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Prostate Cancer Grading: A Decade After the 2005 Modified Gleason Grading System.

To the Editor.--We wish to comment on the prostate cancer grading review by Kryvenko and Epstein, (1) published in Archives of Pathology & Laboratory Medicine. First, we would point out that, contrary to what was stated in the review, the first publications on prostate cancer predate those of Hugh Hampton Young. In his classic text De Sedibus et Causis Morborum, published in 1761, Morgagni refers to 2 cases that were almost certainly carcinoma. Two cases of carcinoma were reported by Brodie in 1832, and, indeed, many other series were published before 1900, including the definitive study of Thompson that showed the tumor to occur commonly. (2)

In their review, the authors report that the International Society of Urological Pathology (ISUP) grading system was validated by a study of 20 845 patients from 5 institutions. (3) In reality, these data do not validate the ISUP grading system because cases were accessioned from 2005 to 2014. The 2005 ISUP consensus conference was held in March 2005, with the definitive publication appearing in September 2005. Although we can accept that the Johns Hopkins Hospital (JHH) material may have been graded according to 2005 criteria, the same does not necessarily apply to the other 4 institutions. Indeed, it is the experience of one of us who contributed to that study, that the 2005 grading criteria took some years to be fully embraced locally. In view of this, the lack of a central review means that data from the 2014 "validation" study must be considered with some caution. Although these have not been referenced by the authors of the review, validation studies of ISUP grading have been reported. (4,5) In these 2 studies, ISUP grade correlated with distant progression-free and prostatic-specific antigen progression-free survival. Despite the significant predictive value of ISUP grading, there is considerable overlap in outcome among some grades. This especially involves ISUP grades 1 and 2, as well as grades 3 and 4. The ISUP grades 1 and 2 overlap is probably due to ISUP grade 2 tumors with limited volume pattern 4 having an outcome similar to ISUP grade 1 (3 + 3 = 6) tumors. The overlap in outcome for ISUP grades 3 and 4 tumors is likely the result of lumping 3 + 5, 5 + 3, and 4 + 4 tumors into ISUP grade 4 (as discussed below). This suggests that the current grading system could be reconfigured to a 4-or even a 3-tier system.

Contrary to the claims of the authors, the consensus conference did not resolve the issues regarding the handling of tertiary grades in the reporting of radical prostatectomy specimens. They stated that tertiary patterns of more than 5% of the tumor nodule should be incorporated into the Gleason score as the secondary pattern (regardless of the volume of the true secondary pattern tumor). At the 2005 ISUP conference, it was agreed that this handling would apply to needle biopsies only. Radical prostatectomy specimens were not similarly upgraded because it was considered that, using the Gleason classic scoring, needle-biopsy scores underestimated the final Gleason score obtained from examination of the radical prostatectomy specimen. The recommendation of the 2005 conference relating to the methodology of deriving a Gleason scoring for radical prostatectomy specimens was not altered at the 2014 consensus conference. (6,7) As a consequence, the suggestion that 3 + 4 = 7 (tertiary 5) in radical prostatectomy specimens be upgraded to 3 + 5 = 8 (ISUP grade 4) is not in accordance with the conference recommendations. In effect, the 2014 ISUP grading cannot be applied to radical prostatectomy specimens because there is no provision for the accommodation of tertiary scores.

In the review, the senior author makes a strong claim to be the originator of the 2014 ISUP grading system for prostate cancer. What he failed to mention is that there was a group of 6 pathologists appointed by ISUP Council to coordinate the conference, and these pathologists were the principal authors of the definitive publication. (7) An early decision of the group was that the grading classification would be known as ISUP grading. The matter was later addressed by the ISUP Council, and it was unanimously resolved that, in parallel with all other grading and classification systems developed under the auspices of the ISUP, (6,8-10) the term ISUP grade would be applied. The term grade grouping is unfortunate because it is inaccurate as groupings are based on score as well as grade, rather than being based on grade alone. Further, ISUP grading is not simply a grouping of grades/scores but includes revised morphologic criteria generated by participants at both the 2005 and 2014 consensus conferences of the ISUP. (6,7)

The authors state the new grading system was first described in work undertaken at JHH; however, we would take issue with that. The concept of grouping components of the Gleason system is hardly novel and, in fact, was proposed by Gleason himself in 1977. As we have noted elsewhere, (11) a variety of groupings have been previously suggested, with the grouping proposed by Donohue et al (12) being almost identical to those in the Pierorazio 2013 study. (13)

