current perspectives on the use of the gleason grading

Belgian Journal of Medical Oncology volume 6, issue 2, 2012 2

Review oncology

IntroductionProstate cancer is a very common type of cancer: in 2004 prostate cancer was the most prevalent cancer in men in the European Union and the third most common cause of death in men.1,2 The Belgian Can-cer Registry showed similar results for prostate cancer incidence and mortality in 2008.3 The development of prostate cancer is usually accompanied by a rise in the concentration of serine protease prostate specific anti-gen (PSA). Screening for PSA has led to an increased number of prostate cancer diagnoses, especially in younger men and at an earlier cancer stage. The diagnosis of prostatic carcinoma is based on histopathological examination of tissue obtained

from the prostate gland. A key feature in a histo-pathological report of cancer is the grading of the aggressiveness. For prostatic carcinoma the most widely used method for this grading was developed by Donald Gleason, and is known as the Gleason scoring system.4,5 This system is unique as it is di-vided into five categories (grade 1-5) with increasing aggressiveness and decreasing tumour differentia-tion, that are solely based on architectural patterns within the tumour. Innovative in this scoring sys-tem as well is that the global score is not defined as the worst grade present within the tumour, but as the sum of the 2 most prevalent grades (global score = grade 1 + grade 2). Despite inception of

Current perspectives on the use of the Gleason grading system for prostate cancerT. 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)

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.

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Belgian Journal of Medical Oncology volume 6, issue 2, 2012

46

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 systemThe 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 this scoring system to the scientific evolutions. The introduction of immunohistochemistry for basal cells had indeed shown that several Gleason grade 1-2 tumours were in fact foci of adenosis and that Gleason grade 3 cribriform tumours were often in situ laesions.7 Nor was the use of multiple prostate biopsies, often taken randomly with the finding of different tumour cores, an issue at the time when Donald Gleason was thinking about a consistent way to score prostate cancer biopsies. Furthermore, the grading of different nodules in a radical prosta-tectomy specimen or reporting on tertiary tumour grades was not addressed in the original Gleason grading system. Other issues that needed to be included in a modified Gleason system were the scoring modalities for rare tumour phenotypes and the overlap of cribriform cancers between Gleason grades 3 and 4.All these issues destabilised the use of the Gleason grading system and a revision became inevitable: a consensus conference on Gleason grading of prostatic carcinoma was held by the International Society of Urological Pathology (ISUP) in 2005 in San Antonio (Texas) (Figures 1 & 2).6 The reported changes are summarised here:6,8,9

- Gleason score 2-4 should rarely if ever be diagnosed on needle biopsy. Such Gleason scores have poor reproducibility between pathologists, show a poor correlation with the prostatectomy grade and may misguide clinicians and patients into believing that the patient has an indolent tumour.

- All cribriform cancer should be graded pattern 4,

since it was the consensus that cribriform archi-tectural patterns do not fit in grade 3 categories.

- Limited patterns of lower grade cancer should be ignored in the setting of high-grade cancer if they occupy less than 5% of the tumour area. The ra-tionale here was that such tumours are expected to have a similar prognosis as 100% high-grade tumours.

- Tertiary patterns should be included in the Glea-son score. Epstein et al defined a tertiary pattern as ‘the presence of a third component of Gleason pat-tern higher than the primary and secondary grades, where the tertiary component is visually estimated to be less than 5%’. Needle biopsies should there-fore be graded as the sum of the primary (most prevalent) and the highest grade. The logic here is that the presence of Gleason patterns 4 and 5 on needle biopsy most likely indicates an over-all high-grade tumour. In radical prostatectomy specimens the Gleason score should be assigned based on the primary and secondary patterns, with a comment on the tertiary pattern, since ter-tiary patterns have been shown to have prognos-tic importance (see below).

Figure 1. Schematic representations of (A) conventional and (B)

modified Gleason grading systems. The most important chang-

es are in patterns 3 and 4. In the modified system, most cribri-

form patterns and also poorly defined glands are included in

pattern 4.6 (Reproduced from Epstein et al. Am J Surg Pathol

2005;29:1228–1242; with permission of Lippincott Williams &

Wilkins, Baltimore, U.S.A.)


- In radical prostatectomy specimens a different Gleason score should be assigned to each domi-nant tumour nodule. It was the consensus that it would be misleading to average the Gleason scores of a high-grade and a low-grade tumour nodule, which can be typically found in the pe-ripheral zone and in the transition zone respec-tively.

- In needle biopsies individual Gleason scores should be assigned to separate tumour cores as long as the cores are submitted in separate con-tainers. If not, one should give an overall score for a container containing different cores. It has repeatedly been demonstrated that the highest Gleason score in a given core correlates better with the Gleason score in the radical prostatec-tomy-specimen than the average or most frequent grade among the cores.

