Case study 10: A case of haematuria

Haematuria

• Post-operative care,
• Pre-operative care,
• Carcinoma of the kidney and bladder.

The trigger is a short case description of 60 year old Asian man who is a retired dye worker. Consequently, he has regular urine cytology screening. Recently abnormal cells had been detected together with microscopic haematuria. At follow-up cystoscopy 4 months later, random mucosal biopsies show multilfocal carcinoma-in-situ, one with early stromal invasion. Treatment options are discussed and the patient has a total cystectomy with construction of an ileal conduit.

The primary implication of describing this case in the way that it has been is that there is likely to be a direct link between the man’s haematuria and his former occupation. You should be aware that work in the dyestuffs industry was, for the major part of the 20th century, associated with an excess risk of cancer of the urinary tract, especially bladder cancer, of which haematuria is a prime presenting sign. You should not jump to conclusions though as other causes of haematuria are more common and most bladder cancers do not result from occupational exposure.

Thus the description“retired dye worker” leaves a number of questions begging. It is necessary to consider:

1. What type of dye worker was he? Was he a dyer or did he make dyestuffs? It is only the latter occupation where there is an historic risk for bladder papilloma or transitional cell carcinoma. The type of dyestuff is also critical and the ones which were causally implicated are often called “aniline dyes” although even that, to be pedantic, is a misnomer. The main agents were β-napthylamine and benzidine. (Can you remember your chemistry and draw out these molecules? Also from your pharmacological and biochemical knowledge, think about what metabolic pathways these agents would be taken up into exert their specific effects on the urinary epithelium).
2. Where was he a dye worker? Was it in the UK, Europe or the developing world?
3. When was he a dye worker?

These latter questions are critical in terms of likely causality. Thus in the UK, the exposure to causal agents began to be regulated in the 1950s and by 1967 controls were very tight, very effective and exposure thereafter was minimal. However elsewhere in the developing world exposure was occurring much later and controls, even when implemented, were poorer.

In the first decade of the 21st century, European workers who had significant exposure are likely to be in their eighties but immigrants may be much younger.

The epidemiology and toxicology of this subject makes a fascinating case history and, if you are interested, you will find it later in this case study. For now let's consider the clinical aspects.

This has two aspects, treatment and management on the one hand and screening on the other.

Haematuria is alarming although often painless. If your patient was a dye worker in one of the risk categories, he may well be aware of the implications. In any case, it is an indication for brisk investigation.

If there is a tumour, it is usually disclosed by standard cytological, imaging and visualisation techniques. It is worth remembering that even the initial investigations such as cystocopy can be very uncomfortable and some patients, anticipating what it is like and what is coming, put off reporting the complaint.

Papillomas of the bladder can quite often be kept at bay by regular, serial diathermy for many years. Such treatment may be combined with BCG infusion. Where the tumour is in the wall of the bladder or elsewhere in the urinary tract, resection and radiotherapy remain the mainstays of treatment. Survival depends on tumour grade, staging, etc.

Medical surveillance of this condition has a very long history and its progression illustrates medical aspirations over the years, the pitfalls of good intent and the technical shortcomings of screening approaches. Way back in 1922, the Chemical Works Regulations came in to ensure that such workers had a regular encounter with a doctor to check on their symptoms. Later on, a smear test derived from a urinary sample was developed by Papanicolai and regular screening of dye workers for so-called "Pap-stains" became the mainstay of surveillance in the latter part of the 20th century.

After a while, the practice was called into question on epidemiological grounds in that:

• It did not affect survival,
• It did not affect quality of survival,
• False positives created unnecessary anxiety and wasted clinical investigative resources,
• False negatives occurred.

The COSHH Regulations now no longer require "Pap" screening but it is still widely done, mainly due to worker resistance to having it phased out.

The issue of "spurious" reassurance from medical screening is much wider than this specific topic but there are lessons from this experience to be extrapolated to other more common screening processes. Of particular relevance are prostate and colonic cancer screening which have both ardent enthusiasts and ardent sceptics. (The same applies, in principle, to breast and cervical screening.)

Rubber (tyre) and cable manufacture have also been found to be associated with an increased incidence of bladder cancer. Related amines are used in these industries which probably metabolise to toxic entities. Also in 1988, an epidemiology study proved an association of bladder cancer with 4-Chloro-ortho-toluidine in the chemical industry. This was accepted by the International Agency for Research into Cancer (IARC) as sufficient grounds to classify this substance as a proven human bladder carcinogen.

The learning points here are from the school of real life, which is that what is being researched at any given time is being researched because it is not obvious or clear. When it has been successfully researched it becomes obvious and then one can start blaming people. It does not follow necessarily that those people are in fact blameworthy.

The mysteries which set this detective puzzle going were two. The use of "aniline dyestuffs" was common by the 1860s, especially in Germany.  In 1895 a German chemical works surgeon, Ludwig Rehn, reported the occurrence of bladder tumours in dyestuffs manufacturing workers. However, the precise agents which caused this effect were quite unclear.

At that time, the idea of toxicology was in its infancy and even when it got going in the early part of the 20th century, scientists were puzzled by a number of facts:

1. When fed to experimental animals (rats, mice) the main suspect agents, β-napthylamine and benzidine did not cause tumours - the animals died of old age.
2. Only some dye workers got the cancers.
3. The cancers only occurred after a time-lag from exposure (4-40 years but typically 8-20 years).

The first puzzle was solved in 1938 when Dr Wilhelm Hueper used dogs for his experiments. They got bladder tumours. By these means, the basic toxicological concepts of metabolic activation and species specific metabolism were enunciated. Now we take them for granted. Less than a century ago, no one had even thought of them.

Similarly, no one had thought that cancer inception might be a multistage process subject to multi-layered preventative surveillance within the body. This explains the other two puzzles (caseness and latent period) but we are still in the midst of elucidating the nuances of these topics even now.

In 1952, Case and co-workers published the first major epidemiological study of sufficient precision to identify specific causal agents. The use of β-napthylamine and benzidine was banned voluntarily in the UK immediately after this report and laws backing this ban were enacted somewhat later in 1967. Case’s study and its methods were highly innovative at the time and contributed much to epidemiological methodological development; again in ways that we now take for granted, for example:

• Careful definition of cases,
• Careful definition of controls,
• Careful identification of exposure.

It is salutary to note that Case’s study took a clutch of workers 7 years to complete, much of the time being spent in methodological development and painstaking data capture. Now the whole job might take one experienced researcher a year or two. That's progress!

The toxicology lessons are also salutary. We now take the testing of chemicals for granted (although we may object vehemently). Other suspect agents have gradually been identified, e.g. dichlorobenzidine, dianisidine and MBOCA and earlier, aurumine, magenta, 4-aminodiphenyl and 4-nitrodiphenyl.

Human susceptibility arises from biological activation and a crucial factor turns out to be acetylation. So called "fast acetylators" are less likely to succumb to the disease given like for like exposure, compared with "slow acetylators". So should we use genetic profiling to test work suitability? (Medical Ethics)

If you are interested in looking at the way occupational carcinogens are defined and regulated you can look up the COSHH and Chemical classification regulations on the Health and Safety Executive websites:

• COSHH regulations
• Chemical classification