IJE Advance Access published online on April 17, 2007
International Journal of Epidemiology, doi:10.1093/ije/dym053
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Commentary: On the incidence of histological prostate cancer and the probable diagnosis of cases with tumours too small to produce symptoms or to attract attention on physical examination—the findings of Dr Arnold Rice Rich
Oncologic Centre, Karolinska University Hospital, CLINTEC, Karolinska Institute, Stockholm, Sweden.
E-mail: jan.adolfsson{at}karolinska.se
Keywords Prostate cancer, histological rate, latent cancer, insignificant cancer
Accepted 5 December 2006
In 1935, Dr Arnold Rice Rich, pathologist, wrote the following:
‘For a number of years the writer has been impressed by the frequency of the small carcinomas that have been found in the prostate in the routine autopsy material of this department (Department of Pathology, John's Hopkins Medical School, Maryland, USA)’.1
The background of this observation was an investigation of the incidence of prostate cancer in a series of 2000 autopsy cases. Of these cases, 292 were male, aged 50 years or older. The prostates of these 292 males were investigated routinely macroscopically and microscopically with one block taken from each prostate. The blocks were taken at palpable lesions or randomly if no obvious macroscopic lesion could be found. Although this procedure is nowhere near today's serial sections of the specimens from radical prostatectomies, Dr Rice Rich found primary prostate cancer in 41 (14%) of the 292 specimens. In 14 of these 41 cases, the cancer had been diagnosed clinically prior to autopsy.
Dr Rice Rich concluded that
‘There is little doubt that a thorough search throughout each gland would have brought to light an even greater number of these tumours, many of which were so small that they were not seen macroscopically at the time of autopsy. The number discovered, however, indicates plainly enough that cancer of the prostate is considerably more frequent than ordinarily supposed. In 65.8% of these 41 cases the tumour was not recognized clinically, having been in most cases of a size too small to have produced symptoms or to have attracted attention on physical examination.’The last observation is particularly interesting in the light of the invariably poor prognosis of diagnosed prostate cancer at that time with virtually no 5 years survivors.2,3
The findings of Dr Rice Rich have been corroborated in several studies in different source materials, such as consecutive autopsies in men in relevant age groups, in series of men undergoing cystoprostatectomy for advanced carcinoma of the urinary bladder and in clinical series.
In a study by Franks4 in the 1950s, the findings of Dr Rice Rich were confirmed with a 30% incidence of cancers in autopsies of men aged 50 years or older, most of these tumours being defined as latent. Later, Dr Franks also concluded that there is no reliable method of distinguishing latent from active carcinomas.5 In a more recent autopsy study of 152 prostate glands from males aged 10–49-year who succumbed mainly because of violent causes, Sakr et al.6 found histologically confirmed prostate cancer in 27% and 34% among those aged 30–39 years and 40–49 years, respectively. Although the incidence of prostate cancer in general is thought to be lower in Mediterranean males, similarly high incidences of prostate cancer have been reported in two autopsy series of Spanish and Greek males.7,8 The autopsy studies are selected since men dying outside hospital are probably less likely to be autopsied and the indications for performing clinical autopsies may also vary.
High rates of histological prostate cancer have also been found in the prostates of men undergoing cystoprostatectomy for bladder cancer with no preoperative suspicion of prostate cancer. Stamey et al.9 found prostate cancer in 40% out of 139 US males whose prostate was step-sectioned after cystoprostatectomy for bladder cancer while Abdelhady et al.10 found a 28% rate of prostate cancer in 204 men in Canadian men undergoing the same procedure. Moreover, Moutzouris et al.11 found a rate of 27% in Greek males undergoing cystoprostatectomy for bladder cancer. For natural reasons, these series suffers from selection bias since only men with advanced bladder cancer are included. One can also assume that they were younger and fitter than men in general who are diagnosed with prostate cancer. Also, an unknown association between the two tumour types cannot be entirely ruled out.