- The grading of variants and subtypes of acinar adenocarcinoma of the prostate, including can-cer with vacuoles, foamy gland carcinoma, ductal adenocarcinoma, pseudohyperplastic carcinoma and small cell carcinoma has been modified.

Prognostic relevance of the original and modified Gleason grading systemsThe Gleason grading system is often presented as

one of the most powerful prognostic factors for prostate cancer.8 According to the College of Ameri-can Pathologists categorical rankings, it has indeed been classified in category I, which groups factors proven to be of prognostic value and useful in clini-cal patient management, and includes PSA, patho-logical stage and surgical margins besides the Glea-son score. Review of the literature, however, shows that the true prognostic value of the Gleason grad-ing system is under debate.10

Several studies on the prognostic value of the Gleason system using prostate cancer death as outcome have been published. Most studies con-firm the Gleason score as a predictor for prostate cancer-related death, but not always with the same strength. Albertsen et al found the Gleason system to be a strong independent predictor of survival in a population-based cohort study with 15 years of follow-up.11 Another 15-years follow-up study on a consecutive series of 305 men with prostate can-cer diagnosed at transurethral resection showed the Gleason score to be a strong prognostic factor for disease-free survival.12 A 20-years follow-up study in Sweden on a population-based cohort of 253 men with prostate cancer diagnosed at transure-thral resection showed that a high Gleason score is a determinant for prostate cancer-related death, however with a relatively low predictive prognostic

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.


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value compared to other factors.13

A common critique on the Gleason score is that the majority of patients is categorised into one group (Gleason score 6-7) with highly variable outcomes, suggesting the Gleason scoring system to be insuffi-cient as prognostic tool.13 Several studies have tried to address this problem by subdividing Gleason score 7 into Gleason score 3 + 4 = 7 and Gleason score 4 + 3 = 7. In radical prostatectomy speci-mens it was shown repeatedly that Gleason score 4 + 3 =7 has a worse prognosis than Gleason score 3 + 4 = 7.14-17 Although less explored in biopsy studies, a similar worse prognostic outcome was found for Gleason score 4 + 3 = 7 versus Gleason score 3 + 4 = 7.17 It was therefore recommended to use 5 categories of cancer grading: well differenti-ated (Gleason score 2-6), moderately differentiated (Gleason score 3 + 4 = 7), moderately to poorly differentiated (Gleason score 4 + 3 = 7), poorly differentiated (Gleason score 8) and undifferenti-ated (Gleason score 9-10). Such extended grading would reflect the prognostic difference between Gleason score 4 + 3 = 7 versus Gleason score 3 + 4 = 7.17 Others proposed that utilizing the per-centage of Gleason pattern 4 may provide further prognostic information.18

The intention of the ISUP with the application of minor adaptations to the Gleason system in 2005 was to accommodate the system to multiple evolu-tions in diagnosis and prognosis of prostate can-cer. One of the underlying goals was to maintain its prognostic relevance. Only few studies have com-pared the prognostic accuracy of the original versus the modified Gleason system. Billis et al showed the modified Gleason system to be superior to the origi-nal system, since the shift of original Gleason scores towards a higher score could identify more patients with a shorter time to biochemical progression-free outcome after radical prostatectomy.19 Similar re-sults were found by Uemura et al.20 Another study showed that the modified Gleason system signifi-cantly increased the concordance between needle and radical prostatectomy grades.21 The relevance of including tertiary components in the Gleason score has been subject of several studies, even before the ISUP consensus meeting. A systematic review and meta-analysis of all studies on the prognostic value of a tertiary Gleason grade supported the prognostic importance of such tertiary grade.22 The presence of

a tertiary grade was reported to be associated with pathological variables indicative of poor prognosis, such as extraprostatic extension, positive surgical margins, but not lymph node metastasis.22 Thus, the first studies comparing both grading systems suggest superiority for the modified system, making it a stronger prognostic tool, although many more studies are warranted for validation of all modifica-tions.A crucial issue in the use and interpretation of the modified Gleason system, especially in retrospec-tive studies, is the so called ‘Will Rogers phenome-non’ (WRP). This phenomenon means the improve-ment in the prognosis of patient groups due to stage or grade reclassification and was first described in 1985 by Feinstein et al.23 Several authors have re-ported on the existence of such a phenomenon in the outcome of prostate cancer due to changes ap-plied to the Gleason system. Yet before the ISUP consensus meeting in 2005 some authors proposed some changes in the Gleason score. Pan et al pro-posed to replace the secondary grade with the tertiary grade when the tertiary grade is higher.24 Epstein concluded that Gleason score 2-4 should not be made based on prostate core biopsies be-cause of their poor reproducibility.25 Both practices resulted in a systematic increase in Gleason score, which was only amplified after the publications of the ISUP modifications to the Gleason system in 2005. Therefore when comparing current data on prostate cancer with historical results, one should always be aware of the possible biassing effects due to the WRP.

