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Defining the threshold for significant versus insignificant prostate cancer

Abstract

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).

References

  1. 1

    Esserman, L., Shieh, Y. & Thompson, I. Rethinking screening for breast cancer and prostate cancer. JAMA 302, 1685–1692 (2009).

    CAS  Google Scholar 

  2. 2

    Schröder, F. H. et al. Screening and prostate-cancer mortality in a randomized European study. N. Engl. J. Med. 360, 1320–1328 (2009).

    Article  Google Scholar 

  3. 3

    Andriole, G. L. et al. Mortality results from a randomized prostate-cancer screening trial. N. Engl. J. Med. 360, 1310–1319 (2009).

    CAS  Article  Google Scholar 

  4. 4

    Loeb, S., Carter, H. B., Berndt, S. I., Ricker, W. & Schaeffer, E. M. Complications after prostate biopsy: data from SEER-Medicare. J. Urol. 186, 1830–1834 (2011).

    Article  Google Scholar 

  5. 5

    Ploussard, G. et al. The contemporary concept of significant versus insignificant prostate cancer. Eur. Urol. 60, 291–303 (2011).

    Article  Google Scholar 

  6. 6

    Epstein, J. I., Walsh, P. C., Carmicheal, M. & Brendler, C. B. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 271, 368–374 (1994).

    CAS  Article  Google Scholar 

  7. 7

    Chun, F. K. et al. Assessment of pathological prostate cancer characteristics in men with favorable biopsy features on predominantly sextant biopsy. Eur. Urol. 55, 617–628 (2009).

    Article  Google Scholar 

  8. 8

    Beauval, J. B. et al. Pathologic findings in radical prostatectomy specimens from patients eligible for active surveillance with highly selective criteria: a multicenter study. Urology 80, 656–660 (2012).

    Article  Google Scholar 

  9. 9

    Delongchamps, N. B. & Haas, G. P. Saturation biopsies for prostate cancer: current uses and future prospects. Nat. Rev. Urol. 6, 645–652 (2009).

    Article  Google Scholar 

  10. 10

    Noguchi, M., Stamey, T. A., McNeal, J. E. & Yemoto, C. M. Relationship between systematic biopsies and histological features of 222 radical prostatectomy specimens: lack of prediction of tumor significance for men with nonpalpable prostate cancer. J. Urol. 166, 104–109 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Van der Kwast, T. H. et al. Guidelines for processing and reporting of prostatic needle biopsies. J. Clin. Pathol. 56, 336–340 (2003).

    Article  Google Scholar 

  12. 12

    Egevad, L. et al. Standardization of Gleason grading among 337 European pathologists. Histopathology (in press).

  13. 13

    Langer, D. L. et al. Intermixed normal tissue within prostate cancer: effect on MR imaging measurements of apparent diffusion coefficient and T2--sparse versus dense cancers. Radiology 249, 900–908 (2008).

    Article  Google Scholar 

  14. 14

    Vargas, H. A. et al. Performance characteristics of MR imaging in the evaluation of clinically low-risk prostate cancer: a prospective study. Radiology (in press).

  15. 15

    Hankey, B. F. et al. Cancer surveillance series: interpreting trends in prostate cancer--part I: Evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J. Natl Cancer Inst. 91, 1017–1024 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Postma, R., Van Leenders, A. G., Roobol, M. J., Schröder, F. H. & Van der Kwast, T. H. Tumour features in the control and screening arm of a randomized trial of prostate cancer. Eur. Urol. 50, 70–75 (2006).

    Article  Google Scholar 

  17. 17

    Etzioni, R. et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control 19, 175–181 (2008).

    Article  Google Scholar 

  18. 18

    Dong, F. et al. Impact on the clinical outcome of prostate cancer by the 2005 international society of urological pathology modified Gleason grading system. Am. J. Surg. Pathol. 36, 838–843 (2012).

    Article  Google Scholar 

  19. 19

    Welch, H. G. & Black, W. C. Overdiagnosis in cancer. J. Natl Cancer Inst. 102, 605–613 (2010).

