year, the total cost of haematuria evaluation per urologist would be E30,OOO or approximately 3% of the consultant’s total annual budget. This does not include the costs of treating the patients who are found to have urological pathology.

Setting aside the benefits to the patient of reduced anxiety from early investigation, the convenience of a single visit and the possible improvement in survival, recognising tumours at an earlier stage may result in less complex, less costly treatment and offset some of these costs. Channelling patients through a one-visit diagnostic clinic should also be more cost efficient than the traditional method of investigation which involves more than one visit to the hospital.

Conclusions

No study to date has satisfactorily supported or refuted the suggestion made 25 years ago that delay in diagnosis and treatment of bladder cancer may influence its prognosis. Unfortunately, unless this influence is very considerable, any study aimed at investigating this further will require very large numbers.

Together with the recent changes proposed by the Government, it is hoped that waiting times for out-patient referral to hospital will be reduced. Haematuria as a symptom offers a golden opportu- nity to expedite diagnosis and treatment of a malignant disease and, although some reorganisa- tion will be required, it seems reasonable to expect urology departments to offer a special service for the diagnosis of haematuria, with the aim of reducing delay in the treatment of bladder cancer. Preferably, this should be an “open access clinic”, with full investigation carried out during the course of a single hospital visit. Not only will this offer a good service to GPs but it will also reduce the

anxiety of patients waiting for investigation, and may improve the prognosis of the disease. At the present time, whilst advances in the treatment of bladder cancer are limited, it seems the only hope we can offer of improving prognosis.

References Abel, P. D. (1988). Prognostic indices in transitional cell

carcinoma of the bladder. Br. J . Urol., 62, 103-109. Abel, P. D., Hall, R. R. and Williams, G. (1988). Should pT1

transitional cell cancers of the bladder still be classified as superficial? Br. J . Urol., 62,235-239.

Appleton, G. V. N., Lutchman, G. D. and Charlton, C. A. C. (1986). A 5-year follow-up of undiagnosed haematuria. Br. J . Urol., 58,526-527.

Banks, R. A., Reynolds,S. and Hanbury, D. (1989). Identification of the source of haematuria by automated measurement of red cell volume. Br. J . Urol., 64,4548.

Brawn, P. N. (1982). The origin of invasive carcinoma of the bladder. Cancer, 50, 515-519.

Britton, J. P., Dowell, A. C. and Whelan, P. (1989). Dipstick haematuria and bladder cancer in men over 60: results of a community study. Br. Med. J . , 299, 101&1012.

Cancer Statistics (Registration 1986) (1991). MBI 19, O.P.C.S. London: H.M.S.O.

Cartwright, R. A., Gadian, T., Garland, J. B. et al. (1981). The influence of malignant cell cytology screening on the survival of industrial bladder cancer cases. J . Epidemiol. Community Health, 35,35538.

Cartwright, R. A., Glashan, R. W. and Gray, B. (1980). Survival of transitional cell carcinoma cases in 2 Yorkshire centres. Br. J . Urol., 52,497499.

Gardner, B. P. and Doyle, P. T. (1987). Symptons of bladder carcinoma. J . R . CON. Gen. Pract., 37, 367.

Gillatt, D. A. and O’Reilly, P. H. (1987). Haematuria analysed- a prospective study. J . R . SOC. Med., 80,559-560.

Gulliford, M. C., Petruckevitch, A. and Burney, P. G. J. (1991). Survival with bladder cancer, evaluation of delay in treatment, type of surgeon, and modality of treatment. Br. Med. J . , 303, 437440.

Hartman, G. W., Hattery, R. R., Witten, D. M. et al. (1982). Mortality during excretory urography : Mayo clinic experience. A.J.R. , 139,919-922.

Hendry, W. F., Manning, N., Perry, N. M. et al. (1981). The effects of a haematuria service on the early diagnosis of bladder cancer. In Bladder Cancer: Principles of‘ Combination Therapy, ed. Oliver, R. T. D., Hendry, W. F. and Bloom, H. J . G. Pp. 19-25. London; Butterworths.

Heney, N. M., Szyfelbeii, W. M., Daly, J. J. et al. (1977). Positive urinary cytology in patients without evident tumor.

