Review oncology Current perspectives on the use of the Gleason grading system for prostate cancer T. Gevaert, H. Van Poppel, S. Joniau, D. De Ridder, E. Lerut For more than four decades the Gleason score is the most widely accepted histopathological grading system for prostate cancer. It is a 5-tier grading system that correlates with tumour differentiation and is solely based on architectural patterns within the tumour. Although robust over time, revision of Gleason grading became unavoidable as diagnosis and treatment of prostate cancer also underwent an enormous evolution over time. In 2005 the International Society of Urological Pathology (ISUP) proposed several modifications to the Gleason system which should keep this grading system timely. This review compares the original system to the modified Gleason system and especially focuses on the prognostic relevance of the modifications. It further deals with the question if the Gleason system will be able to keep its prominent role in the diagnostic and prognostic algorithm for prostate carcinoma, especially in the nearby molecular era. (Belg J Med Oncol 2012;6:45-51) Introduction from the prostate gland. A key feature in a histo- Prostate cancer is a very common type of cancer: in pathological report of cancer is the grading of the 2004 prostate cancer was the most prevalent cancer aggressiveness. For prostatic carcinoma the most in men in the European Union and the third most widely used method for this grading was developed common cause of death in men.1,2 The Belgian Can- by Donald Gleason, and is known as the Gleason cer Registry showed similar results for prostate cancer scoring system.4,5 This system is unique as it is di- incidence and mortality in 2008.3 The development of vided into five categories (grade 1-5) with increasing prostate cancer is usually accompanied by a rise in the aggressiveness and decreasing tumour differentia- concentration of serine protease prostate specific anti- tion, that are solely based on architectural patterns gen (PSA). Screening for PSA has led to an increased within the tumour. Innovative in this scoring sys- number of prostate cancer diagnoses, especially in tem as well is that the global score is not defined younger men and at an earlier cancer stage. as the worst grade present within the tumour, but The diagnosis of prostatic carcinoma is based on as the sum of the 2 most prevalent grades (global histopathological examination of tissue obtained score = grade 1 + grade 2). Despite inception of Authors: T. Gevaert, MD PhD, Department of Urology, Department of Pathology, University Hospital Leuven, Leuven, Belgium, Department of Pathology, AZ Klina, Brasschaat, Belgium; H. Van Poppel, MD PhD, Department of Urology, University Hospital Leuven, Leuven, Belgium; S. Joniau, MD, Department of Urology, University Hospital Leuven, Leuven, Belgium; D. De Ridder, MD PhD, Department of Urology, University Hospital Leuven, Leuven, Belgium; E. Lerut, MD PhD, Department of pathology, University Hospital Leuven, Leuven, Belgium. Please send all correspondence to: T. Gevaert, MD PhD, Department of Experimental Urology, Department of Morphology and Molecular Pathology, Minderbroedersstraat 12, 3000 Leuven, Belgium, e-mail: [email protected]. Conflict of interest: the authors have nothing to disclose and indicate no potential conflicts of interest. Key words: prostate cancer, Gleason, grading system, prognostic factor, review. Belgian Journal of Medical Oncology volume 6, issue 2, 2012 45 2 Review oncology the Gleason system more than 40 years ago it is re- markable that it is still widely used as the standard grading system for prostate cancer. The purpose of this review is to summarise the changes the Gleason system has undergone over the last four decades and to assess whether the Gleason system still has prognostic relevance. Original and modified Gleason grading system The original Gleason grading system was devel- oped in 1966 by Donald Gleason, and was refined in 1974 en 1977.4-6 Since then the Gleason system remained the state of the art classification system for prostate cancer. However, it became more and more apparent that changes were needed to adapt Figure 1. Schematic representations of (A) conventional and (B) this scoring system to the scientific evolutions. The modified Gleason grading systems. The most important chang- introduction of immunohistochemistry for basal es are in patterns 3 and 4. In the modified system, most cribri- cells had indeed shown that several Gleason grade form patterns and also poorly defined glands are included in 1-2 tumours were in fact foci of adenosis and that pattern 4.6 (Reproduced from Epstein et al. Am J Surg Pathol Gleason grade 3 cribriform tumours were often in 2005;29:1228–1242; with permission of Lippincott Williams & situ laesions.7 Nor was the use of multiple prostate Wilkins, Baltimore, U.S.A.) biopsies, often taken randomly with the finding of different tumour cores, an issue at the time when Donald