    Article  Google Scholar 

  20. 20

    Alberran, J. & Hallé, N. Hypertrophie et néoplasies épitheliales de la prostate. Ann. des Mal. Org. Gen-Urin. 17, 797–801 (1898).

    Google Scholar 

  21. 21

    Breslow, N. et al. Latent carcinoma of prostate at autopsy in seven areas. The International Agency for Research on Cancer, Lyons, France. Int. J. Cancer 20, 680–688 (1977).

    CAS  Article  Google Scholar 

  22. 22

    Franks, L. M. Latent carcinoma of the prostate. J. Pathol. Bacteriol. 68, 603–616 (1954).

    CAS  Article  Google Scholar 

  23. 23

    Sakr, W. A. et al. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20–69: an autopsy study of 249 cases. In Vivo 8, 439–443 (1994).

    CAS  Google Scholar 

  24. 24

    Sakr, W. A., Haas, G. P., Cassin, B. F., Pontes, J. E. & Crissman, J. D. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J. Urol. 150, 379–385 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Watanabe, M., Nakayama, T., Shiraishi, T., Stemmermann, G. N. & Yatani, R. Comparative studies of prostate cancer in Japan versus the United States. A review. Urol. Oncol. 5, 274–283 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Erbersdobler, A., Bardenhagen, P. & Henke, R. P. Numerical chromosomal anomalies in latent adenocarcinomas of the prostate. Prostate 38, 92–99 (1999).

    CAS  Article  Google Scholar 

  27. 27

    Soos, G. et al. The prevalence of prostate carcinoma and its precursor in Hungary: an autopsy study. Eur. Urol. 48, 739–744 (2005).

    Article  Google Scholar 

  28. 28

    Haas, G. P. et al. Needle biopsies on autopsy prostates: sensitivity of cancer detection based on true prevalence. J. Natl Cancer Inst. 99, 1484–1489 (2007).

    Article  Google Scholar 

  29. 29

    Stamatiou, K., Alevizos, A., Agapitos, E. & Sofras, F. Incidence of impalpable carcinoma of the prostate and of non-malignant and precarcinomatous lesions in Greek male population: an autopsy study. Prostate 66, 1319–1328 (2006).

    Article  Google Scholar 

  30. 30

    Zlotta, A. R. et al. Prevalence of prostate carcinoma and its precursor lesions in Russian Caucasian and Japanese men in autopsy specimens: A prospective comparative international study with central pathology review. Eur. Urol. 11, e1122 (2012).

    Article  Google Scholar 

  31. 31

    Sánchez-Chapado, M., Olmedilla, G., Cabeza, M., Donat, E. & Ruiz, A. Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study. Prostate 54, 238–247 (2003).

    Article  Google Scholar 

  32. 32

    Grönberg, H. Prostate cancer epidemiology. Lancet 361, 859–864 (2003).

    Article  Google Scholar 

  33. 33

    Weischenfeldt, J. et al. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell 23, 159–170 (2013).

    CAS  Article  Google Scholar 

  34. 34

    Kellen, E. et al. Occurrence of both bladder and prostate cancer in five cancer registries in Belgium, The Netherlands and the United Kingdom. Eur. J. Cancer 43, 1694–1700 (2007).

    Article  Google Scholar 

  35. 35

    Damiano, R. et al. Clinicopathologic features of prostate adenocarcinoma incidentally discovered at the time of radical cystectomy: an evidence-based analysis. Eur. Urol. 52, 648–657 (2007).

    Article  Google Scholar 

  36. 36

    Mazzucchelli, R. et al. Is incidentally detected prostate cancer in patients undergoing radical cystoprostatectomy clinically significant? Am. J. Clin. Pathol. 131, 279–283 (2009).

    Article  Google Scholar 

  37. 37

    Rocco, B. et al. Sensitivity and detection rate of a 12-core trans-perineal prostate biopsy: preliminary report. Eur. Urol. 49, 827–833 (2006).

