Tumor differentiation as measured by the Gleason score is highly predictive of the course of prostatic cancer after diagnosis. Since the introduction of the prostate-specific antigen (PSA) test tumors are diagnosed with a favorable tumor stage and differentiation grade. Does screening with PSA just detect more tumors with favorable characteristics or is dedifferentiation actually being prevented by early detection and consequent treatment? The latter option implies that tumors dedifferentiate in the preclinical screen-detectable phase. To model the natural history of prostate cancer, we analyzed the age-specific distribution of clinical stage and Gleason score of 2,204 tumors diagnosed in the ERSPC-Rotterdam trial. We fitted 2 MISCAN simulation models to the observed data: Model I where tumors dedifferentiate before becoming screen-detectable and Model II where dedifferentiation occurs during the screen-detectable preclinical phase. The hypothesis of dedifferentiation during the screen-detectable phase was tested by a goodness of fit test of both models. In ERSPC-Rotterdam, we observed a significantly more favorable distribution of Gleason scores in screen-detected cancers compared to cancers found in the control arm, and in cancers detected in the second round compared to cancers detected in the first round of screening. Also, a significant association between Gleason score and age at diagnosis was found, most notably in cancers detected in the first round of screening. These findings were reproduced by Model II and less so by Model I, with a significant difference in goodness of fit between the 2 models (p < 0.001).This study provides epidemiological evidence of dedifferentiation as a major mechanism of progression in prostate cancer. Tumors dedifferentiate during the screen-detectable phase and consequently screening with PSA and early treatment can possibly prevent dedifferentiation. ' 2006 Wiley-Liss, Inc.Key words: prostatic neoplasms; Gleason score; screening; computer simulation; aging In the western world the incidence of prostate cancer is increasing because of the general availability of serum tests for prostate specific antigen (PSA) and aging of the population.1 Early detection by PSA testing and curative treatment of prostate cancer may result in a decrease in mortality from prostate cancer, 2 but definite evidence for this effect is not yet given. Nevertheless, trial results show that TNM stage and Gleason score of screen-detected tumors compare favorably to those of clinically diagnosed tumors in the control arms of the trials 3,4 ; in particular Gleason score is predictive for treatment success and survival. 5 It is tempting to deduce that early detection by screening and treatment could prevent tumor growth and dedifferentiation. However, the favorable characteristics of screen-detected cancers might be due to length bias sampling: tumors with favorable characteristics probably grow more slowly and have more chance of being detected; moreover, these tumors might never give rise to clinical sym...

No abstract

No abstract

Epidemiologically, prostate cancer is the most common cancer in the Western world after skin cancer. To date, it is still unknown whether screening for prostate cancer is justified, because results of randomised clinical trials are not yet available. The available screening tests (i.e. prostate-specific antigen (PSA) test) do not always detect cancers that otherwise would have resulted in prostate cancer mortality. Favourable results from prostate cancer screening include an increasing number of men with localised disease and an increase in the number of well-differentiated tumours. However, the risk of overdiagnosis and subsequent over-treatment (due to the diagnosis of localised disease), using aggressive therapies fuels arguments against screening. Therefore, until more evidence is available proving otherwise, prostate cancer screening can only be justified in the context of clinical trials.