Alternatives for the Gleason systemBesides the Gleason score other grading meth-ods exist, such as the World Health Organization (WHO) system, that incorporates both architec-tural changes and nuclear anaplasia.26 It is less fre-quently used than the Gleason system, which is by far the most widely used grading system for prostate cancer. The Gleason system is recommended as the standard and superior grading system for prostate cancer.10 To our knowledge however, no prospective and/or retrospective studies comparing both grad-ing systems have been published so far.As mentioned earlier, a major weakness of the Glea-son system is the large amount of patients with in-


termediate Gleason score 7, whose prognosis is still highly unpredictable, contrasting with Gleason score 6 or 10, having a good and bad prognosis re-spectively. Recommendations have been made to split up and refine the Gleason score 7 group, but in the past decade many studies have also focused on the molecular level in an attempt to refine the prognosis of this group of patients. Several studies reported molecular signatures and pathways based on mRNA expression to distinguish tumours ac-cording to Gleason grade.27-29 A recent study dis-covered a gene signature which shows promising results in understanding tumour dedifferentiation, and which might therefore have clinical applications by further estimating the risk of lethal cancer in men with Gleason score 7 prostate cancer.30

During the past decade many molecular biomarkers have been evaluated - with varying results - for their potential to enhance our ability to predict prostate cancer disease progression, response to therapy and survival. These molecular biomarkers have been categorised as College of American Pathologists consensus category III prognostic factors, meaning that these factors need additional studies to ensure their prognostic utility before undergoing further clinical trials.10 Up to now, none of these markers has really entered clinical practice but some of them look promising. Tomlins et al discovered a recurrent

chromosomal rearrangement (TMPRSS2-ERG gene fusion) in more than half of their analysed prostate cancer cases.30 Several studies have shown that TMPRSS2-ERG fusion prostate cancer is associated with higher tumour stage and tumour-specific death or metastasis.31 Therefore this discovery might lead to prognostic and therapeutic applications.Immunohistochemistry might also improve the di-agnostic and prognostic algorithms for prostate can-cer. A promising biomarker is Ki-67, which indicates the proliferation index of the tumour cells.10,32 Net-to et al report the Ki67-index to be superior to the Gleason score in predicting biochemical recurrence following radical prostatectomy.32 Others, however, have reported conflicting results.32 Further research is warranted to reach consensus on cut-off points. In the group of tumour suppressor genes and onco-genes there is mounting evidence to support a role for p53 in predicting prognosis in prostate cancer.30 Many reports suggest that immunohistochemical p53 evaluation could become a useful parameter clinically, at least in prostatectomy specimens, once cut-offs and immunostaining methodologies are standardised in large, prospective studies.10,32

Until now no reliable alternative for the Gleason system exists, and it is not likely that in the next years an alternative non-histological system will appear that will have the same reproducibility and

Key messages for clinical practice

1. The Gleason grading system remains the most widely accepted grading system for prostate cancer.

2. The modifications proposed by the 2005 ISUP consensus conference have par-tially adapted the Gleason grading system to the evolutions in diagnosis and treat-ment of prostate carcinoma.

3. The Gleason grading system remains one of the important prognostic and predict-ing factors for prostate carcinoma.

4. The prognostic value for patients with Gleason scores 7 needs to be improved.

5. If the Gleason system is regularly monitored and updated it is expected to stay a key element in the prostate cancer diagnostic algorithm, even in the molecular era.

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prognostic strength. Instead it can be expected that refining the Gleason system by uropathology con-sensus meetings and the future prospect of some biomarkers to become category I prognostic factors in prostate cancer, will make surgical and molecu-lar pathology complementary, decreasing the weak-nesses and shortcomings of the Gleason system and increasing its prognostic value in daily clinical prac-tice over the next years.

ConclusionsAfter more than four decades the Gleason grading system still remains the most widely used grading system for prostate carcinoma. Its unique architec-ture-based 5-tiered scheme, with the final score consisting of 2 grades, makes it highly reproducible en adds to its prognostic value. The minor chang-es proposed by the ISUP consensus conference in 2005 have answered the need to adapt the Gleason system to the dramatic evolutions in the diagnosis and treatment of prostate cancer. The enormous progress in molecular diagnostic applications is ex-pected to have significant impact on the existing diagnostic and prognostic algorithms for prostate cancer, but it is unlikely that these new techniques will be able to replace the Gleason grading system. Instead a symbiosis between the existing and new diagnostic techniques might lead to the greatest benefit for patients with prostate cancer. Therefore continuous monitoring and fine-tuning of the Glea-son grading system is mandatory.

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current perspectives on the use of the gleason grading

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