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

Abstract

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...

Association of Insurance and Race/Ethnicity with Disease Severity among Men Diagnosed with Prostate Cancer, National Cancer Database 2004-2006

“…It is thought that many high-grade cancers have a short lead time and greater propensity to grow quickly and invade other tissues from the time they arise (17). However, this study and others suggest that some high-grade cancers have a longer natural history in which they progress from low-to high-grade by dedifferentiation and are potentially amenable to intervention (18). Increased disease severity among patients coded as insured by Medicaid may be due in part to retroactive enrollment of uninsured individuals after their cancer diagnosis, and may not reflect access to care among persons continuously insured by Medicaid.…”

Association Between Older Age and Increasing Gleason Score

“…4,5 However, these trials only included a relatively small number of men over the age of 70 years and did not include any men over the age of 75 years. Some studies have alluded to a direct relationship between age and the likelihood of high-grade or high-risk disease, 6,7 but detailed data specifically analyzing this relationship in a large, modern cohort are not available. Theoretically, such a relationship could mean that healthy older men might represent a higher risk subgroup than the overall younger trial populations, and therefore older men might benefit more from early detection of disease.…”

Change in Prostate Cancer Grade Over Time in Men Followed Expectantly for Stage T1c Disease

“…18 The MISCAN program simulates the development of prostate cancer in individuals as a sequence of tumor states characterized by T-stage and differentiation grades (Gleason scores 2-6, 7 and 8-10). They constructed 2 models: Model I in which the differentiation grade is determined before entering the preclinical screen detectable phase and does not change afterward; and Model II in which dedifferentiation may occur in the screen detectable phase.…”