Feature Article
Sunday, February 5th, 2012

 

Volume 30
October 2008
Number 5

 

   
Recent Trends in Gleason Grading of Prostate Cancer
II. Prognosis, Reproducibility and Reporting

Lars Egevad, M.D., Ph.D.

   

Gleason grading of prostate cancer is the most important histopathologic predictor of prognosis. In recent years, a number of changes have been made in how Gleason grading is performed and reported. A consensus conference was organized in 2005 by the International Society of Urological Pathology for the purpose of standardizing both the perception of histologic patterns and how the grade information is compiled and reported. The recommendations regarding reporting are summarized and discussed in this review. The prognostic importance of the Gleason score, its reproducibility and its role in preoperative assessment are also discussed. (Anal Quant Cytol Histol 2008;30:254–260)

Keywords: Gleason grade, prognosis, prostate cancer.

Prediction of prognosis is one of the greatest challenges in tumor pathology.1 Despite attempts to introduce new biomarkers, histopathologic grade remains the most important tissue-based predictor of prognosis for many cancer types. There is a broad consensus that prostate cancer should be graded based on the Gleason score and that information about the Gleason score of the specimen should be included in the pathology report on needle biopsies, transurethral resection of the prostate (TURP) specimens and radical prostatectomy specimens.2-11 This review covers the prognostic importance of the Gleason score, our ability to correctly predict it from needle biopsies and the interobserver reproducibility of this measure. Recent changes in recommendations for reporting of the Gleason score are also discussed.
   
Gleason Grading and Prediction of Prognosis
The Gleason score correlates with multiple other parameters related to prognosis, such as age,12,13 serum prostate specific antigen (PSA),13,14 clinical stage15 and pathologic stage.13,16,17 Therefore it is not surprising that the Gleason score itself is a strong predictor of outcome. Numerous studies have shown that the Gleason score is an independent and very powerful prognostic factor both for prediction of the natural history of prostate cancer18-21 and for assessment of the risk of recurrence after radical prostatectomy22-25 or radiotherapy.26,27 The major increase in the likelihood of having adverse findings in the prostatectomy specimen or of failure following prostatectomy or radiotherapy correlates with Gleason score 6–7, indicating that the presence of Gleason pattern 4 cancer has a negative effect on prognosis. In line with this, Gleason score 7 cancers with a primary pattern 4 have a more advanced pathologic stage and carry a higher risk of disease progression after prostatectomy than those with a primary pattern 3,28-30 although this was questioned in one study.31
    In recent years a gradual shift has occurred in how the Gleason system is applied, and there has been a trend toward a general upgrading.21,32-34 The clinical impact of these changes has been discussed by Albertsen et al,18 referring to this effect as the “Will Rogers phenomenon.” If most Gleason score 5 tumors are reclassified as score 6, while the worst Gleason score 6 tumors are reclassified as score 7, then the prognosis of Gleason score 6 cancers will evidently improve. This is somewhat problematic because comparisons with results from earlier studies will be more difficult and clinicians may be confused by the changing prognostic implications of pathology reports.
    Efforts have been made to further refine Gleason grading. The percentage of the tumor that is occupied by Gleason patterns 4 or 5 predicts recurrence after prostatectomy as estimated by serum prostate specific antigen (PSA).35-38 In a study on patients with prostate cancer diagnosed in TURP specimens and treated expectantly, percent high-grade cancer was an independent predictor of disease-specific survival together with the Gleason score.39 In a study on 364 specimens from men who underwent radical prostatectomy, the percentage of Gleason patterns 4 and 5 was superior to the Gleason score as a predictor of recurrence.38 Concerns have been raised about the reproducibility of this measure. However, in studies on needle biopises40 and prostatectomy specimens,41 it was shown that the interobserver variability of percent high-grade cancer did not exceed that of the Gleason score. Furthermore, concern has been expressed that percent high-grade cancer would be difficult to predict from preoperative needle biopsies.42 However, in a study by Glaessgen et al,40 the weighted kappa value for agreement between biopsies and prostatectomy specimens was only slightly lower for percent Gleason grade 4/5 (0.57) than for Gleason score (0.68). The univariate correlation for percent Gleason grade 4/5 in biopsies and the main tumor of the prostate was r=0.62.43 Whether this parameter will gain a more widespread use is yet unknown.
    The Gleason score by definition includes the 2 most prevalent patterns. When tertiary patterns of higher grade are present, prognosis is worse than indicated by the Gleason score.44,45 It is recommended that the worst grade found in radical prostatectomy specimens be reported even if it occupies <5% of the tumor and therefore is not included in the Gleason score. In contrast, a recommendation has recently been issued that the worst pattern should always be included in the Gleason score of needle biopsies (see later discussion).46
    