In reality, ISUP grade differs from JHH 2013 grades because JHH grade 4 consists of 4 + 4 = 8 tumors only, whereas ISUP grade 4 also includes 5 + 3 = 8 and 3 + 5 = 8 tumors. (7,13) Perhaps more important is the following question: Are tumors with these scores likely to behave in a manner similar to 4 + 4 = 8 tumors? Growing evidence would indicate that 5 + 3 = 8 tumors are more appropriately classified as ISUP grade 5, and 2 recent studies have validated this suggestion. (11) The authors of the review mentioned those studies and attempted to dismiss those important findings with the suggestion that the grading criteria have changed. This same comment can be applied to the Epstein et al (3) "validation" study that occurred in 2014, which, as we have noted, contains cases accessioned before the publication of the 2005 ISUP modified grading criteria. The reviewers also note that the 5 + 3/3 + 5 tumors are uncommon; however, this does not mean that patients with prostate cancer should not have their tumors graded and treated appropriately. Further, the true incidence of 3 + 5/5 + 3 tumors depends on whether grading is based on a single core or multiple core (case-composite) approach. In view of this evidence, it would appear that ISUP grading categories will require revision in the immediate future.

Brett Delahunt, MD, FRCPA [1]; David J. Grignon, MD [2]; Hemamali Samaratunga, MBBS, FRCPA [3]; John R. Srigley, MD, FRCPC [4]; Katia R. M. Leite, MD [5]; Glen Kristiansen, MD, PhD [6]; Andrew J. Evans, MD [7]; James G. Kench, MBBS, FRCPA [8]; Lars Egevad, MD, PhD [9]

[1] Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; [2] IU Health Pathology Laboratory, Indiana University School of Medicine, Indianapolis; [3] Department of Pathology, Aquesta Uropathology, University of Queensland, Brisbane, Australia; [4] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; [5] Department of Urology, Laboratory of Medical Research, University of Sao Paulo Medical School, Sao Paulo, Brazil; [6] Institute of Pathology, University Hospital Bonn, Bonn, Germany; [7] Department of Pathology, University of Toronto, Toronto, Ontario, Canada; [8] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and Central Clinical School, University of Sydney, Camperdown, Sydney, New South Wales, Australia; [9] Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden

(1.) Kryvenko ON, Epstein JI. Prostate cancer grading: a decade after the 2005 modified Gleason grading system [published online ahead of print January 12, 2016]. Arch Pathol Lab Med. doi:10. 5858/arpa.2015-0487-SA.

(2.) Murphy LJT. The History of Urology. Springfield, IL: CC Thomas;1972:531.

(3.) Epstein JI, Zelefsky MJ, Sjoberg DD, et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol. 2016;69(3):428-435.

(4.) Delahunt B, Egevad L, Srigley JR, et al. Validation of International Society of Urological Pathology (ISUP) grading for prostatic adenocarcinoma in thin core biopsies using TROG 03.04 RADAR trial clinical data. Pathology. 2015;47(6): 520-525.

(5.) Samaratunga H, Delahunt B, Gianduzzo T, et al. The prognostic significance of the 2014 International Society of Urological Pathology (ISUP) grading system for prostate cancer. Pathology. 2015;47(6):515-519.

(6.) Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL; ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostate cancer. Am J Surg Pathol. 2005;29(9):1228-1242.

(7.) Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PH; Grading Committee. The ISUP 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;40(2):244-252.

(8.) Epstein JI, Amin MB, Reuter VR, Mostofi FK; Bladder Consensus Conference Committee. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol. 1998;22(12):1435-1448.

(9.) Srigley JR, Delahunt B, Eble JN, et al; ISUP Renal Tumor Panel. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol. 2013; 37(10):1469-1489.

(10.) Delahunt B, Cheville JC, Martignoni G, et al; Members of the ISUP Renal Tumor Panel. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013; 37(10):1490-1504.

(11.) Egevad L, Delahunt B, Evans AJ, et al. International Society of Urological Pathology (ISUP) grading of prostate cancer. Am J Surg Pathol. 2016; 40(6):858-861.

(12.) Donohue JF, Bianco FJ Jr, Kuroiwa K, et al. Poorly differentiated prostate cancer treated with radical prostatectomy: long-term outcome and incidence of pathological downgrading. J Urol. 2006;176(3):991-995.

(13.) Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic Gleason grade groupings: data based on the modified Gleason scoring system. BJU Int. 2013;111 (5):753-760.

