Gleason score, age and screening: modeling dedifferentiation in prostate cancer

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.