Recently, Thompson et al.12 reported a rate of 24.4% of prostate cancer in the Prostate Cancer Prevention Trial, where in one study arm, men were followed with an yearly test of prostate-specific antigen (PSA) and digital rectal examinations (DRE) for 7 years. Approximately half of those diagnosed with prostate cancer were biopsied because of an increase in PSA or suspicious DRE finding. The remainder of the cases was diagnosed in the end-of-study biopsies which were done at 7 years follow-up irrespective of PSA or findings on DRE. Thus, the reported rate is a summary of a cumulative clinical rate over 7 years and the prevalence found in those biopsied at the end of the study. Thus, although impressive, the reported rate is not strictly either an incidence or a prevalence rate. In this clinical trial, there is of course selection due to inclusion and exclusion criteria, but the study is probably reasonably applicable to men, aged in general 55 years or older.
In summary, although potential biases may act in these studies and each study must be judged individually when generalizing the study results to the general male population, it appears clear that histological findings corresponding to prostate cancer can be found in the prostate glands in a large proportion of men aged 50 years or older if they are investigated thoroughly enough; the more you look, the more you find.
The high incidence of histological prostate cancer in males aged above 50 years of age fits well with the rapidly rising incidence rates of prostate cancer in most Western countries during the 1990s since the general introduction of the PSA test in the late 1980s.13,14 From having been around 6–8%, the life time risk of being diagnosed with prostate cancer has doubled to 
16% in the United States.13 The mortality from prostate cancer in the United States as well as in other countries has, however, been more or less constant or even decreased to some extent during the same period.13,14 Thus, the gap between incidence and mortality from prostate cancer has increased dramatically during the last one and a half decades. There is now a rising concern over a more or less obvious overdiagnosis and also, possibly, an overtreatment.15 Still, as pointed out by Dr L M Franks already in the 1950s,5 we still do not have any reliable prognostic indicators telling us whom to treat or not.16,17 The rate of overdiagnosis is almost impossible to assess but estimations of 29% among whites and 44% among black men in the United States18 and between 40% and 64% of the PSA-detected cases in East Anglia19 have been published. The notion of possible overdiagnosis has led to discussion on significant and non-significant prostate cancer, or latent and active cancers, i.e those tumours which will cause the symptoms and possibly kill the patient and those that never will cause any problems to the host and which would never have been detected in the pre-PSA era. The insignificant or latent cancers have usually been thought to be small and of less aggressive type. Stamey et al.9 defined insignificant cancers as being of low grade and of <0.5 cc in volume. This was based on the aforementioned study with prostate cancers found in a series of cystoprostatectomy cases. According to American cancer statistics, the risk for this group of men at that time was 8% of being diagnosed with prostate cancer. Stamey et al.9 thus identified the 8% of the men with prostate cancer with the largest tumours which resulted in a cut point of 0.5 cc. However, the fact that these males had prostate cancer does not diminish the risk of death from other causes and reasonably some of the men with tumour >0.5 cc would reasonably have died of causes not related to prostate cancer before possibly being diagnosed. Thus, the threshold for a clinically significant prostate cancer in their study should probably have been lower. Epstein and co-workers20 defined this threshold tumour volume as being 0.2 cc and with a Gleason score of <7. This was based on findings in two series, one with 21 patients with clinical T2 tumours have <0.2 cc cancers with no signs of capsular penetration in the specimen after radical surgery and with no disease progression in terms of measurable PSA with a mean follow-up of 5 years and on the aforementioned findings of Stamey et al.9 Thus, the basis for the term insignificant prostate cancer, being defined as <0.2 cc or 0.5 cc, is rather limited and to a very small part based on outcomes of patients.
The studies based on specimens from radical prostatectomies or cystoprostatectomies all have the drawback that it is difficult, or almost impossible, to assess the size of the tumour on the pre-operative biopsies. In the light of a lack of reliable prognostic factors16,17 that can be applied pre-treatment, the patients with small cancers, possibly insignificant, will be treated whether they need it or not. However, complications such as impotence and more infrequent incontinence would probably make even the smallest tumour significant for the patient in question. Thus, the terminology of significance is, for many reasons, obsolete, and it would be better to use for instance low-volume low-grade disease to describe these tumours.
Thus, at the end of the day, the observations done by Dr Rice Rich already in the 1930s, i.e. that there is a large number of men with carcinoma in their prostate if you look thoroughly enough and that many of these cases probably would be undiagnosed and with little consequence to the individual, unfortunately still stands also in the beginning of the 21st century. With the increasing usage of PSA as indicator for prostate cancer that we see over the world overdiagnosis will inevitable occur and we are in desperate need to find indicators and markers that are prognostic for the disease and predictive of treatment outcomes.16
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