By: Dan Sperling, MD

Since 1966, the prostate cancer (PCa) grading system devised by Donald Gleason has been considered the most accurate forecaster of the likelihood of treatment success. It is based on a report from pathology (a visual examination under a microscope of the cellular architecture of prostate tissue) either from needle biopsy samples or from a whole gland specimen removed during radical prostatectomy. The grading process involves assigning a number from one (appears closest to normal) to five (appears completely cancerous). What made the system unique was adding the grades assigned to the two most prevalent (the two largest percentages) of abnormal cells. For example, a traditional Gleason grade might be 3 + 3 or 3 + 4, with the first number indicating the larger of the two percentages.

Without explaining the terms used in cellular pathology, here is the original description of the five grades:

1. One – Very well-differentiated, small, closely packed, uniform glands in essentially circumscribed masses.
2. Two – Similar to pattern 1 but with moderate variation in size and shape of glands and more atypia in the individual cells; cribriform pattern may be present, still essentially circumscribed, but more loosely arranged. [Cribriform means having holes like a sieve]
3. Three – Similar to pattern 2 but marked irregularity in size and shape of glands, with tiny glands or individual cells invading stroma away from circumscribed masses or solid cords and masses with easily identifiable glandular differentiation within most of them.
4. Four – Large clear cells growing in a diffuse pattern resembling hypernephroma; may show gland formation.
5. Five – Very poorly differentiated tumours; usually solid masses or diffuse growth with little or no differentiation into glands.[i]

These descriptions were refined in 1974 and 1976 based on large population studies by the Veterans Administration Cooperative Urological Research Group. In 1977, Gleason commented on the grading system, noting that occasional small areas of a third (worse) pattern seen during analysis did not change the grade. For nearly the next three decades, Gleason pattern 3 was the most commonly identified pattern, reflected in over 80% of diagnoses (reported as 3+3, 3+4 or 4+3).

The years since then have seen dramatic changes in PCa diagnosis. More thorough biopsy techniques, more powerful microscopes, and advances in staining techniques that highlight different cell features have enabled more specific information about the tissues’ cellular architecture. Research findings suggested that the lowest grade (1 + 1) would today be labeled as adenosis, a benign prostate abnormality. Many cases of Gleason pattern 3 “would probably be referred to currently as cribriform high-grade prostatic intraepithelial neoplasia.”[ii] A need was seen to revise the language of the grading system, especially since variations in how it has been used have been observed, e.g. European reporting as a single sum vs. U.S. reporting showing the two numbers that comprise the sum.

In 2005, the International Society of Urological Pathology (ISUP) held a conference in San Antonio, TX with the goal of arriving at consensus on the descriptions of each of the five patterns. This resulted in updates that are known as the 2005 ISUP Modified Gleason System. The descriptions were more precise and more stringent. Specifically, the appearance of cribriform glands that had previously been included in Donald Gleason’s original pattern three was now included in the newer description of pattern 4, along with one or two other characteristics. The most noteworthy outcome of these changes was a drop in the incidence of Gleason pattern 3 in pathology reports, and a rise in the incidence of Gleason pattern 4 in reports. In other words, a trend in upgrading occurred. The true test of the 2005 ISUP Modified Gleason System was validating it against patient outcomes. A number of studies demonstrated that biopsy samples graded using the 2005 system were highly predictive of prostatectomy outcomes, and also correlated with biochemical recurrence (rising PSA) during surgical follow-up.

Despite improved prognostic accuracy, even the modified system had problematic aspects. According to Epstein et al. (2015)[iii],

The Gleason grading system ranges from 2 to 10, yet 6 is the lowest score currently assigned. When patients are told that they have a Gleason score 6 out of 10, it implies that their prognosis is intermediate and contributes to their fear of having a more aggressive cancer. Also, in the literature and for therapeutic purposes, various scores have been incorrectly grouped together with the assumption that they have a similar prognosis. For example, many classification systems consider Gleason score 7 as a single score without distinguishing 3+4 versus 4+3, despite studies showing significantly worse prognosis for the latter.

Therefore, in 2014 an international multidisciplinary consensus conference met to revise the 2005 system. Based on data from his own center, pathology expert Jonathan Epstein (Johns Hopkins) proposed developing a more precise grading scale of numbers 1 through 5 (similar to 5-point scales now being used with prostate MRI imaging reports) to denote prognostically distinct grades Thus, the lowest risk grade would be indicated by 1, with the most aggressive tumors receiving a 5. This system was tested against multi-institutional data from 20,000 prostatectomy specimens, 16,000 needle biopsy samples and 5,000 biopsies followed by radiation therapy, and proved well validated. At the conference, 90% of attendees agreed that the simplified 5-point scale was more accurate than the 2005 ISUP system, and would help to avoid overtreatment for patients who received a grade of 1 at diagnosis. Going forward, “The new grades would, for the foreseeable future, be used in conjunction with the Gleason system [i.e. Gleason score 3+3=6 (Grade Group 1)]. The new grading system and the terminology Grade Groups 1-5 have also been accepted by the World Health Organization for the 2016 edition of Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs.”[iv]

If the 2014 proposal is universally accepted, it will facilitate patients’ understanding of their diagnosis, and aid decision-making. Although no one has correlated the new Grade Groups 1-5 with a radiological reporting system such as PI-RADS, such changes suggest that international consensus on simpler, better-defined 5-point scales will be easier as well as more accurate.

[i] Montironi R, Cheng L, Lopez-Beltran A, Scarpelli M et al. Original Gleason System Versus 2005 ISUP Modified Gleason System: The Importance of Indicating Which System Is Used in the Patient’s Pathology and Clinical Reports. Eur Urol. 2010 Sep;58(3):369-73.

[ii] Ibid.

[iii] Epstein JI, Egevad L, Amin MB, Delahunt B 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. 2015 Oct 21. [Epub ahead of print]

[iv] Ibid.