    Article  Google Scholar 

  38. 38

    Pettus, J. A. et al. Risk assessment of prostatic pathology in patients undergoing radical cystoprostatectomy. Eur. Urol. 53, 370–375 (2008).

    Article  Google Scholar 

  39. 39

    Ruffion, A. et al. Preservation of prostate during radical cystectomy: evaluation of prevalence of prostate cancer associated with bladder cancer. J. Urol. 65, 703–707 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Revelo, M. P. et al. Incidence and location of prostate and urothelial carcinoma in prostates from cystoprostatectomies: implications for possible apical sparing surgery. J. Urol. 171, 646–651 (2004).

    Article  Google Scholar 

  41. 41

    Wolters, T. et al. Comparison of incidentally detected prostate cancer with screen-detected prostate cancer treated by prostatectomy. Prostate 72, 108–115 (2012).

    Article  Google Scholar 

  42. 42

    Konety, B. R., Bird, V. Y., Deorah, S. & Dahmoush, L. Comparison of the incidence of latent prostate cancer detected at autopsy before and after the prostate specific antigen era. J. Urol. 174, 1785–1788 (2005).

    Article  Google Scholar 

  43. 43

    Hoedemaeker, R. F. et al. Pathologic features of prostate cancer found at population-based screening with a four-year interval. J. Natl Cancer Inst. 93, 1153–1158 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Li, J. R., Yang, C. R., Wang, J., Ou, Y. C., Ho, H. C. & Cheng, C. L. Unsuspected prostate cancer after cystoprostatectomy: A comparison between two periods in Taiwan. J. Form. Ass. 108, 409–413 (2009).

    Article  Google Scholar 

  45. 45

    Van der Cruijsen-Koeter, I. W. et al. Tumor characteristics and prognostic factors in two subsequent screening rounds with four-year interval within prostate cancer screening trial, ERSPC Rotterdam. Urology 68, 615–620 (2006).

    Article  Google Scholar 

  46. 46

    Postma, R. et al. Cancer detection and cancer characteristics in the European Randomized Study of Screening for Prostate Cancer (ERSPC)--Section Rotterdam. A comparison of two rounds of screening. Eur. Urol. 52, 89–97 (2007).

    Article  Google Scholar 

  47. 47

    Stamey, T. A. et al. Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 7, 933–938 (1993).

    Article  Google Scholar 

  48. 48

    Martin, R. M., Vatten, L., Gunnell, D., Romundstad, P. & Nilsen, T. I. Lower urinary tract symptoms and risk of prostate cancer: the HUNT 2 Cohort, Norway. Int. J. Cancer 123, 1924–1928 (2008).

    CAS  Article  Google Scholar 

  49. 49

    Samaratunga, H. & Letizia, B. Prostatic ductal adenocarcinoma presenting as a urethral polyp: a clinicopathological study of eight cases of a lesion with the potential to be misdiagnosed as a benign prostatic urethral polyp. Pathology 39, 476–481 (2007).

    Article  Google Scholar 

  50. 50

    Schröder, F. H. et al. Evaluation of the digital rectal examination as a screening test for prostate cancer. Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. J. Natl Cancer Inst. 90, 1817–1823 (1998).

    Article  Google Scholar 

  51. 51

    Cremers, R. G. et al. Prostate cancer: trends in incidence, survival and mortality in the Netherlands, 1989–2006. Eur. J. Cancer 46, 2077–2087 (2010).

    CAS  Article  Google Scholar 

  52. 52

    Draisma, G. et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J. Natl Cancer Inst. 101, 374–383 (2009).

    Article  Google Scholar 

  53. 53

    Etzioni, R. et al. Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends. J. Natl Cancer Inst. 94, 981–990 (2002).

    Article  Google Scholar 

  54. 54

    McGregor, M., Hanley, J. A., Boivin, J. F. & McLean, R. G. Screening for prostate cancer: estimating the magnitude of overdetection. CMAJ 159, 1368–1372 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Draisma, G. et al. 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. 95, 868–878 (2003).