Dedifferentiation
It is not clear whether dedifferentiation of prostate cancer occurs. Tumor grade is, on average, higher in larger tumors.47 However, this may be due to more rapid growth of high-grade cancers. It has been demonstrated that some tumors are already high grade when they are small.48 Many studies addressing the issue of dedifferentiation are flawed by a selection bias because the patients have undergone a repeat transurethral resection or repeat biopsy due to symptoms of tumor progression.49 The observed grade progression may be explained by a growth advantage of a tumor clone of higher grade that was present from the beginning but was undersampled. In a study of patients followed expectantly, there was no evidence of dedifferentiation within 1–1.5 years.50 Others have claimed that dedifferentiation does occur in patients who undergo repeat biopsies in a screening program.12
   
Reproducibility
Pathologists who are inexperienced in the Gleason system tend to undergrade tumors.51,52 The vast majority of tumors graded as Gleason score 2–4 on core biopsy are graded as Gleason scores 5–6 or higher when reviewed by experts in urologic pathology.51 Gleason score 2–4 on core biopsy has poor reproducibility even among urologic pathology experts and should be avoided. In a study of interobserver reproducibility among general pathologists, the overall agreement for Gleason score groups 2–4, 5–6, 7 and 8–10 was only in the moderate range.53 Interobserver agreement among urologic pathologists has been described as moderate to substantial. In a study based on selected needle biopsy specimens, weighted kappa was between 0.56 and 0.70.54 In another study using a consecutive series of 69 total prostatectomy specimens, the weighted kappa of 4 urologic pathologists was between 0.52 and 0.66 (overall mean 0.56).41 A British group of pathologists reached a weighted kappa 0.54 for Gleason score groups 2–4, 5–6, 7 and 8–10.55 Undergrading can be decreased with teaching efforts, and a substantial interobserver reproducibility can be obtained.52,54,56
   
Gleason Grading of Core Biopsies
Correlation with Prostatectomy Grade
Prostate cancer displays a remarkable degree of intratumoral grade heterogeneity. More than 50% of radical prostatectomy specimens contain cancer of at least 3 different Gleason grades,57 and cancer of a single grade is present in only 16% of the specimens.58 Of individual tumor foci, 58% have a single grade, but most of these foci are very small.58 In a study by Arora et al,59 2 or more cancer foci were present in 87% of all radical prostatectomy specimens. In only 9% of the cases with multifocal cancer did all tumor foci have Gleason grades that were the same as the overall Gleason grades of the case.59 This raises concern about the ability of biopsies to predict Gleason grade found on prostatectomy.
    Several studies that compared biopsy and prostatectomy Gleason score51,60-65 were recently reviewed by Mazzucchelli et al.66 Exact correlation was observed in 28.2–67.9% of the cases. The biopsies undergraded in 24.5–60.0% and overgraded in 5.2–32.2%. Thus undergrading generally seems to be a more prevalent problem than overgrading.63,67,68 Some of the concordance can be attributed to the high proportion of tumors assigned a Gleason score 6 or 7 in core biopsies as well as in prostatectomy specimens. However, weighted kappa values of 0.41–0.50 have been reported, indicating an agreement that exceeds what can be explained by clustering of the Gleason scores.61,69 
    Causes for biopsy grading errors include undersampling of higher or lower grades, borderline histology and misinterpretation of patterns.51 Sampling errors often result in undergrading or overgrading by only 1 step because prostate cancer tends to be composed of adjacent tumors with similar Gleason grades and the concordance between the biopsy and prostatectomy Gleason score is within 1 Gleason score in >90% of cases.61 Increasing the number of biopsy cores may improve the accuracy of grade prediction.70-74
   
Grading Minimal Cancer on Biopsy
The concordance between Gleason scores determined by biopsy and those determined by prostatectomy is equivalent or only marginally worse with minimal cancer on biopsy.51,61,69 It is recommended that a Gleason score be reported even when a minimal focus of cancer is present. It is potentially confusing if the Gleason pattern is given in some cases and the Gleason score in others. Small cancers arising in the peripheral zone are usually Gleason score 3+3=6, and the same is true for focal cancer on core biopsy.
   