Gleason was thinking about a consistent since it was the consensus that cribriform archi- way to score prostate cancer biopsies. Furthermore, tectural patterns do not fit in grade 3 categories. the grading of different nodules in a radical prosta- - Limited patterns of lower grade cancer should be tectomy specimen or reporting on tertiary tumour ignored in the setting of high-grade cancer if they grades was not addressed in the original Gleason occupy less than 5% of the tumour area. The ra- grading system. Other issues that needed to be tionale here was that such tumours are expected included in a modified Gleason system were the to have a similar prognosis as 100% high-grade scoring modalities for rare tumour phenotypes and tumours. the overlap of cribriform cancers between Gleason - Tertiary patterns should be included in the Glea- grades 3 and 4. son score. Epstein et al defined a tertiary pattern All these issues destabilised the use of the Gleason as ‘the presence of a third component of Gleason pat- grading system and a revision became inevitable: tern higher than the primary and secondary grades, a consensus conference on Gleason grading of where the tertiary component is visually estimated prostatic carcinoma was held by the International to be less than 5%’. Needle biopsies should there- Society of Urological Pathology (ISUP) in 2005 in fore be graded as the sum of the primary (most San Antonio (Texas) (Figures 1 & 2).6 The reported prevalent) and the highest grade. The logic here changes are summarised here:6,8,9 is that the presence of Gleason patterns 4 and 5 - Gleason score 2-4 should rarely if ever be diagnosed on needle biopsy most likely indicates an over- on needle biopsy. Such Gleason scores have poor all high-grade tumour. In radical prostatectomy reproducibility between pathologists, show a poor specimens the Gleason score should be assigned correlation with the prostatectomy grade and may based on the primary and secondary patterns, misguide clinicians and patients into believing that with a comment on the tertiary pattern, since ter- the patient has an indolent tumour. tiary patterns have been shown to have prognos- - All cribriform cancer should be graded pattern 4, tic importance (see below). Belgian Journal of Medical Oncology volume 6, issue 2, 2012 46 Figure 2. Low grade prostatic adenocarcinoma, Gleason score 3+3=6 (left) versus high grade prostatic adenocarcinoma, Glea- son score 5+4 (right). The low grade tumour is composed of well-preserved glandular structures, sometimes irregularly structured (Grade 3 patterns). Several tumour glands have typical intraluminal eosinophilic debris (black arrows). The high grade tumour is predominantly composed of single tumour cells and solid tumour sheets (Grade 5) with only sparse recognisable irregularly formed tumour glands (Grade 4, black arrows). Derived from magnification 200x. - In radical prostatectomy specimens a different one of the most powerful prognostic factors for Gleason score should be assigned to each domi- prostate cancer.8 According to the College of Ameri- nant tumour nodule. It was the consensus that can Pathologists categorical rankings, it has indeed it would be misleading to average the Gleason been classified in category I, which groups factors scores of a high-grade and a low-grade tumour proven to be of prognostic value and useful in clini- nodule, which can be typically found in the pe- cal patient management, and includes PSA, patho- ripheral zone and in the transition zone respec- logical stage and surgical margins besides the Glea- tively. son score. Review of the literature, however, shows - In needle biopsies individual Gleason scores that the true prognostic value of the Gleason grad- should be assigned to separate tumour cores as ing system is under debate.10 long as the cores are submitted in separate con- Several studies on the prognostic value of the tainers. If not, one should give an overall score Gleason system using prostate cancer death as for a container containing different cores. It has outcome have been published. Most studies con- repeatedly been demonstrated that the highest firm the Gleason score as a predictor for prostate Gleason score in a given core correlates better cancer-related death, but not always with the same with the Gleason score in the radical prostatec- strength. Albertsen et al found the Gleason system tomy-specimen than the average or most frequent to be a strong independent predictor of survival in grade among the cores. a population-based cohort study with 15 years of - The grading of variants and subtypes of acinar follow-up.11 Another 15-years follow-up study on a adenocarcinoma of the prostate, including can- consecutive series of 305 men with prostate can- cer with vacuoles, foamy gland carcinoma, ductal cer diagnosed at transurethral resection showed the adenocarcinoma, pseudohyperplastic carcinoma Gleason score to be a strong prognostic factor for and small cell carcinoma has been modified.