    Article  Google Scholar 

  56. 56

    Parker, C., Muston, D., Melia, J., Moss, S. & Dearnaley, D. A model of the natural history of screen-detected prostate cancer, and the effect of radical treatment on overall survival. Br. J. Cancer 94, 1361–1368 (2006).

    CAS  Article  Google Scholar 

  57. 57

    Pashayan, N. et al. Mean sojourn time, overdiagnosis, and reduction in advanced stage prostate cancer due to screening with PSA: implications of sojourn time on screening. Br. J. Cancer 100, 1198–1204 (2009).

    CAS  Article  Google Scholar 

  58. 58

    Gulati, R. et al. What if I don't treat my PSA-detected prostate cancer? Answers from three natural history models. Cancer Epidemiol. Biomarkers Prev. 20, 740–750 (2011).

    Article  Google Scholar 

  59. 59

    Whittemore, A. S., Keller, J. B. & Betensky, R. Low-grade, latent prostate cancer volume: predictor of clinical cancer incidence? J. Natl Cancer Inst. 83, 1231–1235 (1991).

    CAS  Article  Google Scholar 

  60. 60

    Carter, H. B., Piantadosi, S. & Isaacs, J. T. Clinical evidence for and implications of the multistep development of prostate cancer. J. Urol. 143, 742–746 (1990).

    CAS  Article  Google Scholar 

  61. 61

    Johansson, J. E. et al. Natural history of early, localized prostate cancer. JAMA 291, 2713–2719 (2004).

    CAS  Article  Google Scholar 

  62. 62

    Albertsen, P. C., Hanley, J. A. & Fine, J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293, 2095–2101 (2005).

    CAS  Article  Google Scholar 

  63. 63

    Draisma, G., Postma, R., Schröder, F. H., Van der Kwast, T. H. & De Koning, H. J. Gleason score, age and screening: modeling dedifferentiation in prostate cancer. Int. J. Cancer 119, 2366–2371 (2006).

    CAS  Article  Google Scholar 

  64. 64

    Sowalsky, A. G., Ye, H., Bubley, G. J. & Balk, S. P. Clonal progression of prostate cancers from Gleason grade 3 to grade 4. Cancer Res. 73, 1050–1055 (2013).

    CAS  Article  Google Scholar 

  65. 65

    Cooperberg, M. R., Carroll, P. R. & Klotz, L. Active surveillance for prostate cancer: progress and promise. J. Clin. Oncol. 29, 3669–3676 (2011).

    Article  Google Scholar 

  66. 66

    Hoedemaeker, R. F., Rietbergen, J. B. W., Kranse, R., Van der Kwast, T. H. & Schröder, F. H. Comparison of pathological characteristics of T1c and non-T1c cancers detected in a population-based screening study, the European Randomized Study of Screening for Prostate Cancer. World J. Urol. 15, 339–345 (1997).

    CAS  Article  Google Scholar 

  67. 67

    Dugan, J. A., Bostwick, D. G., Myers, R. P., Qian, J., Bergstralh, E. J. & Oesterling, J. E. The definition and preoperative prediction of clinically insignificant prostate cancer. JAMA 275, 288–294 (1996).

    CAS  Article  Google Scholar 

  68. 68

    Bostwick, D. G. et al. Staging of early prostate cancer: a proposed tumor volume-based prognostic index. Urology 41, 403–411 (1993).

    CAS  Article  Google Scholar 

  69. 69

    Stamey, T. A. Editorial: More information on prostate specific antigen and prostate cancer. J. Urol. 170, 457–458 (2003).

    Article  Google Scholar 

  70. 70

    Winkler, M. H., Livni, N., Mannion, E. M., Hrouda, D. & Christmas, T. Characteristics of incidental prostatic adenocarcinoma in contemporary radical cystoprostatectomy specimens. Br. J. Urol. Int. 99, 554–558 (2007).

    Article  Google Scholar 

  71. 71

    Wolters, T. et al. A critical analysis of the tumor volume threshold for clinically insignificant prostate cancer using a data set of a randomized screening trial. J. Urol. 185, 121–125 (2011).

