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Defining the threshold for significant versus insignificant prostate cancer


Autopsy studies have shown the presence of a large reservoir of latent prostate cancers in adult men. Serum PSA testing of asymptomatic men leads to the detection of a proportion of these latent prostate cancers. The unequivocal demonstration of a substantial (30–50%) risk of overdiagnosis by the two largest randomized population-based screening trials has led to a growing awareness of this unwanted effect. Unsurprisingly, active surveillance is now becoming the favoured strategy for deferring active treatment in men diagnosed with low-risk prostate cancer and reducing their risk of overtreatment. Almost all eligibility criteria for active surveillance refer to a strict pathological definition of insignificant prostate cancer, based on two landmark studies published about 20 years ago. However, current epidemiological data suggest that this original pathological definition of insignificant prostate cancer is too restrictive. In addition, the International Society of Urological Pathology (ISUP) 2005 modification to the Gleason grading system might have resulted in a marked upgrading of biopsy-diagnosed prostate cancers, reducing the number of men eligible for active surveillance. An updated definition of insignificant prostate cancer should reflect the optimal trade-off between reducing the risk of underestimating a significant prostate cancer and including as many men as possible in active surveillance programmes.

Key Points

  • Contemporary autopsy and cystoprostatectomy studies reveal a 10% prevalence of high-grade (Gleason score ≥7) prostate cancers in the latent prostate cancer reservoir

  • The kinetics of progression of Gleason score ≤6 (3 + 3) prostate cancers (with a 20–30% prevalence in the latent pool of men aged 40–50 years) is not well understood

  • A shift in the histopathological prognosticators of prostate cancer over the past decade has necessitated a review of the current histopathological definition of insignificant prostate cancer

  • Epidemiological calculations tend to underestimate PSA-induced overdiagnosis of prostate cancer because of the unclear definition of clinical prostate cancer

  • The current pathological definition of insignificant prostate cancer is too restrictive and should probably include all organ-confined prostate cancers with a Gleason score ≤6 (3 + 3)

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Figure 1: Scheme depicting the age-related natural history of five hypothetical forms of prostate cancer (presented by the curved lines I–V) in relationship to their clinical signs and symptoms, visualizing their sojourn time in the latent reservoir (grey coloured zone).
Figure 2: A small-sized Gleason score 8 (4 + 4) adenocarcinoma identified in a cystoprostatectomy specimen.41
Figure 3: Relationship between prostate cancer volume and Gleason score (ERSPC-Rotterdam data).


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Both authors researched the available data, contributed to discussions of content, and edited the manuscript prior to submission. T. H. Van der Kwast wrote this Review article.

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Correspondence to Theo H. Van der Kwast.

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Van der Kwast, T., Roobol, M. Defining the threshold for significant versus insignificant prostate cancer. Nat Rev Urol 10, 473–482 (2013).

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