Jones, M. W., Cox, R., Davies, K. I. et al. (1988). The value of the pre-clinic intravenous urogram in the earlier diagnosis of the cause of haematuria. Br. J . Urol., 62, 11-12.

Juul, N., Torp-Pedersen, S., Larsen, S. et al. (1986). Bladder tumour control by abdominal ultrasound and urine cytology. Scand. J . Urol. Nephrol., 20,275-278.

Kaye, K. W. and Lange, P. H. (1982). Mode of presentation of invasive bladder cancer: reassessment of the problem. J .

Koss, L. G. (1979). Mapping of the urinary bladder; its impact on the concepts of bladder cancer. Hum. Pathol., 10,533-548.

J . Urol., 117, 223-224.

Urol., 128, 31-33.


Loosemore, T. M., Woodhouse, C. R. J. and Shearer, R. J. (1 99 1). Role of ultrasound in the investigation of haematuria after normal intravenous urography and cystoscopy. Eur. Urol., 19, 6-7.

Malone, P. R., Weston-Underwood, J., Aron, P. M. et d (1986). The use of transabdominal ultrasound in the detection of early bladder tumours. Br. J.Urol., 58, 52&522.

Mant, D. and Fowler, G. (1990). Urine analysis for glucose and protein: are the requirements of the new contract sensible? Br. Med. J., 300,1053-1055.

Mariani, A. J., Mariani, M. C., Macchioni, C. et aL (1989). The significance of adult hematuria; 1000 hematuria evaluations including a risk-benefit and cost-effectiveness analysis. J. Urol., 141, 35&355.

Miller, A., Mitchell, J. P. and Brown, N. J. (1969). The Bristol bladder tumour registry. Br. J. Urol. (Suppl.), 41, 1-64.

Mommsen, S., Aagaard, J. and Sell, A. (1983). Presenting symptoms, treatment delay and survival in bladder cancer. Scand. J. Urol. Nephrol., 17, 163-167.

Mortality Statistics (Registration 1986) (1988). DH2 13. O.P.C.S. London: H.M.S.O.

Paivansalo, M., Suramo, I., Myllyla, V. et uf. (1983). Real-time ultrasonography as the primary imaging method in suspect renal pathology of adults. Diugn. Imag., 52,202-207.

Silman, A. J. and Evans, S. J. W. (1981). Regional differences in survival from cancer. Community Med., 3,291-297.

Spencer, J., Lindsell, D. and Mastorakou, I. (1990). Ultrasonog- raphy compared with intravenous urography in the investi- gationof adults with haematuria. Br. Med. J., 301,1074-1076.

Stonelake, P. S. and Wallace, D. M. A. (1990). Investigation of adults with haematuria. Br. Med. J., 301,1396.

Stower, M. J. (1988). Delays in diagnosing and treating bladder cancer. Br. Med. J., 2%, 1228-1229.

Talbot, R. W., Bannister, J. J. and Hills, N. H. (1984). A haematuria diagnostic service in a district general hospital. Ann. R . Coll. Surg. Engl., 66,348-350.

Teruel, J. I., Marcen, R., Onaindia, J. M. et aL (1981). Renal function impairment caused by intravenous urography . A prospective study. Arch. Intern. hied., 141, 1271-1274.

Turner, A. G., Hendry, W. F., Williams, G. B. el d (1977). A haematuria diagnostic service. Br. Med. J., 2,29-31.

Vallancien, G., Veillon, B., Charton, M. et d (1986). Can transabdominal ultrasonography of the bladder replace cystoscopy in the followup of superficial bladder tumors? J . Urol.,

Wallace, D. M. and Harris, D. L. (1965). Delay in treating bladder tumours. Luncet, ii, 332-334.

Warshauer, D. M., McCarthy, S. M., Street, L. et d (1988) Detection of renal masses : sensitivities and specificities of excretory urography/linear tomography, US, and CT. Radiol-

136,32-34.

ogy, 169,363-365.

The Author J . P. Britton, MD, FRCS, Senior Registrar, Department of

Urology, Guy’s Hospital, St Thomas Street, London SEI 9RT.

effectiveness of haematuria clinics

Documents