The authors have no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2016-0300-LE

In Reply.--This letter by Delahunt et al is a rehash of a prior letter that was written to the American Journal of Surgical Pathology (AJSP). We refer the readership to our response in AJSP, rather than repeat our thorough rebuttal. (1) However, there are a few new issues that we would like to address.

The authors continue to refer to the new grading system as the International Society of Urological Pathology (ISUP) grading system, despite the fact that the new system was published in 2013 by work at Johns Hopkins Hospital before the 2014 ISUP conference. (2) Similarly, the results of the multi-institutional validation study of more than 20 000 patients3 were presented at the 2014 ISUP grading conference and were the driving factor for acceptance to the new grading system both for ISUP and other subsequent organizations, such as the World Health Organization and the College of American Pathologists. Delahunt et al falsely claim, "An early decision of the group was that the grading classification would be known as ISUP grading." Several of the organizers may have assumed this to be true, but as a coleader of the organizing committee and lead author on the publication resulting from the conference, (4) one of the current authors assures readers that no such discussion or agreement on nomenclature was reached before the 2014 consensus conference. As to the subsequent ISUP Council vote on the nomenclature of the new grade groups, it is merely the opinion of a few individuals who have no mandate to dictate policy for all issues relating to urologic pathology. They have no right to usurp the name of the new grading system, in which the original concept and research, nomenclature, and subsequent critical validation study were done by others.

It is one thing for others to group various grades together for study purposes, and quite another to propose a simple, patient-centric, (5) new, 5-group grading system, as was done in 2013. (2) The original manuscript in 2013, the subsequent multi-institutional validation study, the AJSP publication on the 2014 ISUP grading conference, and the World Health Organization all avoid referring to the new grading system as ISUP grades, but rather as grade groups 1 to 5. Most recently, the College of American Pathologists adopted the terminology of grade groups 1 to 5, which will be recommended in the latest updates of prostate cancer protocols, which are widely used throughout the United States. In the "Explanatory Notes" of the protocol, it states, "The 9 Gleason scores (2-10) have been variably lumped into different groups for prognosis and patient management purposes. Epstein et al (3) proposed grouping scores into 5 prognostic categories, prognostic Grade Groups 1-5." The validation studies by Delahunt et al (6) and Samaratunga et al (7) from New Zealand and Australia, respectively, cited in the accompanying letter were initiated after the authors of those studies were presented with the findings of the multi-institutional study by Epstein et al (2,3) at the 2014 ISUP conference. Their studies were published before our validation study was published in European Urology only because they are in Pathology, the journal of the Royal College of Pathologists of Australasia, where the editor, Dr Delahunt, could have fast-tracked their publications to make it appear that our multi-institutional study of more than 20 000 patients was just one of several validation studies, rather than the key one that led to the acceptance of the new grading system and the spawning of subsequent, smaller validation studies in journals with lower impact factors.

Delahunt et al also raise a question about whether pattern combinations included in grade group 4 (4 + 4 = 8, 3 + 5 = 8, and 5 + 3 = 8) are appropriately grouped and have similar clinical behaviors and prognostic significance. In our review article, (8) we discussed the limitations of the 2 manuscripts Delahunt et al cite. With contemporary rereview, the clinical outcomes of 3 + 5 = 8 and 4 + 4 = 8 biopsy cases are not different. (9) Gleason score 5 + 3 = 8, as the highest grade core at biopsy or nodule at radical prostatectomy, is relatively rare. In our prior multiinstitutional study, only 4 of 20 824 radical prostatectomies (0.02%) and 6 of 16 172 needle biopsies (0.04%) were Gleason score 5 + 3 = 8 (J.I.E., unpublished data, 2016). From 3 large academic institutions from 2005 to 2016, we recently studied 16 biopsies and 23 radical prostatectomies retrospectively reported as Gleason score 5 + 3 = 8 (O.N.K. and J.I.E., unpublished data, 2016). Of these, only 2 biopsies and 4 radical prostatectomies were contemporarily regraded as Gleason score 5 + 3 = 8. If new, large studies grading 5 + 3 = 8 correctly convincingly show that it belongs to a different grade group, then modifications can be made in the new system to reflect new knowledge generated on cases pathologically graded according to contemporary standards.