ISUP Recommendations for Reporting of Gleason Grade of Core Biopsies
The ISUP consensus meeting issued several recommendations for the reporting of needle biopsies46 (Table I). A Gleason score should be assigned to each separate biopsy or each separate container of biopsies (because it may be difficult to identify separate biopsies in a fragmented, blocked material)75 (Table II). Many urologists use the highest Gleason score of an individual biopsy to guide the treatment decision.76 However, a global Gleason score may also be given in the bottom-line diagnosis, summarizing all cancer present in the biopsies. The clinicians must then determine which Gleason score to use for the treatment decision.
    

 


     
    The ISUP working group concluded that high-grade tumor of any quantity on needle biopsy should be included in the Gleason score. When three Gleason pattern are present, such as patterns 3, 4 and 5 in various proportions, the tumor should be classified as high grade (Gleason score 8–10).
     
ISUP Recommendations for Reporting of Gleason Grade of Radical Prostatectomy Specimens
With radical prostatectomy specimens the entire tumor is available for examination, which provides a significant advantage over needle biopsy specimens. The consensus of the group was that for a radical prostatectomy specimen the Gleason score should include the primary and secondary patterns with a separate comment on the presence of a tertiary pattern (Table II). Furthermore, the group concluded that Gleason score should be based on the main tumor and not on all cancer present in the radical prostatectomy specimen.77

   
Studies on Modified Gleason Grading
With the ISUP recommendations it may be necessary to reiterate some previous studies on the Gleason score. We have recently reported on the reproducibility and distribution of modified Gleason score and its correlation with other prognostic factors such as age, stage and serum PSA.13,17,78,79 
    Helpap and Egevad78 compared conventional and modified Gleason grading in 368 radical prostatectomy specimens and their preoperative biopsies. The major changes of Gleason score distribution in needle biopsies were that Gleason scores 2–4 decreased from 2.7% to 0%, score 5 decreased from 12.2% to 0.3%, score 6 decreased from 48.4% to 22.0% and score 7 increased from 25.5% to 67.9%. The exact agreements between needle biopsies and radical prostatectomy specimens with conventional and modified grading were 58% and 72%, respectively.
    This series was later extended to 649 consecutive radical prostatectomy specimens that were graded according to conventional and modified Gleason grading.17 A total of 29% of the tumors were upgraded. Both variants of Gleason score correlated with pathologic stage.
    In 828 consecutive needle biopsies from the years 1995, 2000, 2006 and 2007, both conventional and modified Gleason grading correlated with age, serum PSA, percent positive biopsies and percent cancer length.13 The average Gleason scores were higher in 2006 and 2007 when modified Gleason grading was used, despite a stage shift downward as indicated by lower serum PSA and percent positive cores.
    The reproducibility of modified Gleason grading among 4 genitourinary pathologists was studied on a set of 69 consecutive radical prostatectomy specimens.79 Mean weighted kappa for conventional and modified Gleason scores was 0.56 (range, 0.52–0.66) and 0.58 (range, 0.49–0.74), respectively. However, there was a clustering of modified Gleason scores in odd scores (5, 7 or 9), and severe disagreement (>1 score unit) was more commonly observed than with conventional grading.
    In recent years, there has been a trend toward upgrading of prostate cancer. This is partly due to an altered perception of histologic patterns. In addition to this, recommendations have recently been issued to include the highest patterns in the Gleason score of needle biopsies (modified Gleason score) and also to use the highest Gleason score of an individual biopsy core rather than the global Gleason score. All of these changes contribute to a rather pronounced Gleason score inflation. This will make comparisons with results from earlier studies difficult, and clinicians may be misled by changing prognostic relevance of the histopathologic grade. Systems for grading and staging of tumors must be revised continuously as our knowledge of tumor biology increases. However, there are also good reasons to retain a certain stability in these systems. This balance between evolution and stability requires good judgment from the experts who guide the practicing pathologists. The prognostic impact of the modified Gleason score on needle biopsies and the changed pattern recognition must be carefully surveyed. Despite these controversies, the Gleason score remains the single most important tissue-based prognostic factor of prostate cancer.
    
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From the International Agency for Research on Cancer, Lyon, France.

Dr. Egevad is Associate Professor.

Address correspondence to: Lars Egevad, M.D., Ph.D., Pathology Group, International Agency for Research on Cancer, World Health Organization, 150, Cours Albert Thomas, 69372 Lyon Cedex 08, France (egevadl@iarc.fr, lars.egevad@ki.se).

Financial Disclosure: The author has no connection to any companies or products mentioned in this article.

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