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Fifty years ago, Donald Gleason published his eponymous grading system and demonstrated its prognostic utility in clinical trials designed to investigate hormonal therapies for prostate cancer.1 Over the ensuing decades, the Gleason system has been widely used in clinical practice and research, and has been endorsed as the global grading standard for prostate cancer by numerous organizations, including the World Health Organization (WHO) and the Union for International Cancer Control (UICC).2,3 The diagnosis and treatment of prostate cancer has changed dramatically in recent decades and as the new millennium dawned, a modernization of the Gleason system commenced. In 2005, the International Society of Urological Pathology (ISUP) convened a consensus conference at which the patterns comprising the various Gleason grades were clarified, along with the practical rules for their application.4 There was emphasis on how the grading system should be employed in biopsy practice. It was agreed that Gleason grades 1 and 2 should not be used in biopsy reporting. The consensus was that these uncommon patterns should be restricted to occasional tumours, usually originating in the transition zone, that were only diagnosable in transurethral resections or radical prostatectomy specimens. As a consequence of this, the Gleason scale for biopsies started at Gleason score six. Cribriform patterns, with the exception of the uncommon small, round, and regular cribriform structures, and so-called poorly formed glands (without wellformed lumens) were included as features of Gleason pattern (grade) 4. Additionally, it was decided that in biopsies where three Gleason patterns are present, the dominant pattern and worst remaining one, irrespective of its extent should comprise the Gleason score. Over the following decade, the changes endorsed by ISUP in 2005 resulted in an upgrading of prostate cancer, with a greater proportion of patients being classified within high-risk categories.5-7 Additionally, the recalibration of the Gleason scale resulted in practical problems for both urologists and oncologists, who had to explain to patients that Gleason 6 cancer was a low-grade tumour and that active surveillance, in many cases, was the treatment of choice. With the availability of information from the web and other sources, patients were often left confused by the concept of Gleason 6 being considered the most favourable grade on biopsy, when the Gleason system spanned scores 2‒10. They were asking, “Wouldn’t my Gleason 6 cancer be considered intermediate grade?” Even for stratification of patients into a high-profile clinical trial, Gleason 6 was considered intermediate-grade rather than low-grade.8 Additionally, there was a suggestion by some clinicians, epidemiologists, and public health physicians to re-name Gleason 6 adenocarcinoma as “indolent lesion of epithelial origin (IDLE).”9 Because of these and other unresolved issues from the 2005 consensus conference, the ISUP convened a second meeting in 2014 to further clarify details of prostate cancer grading based on evidence generated since 2005 wherever possible. This conference was attended by 65 pathologists and 17 clinicians from 19 countries.10 At the meeting it was agreed that all cribriform and glomeruloid patterns should be classified as Gleason grade 4. It was further agreed that grading for mucinous tumours should be based upon the underlying architectural pattern and not be influenced by the mucin component. Finally, intraductal carcinoma of prostate, which has come to prominence as an important adverse prognostic factor in the last decade, would not be graded and only the associated invasive component would be assigned a Gleason score. A major focus of the 2014 meeting was the refinement and endorsement of a prognostic grouping system initially proposed by Eifler et al in 2012.11 Over the years, numerous grade grouping systems have been proposed and the current system is a natural progression of this (Table 1).12-25 The ISUP grades, which are based on the grouping of Gleason scores and patterns, are shown in Table 2. Arguably, the John R. Srigley, MD;1 Brett Delahunt, MD;2 Lars Egevad, MD;3 Hemamali Samaratunga, MD;4 John Yaxley, MD;5 Andrew J. Evans, MD6

One is the new six: The International Society of Urological Pathology (ISUP) patient-focused approach to Gleason grading