Prostate Cancer: Amended Gleason Score Underestimates Adverse Effect of Cribriform Pathology Interview with:

Kenneth A. Iczkowski, M.D. Department of Pathology Medical College of Wisconsin Milwaukee, WI 53226

Dr. Kenneth Iczkowski,

Kenneth A. Iczkowski, M.D.
Department of Pathology
Medical College of Wisconsin
Milwaukee, WI 53226 What is the background for this study?

Dr. Iczkowski: The International Society of Urological Pathology (ISUP) in 2014 proposed use of a new 5-tier grade grouping system to supplement traditional Gleason grading to facilitate prognosis stratification and treatment1. The 5 categories subsume: Gleason 3+3=6, Gleason 3+4=7, Gleason 4+3=7, Gleason 8, and Gleason 9-10.

We desired to determine whether men with a highest Gleason score of 3+5=8 or 5+3=8 in their set of prostate biopsy specimens, would have differing outcomes from those with Gleason 4+4=8. Because Gleason 5 cancer has been demonstrated to have a higher biologic potential than Gleason 4, it was expected that Gleason score 8 pattern with any Gleason 5 pattern would have a worse outcome. What are the main findings?

Dr. Iczkowski: Follow-up data showed only a weak tendency for certain outcome measures to be worse among men with initial Gleason 3+5=8 biopsies. However, the biochemical recurrence rate was actually somewhat worse for Gleason 4+4=8. In general, this supports grouping all the Gleason score 8 cancers together.

When we stratified the Gleason 8 cases according to the presence or absence of a growth pattern called “cribriform,” however, cribriform growth turned out to exert a major effect on outcome, far greater than the differences between 3+5=8, 5+3=8, and 4+4=8. Cribriform growth also subsumes most of the lesions currently designated as “intraductal carcinoma.” What should readers take away from your report?

Dr. Iczkowski: This study adds to the 11 other studies since Egevad’s 1999 study2 that have demonstrated a distinct adverse outcome effect2-11 from the presence of the cribriform growth pattern. Both prostatic biopsy material and prostatectomy material have been the sources for data in the studies cited, as well as our current Journal of Urology study.

Our 2011 study used biochemical recurrence of prostate cancer as an endpoint3 and found that the presence of cribriform growth imparted a 6-fold hazard ratio for biochemical recurrence. Kweldam et al. in 2015-2016 used prostate cancer death as an endpoint11-12 and also found highly significant effects from cribriform growth.
In order to support a higher biologic potential of cribriform cancer, we are currently studying differences in PTEN loss and p27 loss at the protein and RNA levels. What recommendations do you have for future research as a result of this study?

Dr. Iczkowski:  The revisions to the 2005 and 2014 Gleason grading system have done much to bring it in line with current practice and outcome-based evidence. Prior to 2005, cribriform prostate cancer was accepted as Gleason grade 3 cancer, and now most or all cribriform growth is accepted as Gleason 4. While the grading system has its merits, urologic pathologists would do well to stop their tug-of-war over whether naming rights for the new Gleason grading system belong to the ISUP13 or to Johns Hopkins University14 and address its one persistent shortcoming. Its shortcoming is that it still underestimates the biologic potential of cribriform growth. We now have a dozen studies with evidence supporting that any prostate cancer with cribriform growth should be rated in the top tier of biologic potential of any grading scheme.

These studies support a revision of grade grouping as follows:

1. Gleason 3+3 = 6 (Indolent lesion of epithelial origin, IDLE)
2. Gleason 3+4 without cribriform growth (but including fused small glands and very poorly-formed glands)
3. Gleason 4+3 or 4+4 without cribriform growth (but including fused small glands and very poorly-formed glands)
4. Any cancer with cribriform growth (now = grade 4) or individual cells (now = grade 5) Is there anything else you would like to add?

1. Epstein JI, Egevad L, Amin MB, et al. 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. 2016 Feb;40:244-52.

2. Egevad L, Engstrom K, Wester K, Mattson S, Busch C. Heterogeneity of DNA ploidy in prostate cancer. J Urol Pathol 1999;10:23-37.

3. Iczkowski KA, Torkko KC, Kotnis GR, et al: Digital quantification of five high-grade prostate cancer patterns, including the cribriform pattern, and their association with adverse outcome. Am J Clin Pathol 2011;136:98
4. Kryvenko ON, Gupta NS, Virani N, et al. Gleason score 7 adenocarcinoma of the prostate with lymph node metastases: analysis of 184 radical prostatectomy specimens. Arch Pathol Lab Med 2013;137:61.

5. Dong F, Yang P, Wang C, Wu S, Xiao Y, McDougal WS, Young RH, Wu CL. Architectural heterogeneity and cribriform pattern predict adverse clinical outcome for Gleason grade 4 prostatic adenocarcinoma. Am J Surg Pathol. 2013;37:1855-61.

6. Trudel D, Downes MR, Sykes J, Kron KJ, Trachtenberg J, van der Kwast TH. Prognostic impact of intraductal carcinoma and large cribriform carcinoma architecture after prostatectomy in a contemporary cohort. Eur J Cancer. 2014;50:1610-6.

7. Sarbay BC, Kir G, Topal CS, Gumus E. Significance of the cribriform pattern in prostatic adenocarcinomas. Pathol Res Pract. 2014;210:554-7.

8. Kir G, Sarbay BC, Gümüş E, Topal CS. The association of the cribriform pattern with outcome for prostatic adenocarcinomas. Pathol Res Pract. 2014;210:640-4.

9. Siadat F, Sykes J, Zlotta AR, Aldaoud N, Egawa S, Pushkar D, Kuk C, Bristow RG, Montironi R, van der Kwast T. Not all Gleason pattern 4 prostate cancers are created equal: A study of latent prostatic carcinomas in a cystoprostatectomy and autopsy series. Prostate. 2015;75:1277-84.

10. Keefe DT, Schieda N, El Hallani S, Breau RH, Morash C, Robertson SJ, Mai KT, Belanger EC, Flood TA. Cribriform morphology predicts upstaging after radical prostatectomy in patients with Gleason score 3 + 4 = 7 prostate cancer at transrectal ultrasound (TRUS)-guided needle biopsy. Virchows Arch. 2015;467:437-42.

11. Kweldam CF, Wildhagen MF, Steyerberg EW, Bangma CH, van der Kwast, van Leenders GJ. Cribriform growth is highly predictive for postoperative metastasis and disease-specific death in Gleason score 7 prostate cancer. Mod Pathol 2015;28:457-464.

12. Kweldam CF, Kümmerlin IP, Nieboer D, Verhoef EI, Steyerberg EW, van der Kwast TH, Roobol MJ, van Leenders GJ. Disease-specific survival of patients with invasive cribriform and intraductal prostate cancer at diagnostic biopsy. Mod Pathol. 2016 Mar 4. doi: 10.1038/modpathol.2016.49. [Epub ahead of print]

13. Egevad L, Delahunt B, Evans AJ, et al. International Society of Urologic Pathology (ISUP) grading of prostate cancer. Am J Surg Pathol 2016;40:858-861.

14. Epstein JI. International Society of Urologic Pathology (ISUP) grading of prostate cancer: author’s reply. Am J Surg Pathol 2016;40:862-864. Thank you for your contribution to the community.

Outcome of Gleason 3+5=8 Prostate Cancer Diagnosed on Needle Biopsy: Prognostic Comparison with Gleason 4+4=8
Harding-Jackson, Nicholas et al.
The Journal of Urology Published Online:June 02, 2016


Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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