Finally, there is the following issue that Delahunt et al bring up, "In effect 2014 ISUP grading cannot be applied to radical prostatectomy specimens as there is no provision for the accommodation of tertiary scores." There was discussion at the 2014 consensus conference on this issue. It was decided by a large majority that tertiary-grade patterns, also referred to as minor, high-grade patterns, were to be restricted to cases with less than 5% of the higher-grade pattern. Subsequent discussions and voting by the attendees of the consensus conference recommended to record the percentage of pattern 4 for Gleason score 7. Consequently, radical prostatectomy specimens with 98% pattern 3 and 2% pattern 4 would be graded as "3 + 4 = 7 with less than 5% pattern 4," as opposed to "3 + 3 = 6 with tertiary pattern 4."10 "Tertiary" higher grade would, therefore, only be used for radical prostatectomy specimens with Gleason scores 3 + 4 = 7 and 4 + 3 = 7 with less than 5% pattern 5. It follows that, in cases with more than 5% pattern 5, the higher grade would be included as the secondary pattern within the Gleason score. Otherwise, according to the 2005 grading rules, a tumor with 80% pattern 3 and 20% pattern 5 would be a Gleason score 3 + 5 = 8, and another tumor with 50% pattern 3, 30% pattern 4, and 20% pattern 5 would be graded 3 + 4 = 7, which makes no sense, given that both have the same large amount of Gleason pattern 5 cancer. As noted in the previous AJSP response, (1) "Several members of the 2014 organizing committee, instead of incorporating the issue of tertiary patterns and the recommendation to report the percentage of pattern 4 in the 2014 consensus conference published in AJSP in 2016, as I recommended, argued to split these topics into an additional manuscript. There is not even a circulated draft of this additional manuscript over 2 years after the consensus conference. It has led to confusion among pathologists relating to the issue of tertiary grades and recording percent pattern 4." It is ironic that Delahunt et al criticize the consensus conference for not dealing with tertiary patterns in radical prostatectomy specimens, yet the 3 members of the 2014 consensus conference who argued for splitting off this topic are authors on the accompanying letter from Delahunt et al.

Jonathan I. Epstein, MD [1]; Oleksandr N. Kryvenko, MD [2]

[1] Departments of Pathology, Urology, and Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland;

[2] Departments of Pathology and Laboratory Medicine, and Urology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.

(1.) Epstein JI. International Society of Urological Pathology (ISUP) grading of prostate cancer: author's reply. Am J Surg Pathol. 2016;40(6):862-864.

(2.) Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int. 2013;111 (5):753-760.

(3.) Epstein JI, Zelefsky MJ, Sjoberg DD, et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol. 2016;69(3):428-435.

(4.) Epstein JI, Egevad L, Amin MB, et al; Grading Committee. 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;40(2):244252.

(5.) Kryvenko ON, Epstein JI. Changes in prostate cancer grading: including a new patient-centric grading system. Prostate. 2016;76(5):427-433.

(6.) Delahunt B, Egevad L, Srigley JR, et al. Validation of International Society of Urological Pathology (ISUP) grading for prostatic adenocarcinoma in thin core biopsies using TROG 03.04 'RADAR' trial clinical data. Pathology. 2015;47(6): 520-525.

(7.) Samaratunga H, Delahunt B, Gianduzzo T, et al. The prognostic significance of the 2014 International Society of Urological Pathology (ISUP) grading system for prostate cancer. Pathology. 2015(6);47:515-519.

(8.) Kryvenko ON, Epstein JI. Prostate cancer grading: a decade after the 2005 modified Gleason grading system [published online ahead of print January 12, 2016]. Arch Pathol Lab Med. doi:10. 5858/arpa.2015-0487-SA.

(9.) Harding-Jackson N, Kryvenko ON, Whittington EE, et al. Outcome of Gleason 3 + 5 = 8 prostate cancer diagnosed on needle biopsy: prognostic comparison with Gleason 4 + 4 = 8 [published online ahead of print June 2, 2016]. J Urol. doi:10. 1016/j.juro.2016.05.105. [Epub ahead of print].

(10.) Kryvenko ON, Epstein JI. Re: Clinical significance of prospectively assigned Gleason tertiary pattern 4 in contemporary Gleason score 3 + 3 = 6 prostate cancer. Prostate. 2016;76(12):1130-1131.

The authors have no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2016-0434-LE
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Title Annotation:Letters to the Editor
Author:Delahunt, Brett; Grignon, David J.; Samaratunga, Hemamali; Srigley, John R.; Leite, Katia R.M.; Kris
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:Feb 1, 2017
Words:3292
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