Bad Grades for Gleason

Prostate cancer is the fourth most common cancer in the world – and for men, the second most common cancer. And with incidence rates projected to rise significantly over the next decades, it’s more important than ever to gain a full understanding of this highly variable disease. From vague symptoms to controversial tests (1), it can be difficult to conclusively evaluate a patient’s risk even after diagnosis. Some forms of prostate cancer grow quickly, whereas others may remain indolent for years; some respond well to surgery alone, whereas others may need a range of additional therapies. So how can pathologists determine which prostate cancers present the highest risk – and which patients should be offered more aggressive treatment options? At the moment, the answer relies on classification tools like the Gleason score – but that system was first conceived over 50 years ago and is in desperate need of an update.

A brief history of grading

Donald Gleason developed our current prostate cancer grading system between 1966 and 1974. Over the subsequent decades, the histological and clinical diagnosis of the disease – not to mention its treatment – has evolved. As a result, the first revisions of the original Gleason system were codified in 2005. But medical science moves quickly, and in November of 2014, 65 prostate cancer pathology experts and 17 clinicians (including urologists, radiation oncologists, and medical oncologists) from 19 different countries gathered in a consensus conference to further update the grading of prostate cancer.

Despite our attempts to keep pace with our growing understanding of the disease, both pathologists and clinicians agree that there are significant deficiencies with the Gleason scale. For instance, the 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, they hear that they have a more aggressive cancer and an intermediate prognosis – and, understandably, that frightens them. Every day, I talk to patients whose cases have been sent to me in consultation, and if they have a Gleason 6 cancer, I first say, “That’s the best grade you can have,” hoping to allay precisely that concern. Recently, I had a patient with newly diagnosed prostate cancer whose wife was battling a high-grade brain tumor. The husband was almost in tears because he had a Gleason 7 (3+4=7) cancer on biopsy, and he was convinced that meant he would not be around in the next few years to help take care of his wife. But despite a Gleason score of “7 out of 10” (which sounds advanced), Gleason score 3+4=7 cancers are relatively low-grade and virtually never result in death within even 10 years of diagnosis.

Also, both 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 7 as a single score without distinguishing between 3+4 and 4+3, despite studies showing that the latter carries a significantly worse prognosis.

A simpler system

In 2013, my colleagues and I proposed the basis for a new grading system based on data from Johns Hopkins Hospital that suggested five prognostically distinct Grade Groups (2). The definition for the new grading system is based on the modified Gleason grading system and incorporates changes made in 2005 and 2014 (see Table 1). The new system was validated in a multi-institutional study of over 20,000 radical prostatectomy specimens, over 16,000 needle biopsy specimens, and over 5,000 biopsies followed by radiation therapy (3). The five-year biochemical recurrence-free progression probabilities for radical prostatectomy in Grade Groups 1 through 5 were 96, 88, 63, 48, and 26 percent, respectively. In the 2014 grading consensus meeting, there was broad (90 percent) agreement in favor of adopting this new system. Why? Four reasons:

• The new classification provides more accurate stratification of tumors than the current system.
• The classification simplifies the number of grading categories. Instead of Gleason scores 2 to 10, with even more permutations based on different pattern combinations, it proposes Grade Groups 1 to 5.
• The lowest grade is 1 – not 6, as on the Gleason scale – with the potential to reduce overtreatment of indolent cancer.
• The current modified Gleason grading, which forms the basis for the new grade groups, bears little resemblance to the original Gleason system.

The new grades would, for the foreseeable future, be used in conjunction with the Gleason system. Patients would receive both: “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.

So what should pathologists and laboratory medicine professionals involved in prostate cancer diagnostics do? My recommendation is to familiarize yourselves with the new grading system and its histological definitions and – if possible – begin using it alongside your standard Gleason scoring. I hope to see widespread adoption of the new system in future, and I’m optimistic that it will assist with patient stratification, prevent over- and under-treatment, and, of course, improve outcomes for those diagnosed with the disease.