ISUP Group 4 – a Homogenous Group of Prostate Cancers?


The International Society of Urological Pathology (ISUP) and the World Health Organisation have adopted a five-tiered prognostic grade group for prostate cancer in 2014. Grade group 4 is comprised of Gleason patterns 4 + 4, 3 + 5 and 5 + 3. Recent articles have suggested heterogeneity in their prognostic outcomes. We aimed to determine whether there was a difference in mortality outcomes within the ISUP 4 grouping, as identified on needle biopsy. A total of 4080 men who were diagnosed with non-metastatic (N0 M0) prostate cancer on biopsy with Gleason scores of 7, 8 and 9 were included. Multi-variable Cox Regression and Fine and Grey competing risk analysis were used to determine the All-Cause Mortality (ACM) and the Prostate Cancer Specific Mortality (PCSM) as a function of Gleason Scores (Gleason 3 + 4, 4 + 3, 4 + 4, 3 + 5/5 + 3, 9). Gleason score 4 + 4 was utilized as the referent. The 60 months’ prostate cancer specific mortality with Gleason patterns 4 + 4 and 3 + 5/5 + 3 were 17% and 20% respectively (P < 0.01). Patients with 3 + 5/5 + 3 disease, had no statistically significant difference in the ACM (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [Cl] 0.68–1.4, p = 0.99) and PCSM risk (aHR 0.77, 95% Cl 0.47–1.2, p = 0.31) when compare with the referent group of patients. Patients with Gleason patterns 4 + 3 and 9 had statistically significant difference in their PCSM risk (aHR 0.70, 95% CI 0.54–0.91, P < 0.001 and aHR 1.5, 95% Cl 1.2–1.9, P < 0.001) when compared to the referent group. Our analysis suggest that ISUP group 4 is homogenous in terms of the all-cause mortality and the prostate cancer specific morality risk as differentiated by the presence of Gleason 5 score.

This is a preview of subscription content, log in to check access.

Fig. 1


  1. 1.

    Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA (2016) The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol 40(2):244–252.

    PubMed  Article  Google Scholar 

  2. 2.

    Huynh MA, Chen MH, Wu J, Braccioforte MH, Moran BJ, D'Amico AV (2015) Gleason score 3 + 5 or 5 + 3 versus 4 + 4 prostate cancer: the risk of death. Eur Urol.

  3. 3.

    Rusthoven CG, Waxweiler TV, DeWitt PE, Flaig TW, Raben D, Kavanagh BD (2015) Gleason stratifications prognostic for survival in men receiving definitive external beam radiation therapy for localized prostate cancer. Urol Oncol 33(2):71.e11–71.e79.

    Article  Google Scholar 

  4. 4.

    Harding-Jackson N, Kryvenko ON, Whittington EE, Eastwood DC, Tjionas GA, Jorda M, Iczkowski KA (2016) Outcome of Gleason 3 + 5 = 8 prostate cancer diagnosed on needle biopsy: prognostic comparison with Gleason 4 + 4 = 8. J Urol 196(4):1076–1081.

    Article  PubMed  Google Scholar 

  5. 5.

    van den Bergh RC, van der Kwast TH, de Jong J, Zargar H, Ryan AJ, Costello AJ, Murphy DG, van der Poel HG (2016) Validation of the novel International Society of Urological Pathology 2014 five-tier Gleason grade grouping: biochemical recurrence rates for 3+5 disease may be overestimated. BJU Int 118(4):502–505.

    Article  PubMed  Google Scholar 

  6. 6.

    Mahal BA, Muralidhar V, Chen YW, Choueiri TK, Hoffman KE, JC H, Sweeney CJ, JB Y, Feng FY, Trinh QD, Nguyen PL (2015) Gleason score 5 + 3 = 8 prostate cancer: much more like Gleason score 9? BJU Int.

  7. 7.

    Jackson W, Hamstra DA, Johnson S, Zhou J, Foster B, Foster C, Li D, Song Y, Palapattu GS, Kunju LP, Mehra R, Feng FY (2013) Gleason pattern 5 is the strongest pathologic predictor of recurrence, metastasis, and prostate cancer-specific death in patients receiving salvage radiation therapy following radical prostatectomy. Cancer 119(18):3287–3294.

    Article  PubMed  Google Scholar 

  8. 8.

    Sabolch A, Feng FY, Daignault-Newton S, Halverson S, Blas K, Phelps L, Olson KB, Sandler HM, Hamstra DA (2011) Gleason pattern 5 is the greatest risk factor for clinical failure and death from prostate cancer after dose-escalated radiation therapy and hormonal ablation. Int J Radiat Oncol Biol Phys 81(4):e351–e360.

    Article  PubMed  Google Scholar 

  9. 9.

    Esserman LJ, Thompson IM, Reid B, Nelson P, Ransohoff DF, Welch HG, Hwang S, Berry DA, Kinzler KW, Black WC, Bissell M, Parnes H, Srivastava S (2014) Addressing overdiagnosis and overtreatment in cancer: a prescription for change. The Lancet Oncology 15(6):e234–e242.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Epstein JI, Zelefsky MJ, Sjoberg DD, Nelson JB, Egevad L, Magi-Galluzzi C, Vickers AJ, Parwani AV, Reuter VE, Fine SW, Eastham JA, Wiklund P, Han M, Reddy CA, Ciezki JP, Nyberg T, Klein EA (2016) A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 69(3):428–435.

    Article  PubMed  Google Scholar 

Download references


Thomas Lu is a University of Adelaide summer research scholar. Bursary was partially funded by the Freemasons Foundation Centre of Men’s Health.

Author information



Corresponding author

Correspondence to Thomas Chengxuan Lu.

Ethics declarations

Conflict of Interest


Ethical Approval

All data utilised in the study was attained from the South Australian Prostate Cancer Clinical Outcomes Collaboration. Ethical approval is provided for analyses using de-identified data, a condition which this study met.

Informed Consent

The South Australian Prostate Cancer Clinical Outcomes Collaboration database operates under an ethically approved opt-out consent model.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lu, T.C., Moretti, K., Beckmann, K. et al. ISUP Group 4 – a Homogenous Group of Prostate Cancers?. Pathol. Oncol. Res. 24, 921–925 (2018).

Download citation


  • Prostate cancer
  • Gleason score
  • Grade group 4
  • Biopsy
  • Prostate cancer specific mortality