    Article  Google Scholar 

  72. 72

    Van der Kwast, T. H. et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 2: T2 substaging and prostate cancer volume. Mod. Pathol. 24, 16–25 (2011).

    Article  Google Scholar 

  73. 73

    Roobol, M. J. et al. Prostate cancer mortality reduction by prostate-specific antigen-based screening adjusted for nonattendance and contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Eur. Urol. 56, 584–591 (2009).

    Article  Google Scholar 

  74. 74

    Bangma, C. H. et al. Active surveillance for low-risk prostate cancer. Crit. Rev. Oncol. Hematol. (in press).

  75. 75

    Epstein, J. I. et al. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am. J. Surg. Pathol. 29, 1228–1242 (2005).

    Article  Google Scholar 

  76. 76

    Helpap, B. & Egevad, L. The significance of modified Gleason grading of prostatic carcinoma in biopsy and radical prostatectomy specimens. Virchows Arch. 449, 622–627 (2006).

    Article  Google Scholar 

  77. 77

    Billis, A. et al. The impact of the 2005 International Society of Urological Pathology Consensus Conference on standard Gleason grading of prostatic carcinoma in needle biopsies. J. Urol. 180, 548–553 (2008).

    Article  Google Scholar 

  78. 78

    Epstein, J., Feng, Z., Trock, B. J. & Pierorazio, P. M. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur. Urol. 61, 1019–1024 (2012).

    Article  Google Scholar 

  79. 79

    Albertsen, P. C. et al. Prostate cancer and the Will Rogers phenomenon. J. Natl Cancer Inst. 97, 1248–1253 (2005).

    Article  Google Scholar 

  80. 80

    Cheng, L. et al. The combined percentage of Gleason patterns 4 and 5 is the best predictor of cancer progression after radical prostatectomy. J. Clin. Oncol. 23, 2911–2917 (2005).

    Article  Google Scholar 

  81. 81

    Vis, A. N., Roemeling, S., Kranse, R., Schröder, F. H. & Van der Kwast, T. H. Should we replace the Gleason score with the amount of high-grade prostate cancer? Eur. Urol. 51, 931–939 (2007).

    CAS  Article  Google Scholar 

  82. 82

    Guo, C. C., Gonzalgo, M. L., Magheli, A., Loeb, S. & Epstein, J. I. Tertiary Gleason patterns and biochemical recurrence after prostatectomy: Proposal for a modified Gleason scoring system. J. Urol. 182, 1364–1370 (2009).

    Article  Google Scholar 

  83. 83

    Servoll, E. et al. Impact of a tertiary Gleason pattern 4 or 5 on clinical failure and mortality after radical prostatectomy for clinically localized prostate cancer. Br. J. Urol. Int. 109, 1489–1494 (2012).

    Article  Google Scholar 

  84. 84

    Ross, H. M. et al. Do adenocarcinomas of the prostate with Gleason score (GS)≤6 have the potential to metastasize to lymph nodes? Am. J. Surg. Pathol. 36, 1346–1352 (2012).

    Article  Google Scholar 

  85. 85

    Wilt, T. J. et al. Radical prostatectomy versus observation for localized prostate cancer. N. Engl. J. Med. 367, 203–213 (2012).

    CAS  Article  Google Scholar 

  86. 86

    Abern, M. R. et al. Delayed radical prostatectomy for intermediate-risk prostate cancer is associated with biochemical recurrence: Possible implications for active surveillance from the SEARCH database. Prostate (in press).

  87. 87

    Iremashvili, V. et al. Pathological prostate cancer characteristics in patients eligible for active surveillance: A head-to-head comparison of contemporary protocols. Eur. Urol. (in press).

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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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Van der Kwast, T., Roobol, M. Defining the threshold for significant versus insignificant prostate cancer. Nat Rev Urol 10, 473–482 (2013). https://doi.org/10.1038/nrurol.2013.112

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