Commentary: Occult prostate cancer—imposter or the real deal?
University of Connecticut Health Center, Division of Urology, Urology Office, 263 Farmington Avenue, Farmington, CT 06030-2817, USA.
E-mail: Albertsen{at}NSO.UCHC.EDU
Keywords Prostate neoplasm, prostate cancer pathology
Accepted 23 August 2006
On 25 May 1934, Dr Arnold Rice Rich presented a paper at the annual meeting of the American Urological Association entitled: ‘On the frequency of occurrence of occult carcinoma of the prostate’ which was subsequently published in the Journal of Urology one year later.1 At the time, the paper probably garnered the usual polite applause and then was promptly forgotten.
When reviewed again in 2006 the observations noted are quite astounding. Based on the information derived from 292 autopsies of men aged 50 years and over performed at the Johns Hopkins Hospital during the early 1930s, Dr Rich noted that (i) multiple small foci of prostate cancer were common findings at autopsy, (ii) most of the tumours were located in the peripheral zone of the prostate mostly laterally and posteriorly, (iii) that the prostate capsule was frequently invaded before the prostate itself had enlarged and (iv) the vast majority of these tumours were unsuspected clinically.
Unfortunately it has taken over 70 years before the true significance of these observations has been fully appreciated. Over the years, several other pathologists have made important contributions to our understanding of the prostate and prostate cancer. Rich originally reported a 14% incidence of prostate cancer among the 292 autopsies performed, but tissue sampling frequently consisted of only a single slide. In 1954, Franks2 performed a more systematic analysis of prostate cancer in men undergoing autopsies and noted that 38% of men older than 50 years had microscopic prostate cancer. Sakr et al.3 extended this work in 1993 and found that as many as 34% of men in their 40s had early evidence of prostate cancer.
The clinical importance of these findings has recently been highlighted by the report of Thompson et al.4 that documented an extraordinarily high incidence of prostate cancer among 2950 healthy men participating in a prostate cancer chemoprevention study comparing finasteride vs placebo. All of these men had PSAs <4.0 ng/ml at the start of the study and most of these men had PSAs that remained <4.0 during the seven years of follow-up. Remarkably, 6.6% of the men with a PSA <0.5 ng/ml had prostate cancer and 26.9% of the men with a PSA between 3.1 and 4.0 ng/ml had prostate cancer. These findings were not based on a step-section analysis at autopsy, but rather using sextant biopsy techniques that sampled only a fraction of the entire gland. These cases appear to be similar to the prostate cancers described by Rich in 1934. He emphasized that ‘in each instance recorded in this paper the growth in question represents a true carcinoma’. The tumours identified in the finasteride study have also undergone careful scrutiny and have been confirmed to be true prostate cancers.
In his article, Dr Rich stated that ‘in each instance the tumor is composed of plump epithelial cells growing irregularly in strands and in acinar formation, and invading the neighboring tissue in a manner characteristic of carcinoma’. His description is typical of the era preceding Dr Donald Gleason's scoring system. As a member of the Veterans Administation Cooperative Urological Research Group, Dr Gleason evaluated pathology specimens from 2911 men undergoing prostate biopsies and developed the classification system that bears his name.5 His system is based on the evaluation of glandular patterns under low magnification. Later on, using step-section analyses of prostates removed as part of a radical prostatectomy, Dr John McNeal6 was able to confirm Rich's original findings that prostate cancers most often originate in the peripheral zone of the prostate and extended his observations by providing a description of the zonal anatomy of the prostate gland.
One of Rich's most interesting observations was that prostate cancers frequently invade the prostate capsule before they cause any change in prostate size. McNeal reported that prostate cancers only became clinically significant when they reached a size of 0.5 cm2.6 Epstein7 subsequently showed that tumour close to the capsule or to the margins of resection does not result in a higher risk of recurrence.
Probably the most important consequence of Rich's observations are the epidemiological implications. Widespread use of PSA testing in North America has prompted many urologists to recommend a prostate cancer biopsy. As a consequence, urologists are finding many of the small tumours originally described by Rich. Epidemiologists have long known that, over time, repeated use of a screening test will more frequently identify relatively asymptomatic, slow growing tumours as compared with aggressive tumours. Unfortunately, in prostate cancer this has become an increasingly common event. Draisma8 has estimated that at the age of 55 years PSA testing leads to an over-detection rate of 27%. By the age of 75 years, they have estimated that the rate of over-detection increases to 56%. Their model suggests that screening all men aged 55–67 years annually would detect indolent disease in 
50% of the cases. This is considerably higher than Dr Rich's estimate of 14%, but Dr Rich performed only one sampling. Contemporary practice in the United States calls for 10–12 biopsies to evaluate a man with an elevated PSA.
Dr Arnold Rich reported his observations in 1934. We are still struggling to understand the full implications of his findings and how best to treat this disease. With the advent of widespread PSA testing we have the potential of diagnosing occult prostate cancer in as many as half of all new diagnoses. Clearly, we need better genetic markers that will help differentiate clinically significant disease from occult tumours. Imagine what Dr Rich might have reported if he knew about the structure of DNA!
 |
References |
|---|
 Top References |
|---|
1 Rich AR. On the frequency of occurrence of occult carcinoma of the prostate. Journal of Urology (1935) 33:215–23. (Reprinted Int J Epidemiol. 2007;36:274–77).[Web of Science]
2 Franks LM. Latency and progression in tumors: the natural history of prostatic cancer. Lancet (1956) 2:1037–39.
3 Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. The frequency of carcinoma and intraepithelial neoplasia of the prostate in you male patients. J Urol (1993) 150:379–85.[Web of Science][Medline]
4 Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med (2004) 350:2239–46.
5 Gleason DF, Mellinger GT. Veterans Administration Cooperative Urological Research Group: prediction of prognosis for prostatic adenocarcinoma by combined histologic grading and clinical staging. J Urol (1974) 111:58–64.[Web of Science][Medline]
6 McNeal JE. Cancer volume and site of origin of adenocarcinoma of the prostate: relationship to local and distant spread. Hum Pathol (1992) 23:258–66.[CrossRef][Web of Science][Medline]
7 Epstein JI. Evaluation of radical prostatectomy capsular margins of resection: The significance of margins designated as negative, closely approaching and positive. Am J Surg Pathol (1990) 14:626–32.[Web of Science][Medline]
8 Draisma G. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst (2003) 95:868–78.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||