Feature Article
Saturday, July 31st, 2010

 

Volume 30
February 2008
Number 1

 

   
Correlation of Modified Gleason Grading with pT Stage of Prostatic Carcinoma After Radical Prostatectomy

Burkhard Helpap, M.D., Ph.D., and Lars Egevad, M.D., Ph.D.

   

   

OBJECTIVE: To study the correlation between modified Gleason score (GS) and pT stage of radical prostatectomy (RP) specimens.
STUDY DESIGN: Six hundred forty-nine consecutive RP specimens were graded according to the conventional and the modified Gleason grading systems.
RESULTS: A total of 29% of the tumors were upgraded. Both variants of GS correlated with pathologic stage. Stage pT2 tumors were assigned a GS of 3–6 less often with modified grading than with conventional grading (29% and 84%, respectively). The only significant difference of stage distribution between conventional and modified GS was for GS 7, where pT2 was the most common stage with modified grading (54%) and pT3 was most common with conventional grading (67%). Of GS 3 + 4 = 7a tumors, 95% were stage pT2, while 79% of GS 4 + 3 = 7b tumors were stage pT3–4.
CONCLUSION: The stage distribution of modified GSs of RP specimens differs from that of conventional GSs, but a good correlation exists between grade and pT stage. Notably, GS 4 + 3 = 7b was more often associated with high stage than was GS 3 + 4 = 7a. (Anal Quant Cytol Histol 2008;30:1–7)

Keywords: Gleason score, modified; prostate, adenocarcinoma of; pT stage; radical prostatectomy.

The Gleason grading system underwent a major revision in 2005 when the International Society of Urological Pathology (ISUP) organized a consensus conference in San Antonio, Texas, U.S.A.1 The changes proposed by the meeting pertained both to pattern interpretation and reporting. In a recent study, we showed how modified Gleason grading changed the grade distribution and the correlation between grades of needle biopsies and radical prostatectomy (RP) specimens at a German pathology department.2 We reported upgrading of both needle biopsies and RP specimens. We also found an improved grade agreement between these specimens with the modified grading.
    Gleason score (GS), preoperative serum prostate specific antigen (PSA) and tumor stage are the clinically most important prognostic factors of prostate cancer.3-10 In this study, we investigate the correlation of RP GS with pathologic stage using the conventional and modified Gleason grading systems.
    
Materials and Methods
Between January 1996 and December 2000, 649 RP specimens were histologically analyzed at the Department of Pathology, General Hospital, Singen, Germany. The prostate tissue was formalin-fixed in 4% formaldehyde, usually for 24–36 hours. RP specimens were processed according to a modified Stan­­ford method.11 Every second slice was embedded in paraffin. Specimens were cut at 3 µm and stained with hematoxylin-eosin. At low magnification (¥4–10 lens magnification), prostatic carcinomas were graded according to the conventional Gleason grading system and subsequently regraded according to the modified Gleason grading system (Figure 1).1,2,12-14 Modified GSs of 7 were separated into 3 + 4 = 7a and 4 + 3 = 7b. However, in the original reports, conventional GSs were given without mentioning whether grade 3 or 4 was primary. TNM Classification of Malignant Tumors, Sixth edition, was used, with the modification that stages pT2a–c and pT3a–b were grouped as single-stage categories for analysis purposes.15 Hence tumors were assigned a pT stage of 2, 3 or 4.
   
Figure 1    Schematic representations of (A) conventional and (B) modified Gleason grading systems. The most important changes between them are in patterns 3 and 4. In the modified system, most cribriform patterns and also poorly defined glands are included in pattern 4. Reproduced­ from Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL; and the ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005;29:1228–1242 with permission of Lippincott Williams & Wilkins, Baltimore, U.S.A.
      
    The Mann-Whitney test was used for comparison of the distributions of conventional and modified GSs within each stage and the distributions of stages within each conventional and modified GS. The 2 tests were used for comparison of proportions. Spearman rank was used for correlation between grade and stage. A p value <0.05 was considered significant.
   
Results
The distribution of conventional and modified GSs among pT stages is presented in Table I and Figure 2. With both grading systems, the most common GS was 7. Conventional GSs of 3–6, 7 and 8–9 were assigned in 40%, 36% and 24% of cases, respectively, while modified GSs 3–6, 7 and 8–9 were assigned in 14%, 56% and 30% of cases, respectively (p<0.001). Of GS 5, 6, 7 and 8 tumors, a total of 29% were upgraded 1 score unit (185 of 649). There was an upgrading of the tumors from conventional to modified Gleason grading within each of the stages pT2, pT3 and pT4 (p<0.001, p=0.022 and p<0.001, respectively).
   

   
   
Figure 2    Distribution of GSs among the pT stages with conventional­ and modified grading. Light gray = conventional GSs, dark gray = modified GSs.
    
    Both conventional and modified GSs correlated to stage (p<0.001). Stage pT2 tumors were assigned a GS of 3–6 less often with modified grading than with conventional grading (29% and 84%, respectively [p<0.001]). GSs of 3–6 in stage pT3 and pT4 tumors were almost equally rare with both grading variants (2.4% and 1.2% with conventional grading, respectively, and 1.0% and 0% with modified grading, respectively). In GS 7 tumors, pT2 was the most common stage with modified grading (54%), while pT3 was most common with conventional grading (67%) (p<0.001).
    The pT stages were 2, 3 and 4 in 46%, 39% and 15% of cases, respectively. The distribution of pT stages among conventional and modified GSs is presented in Table II. The only significant difference in stage distribution between conventional and modified GSs was for GS 7 (p<0.001), where a stage pT3 was most common (67%) with conventional Gleason grading compared with pT2 with modified Gleason grading (54%).
   

   
    Of modified GS 7 tumors, 44% were 3 + 4 = 7a and 56% were 4 + 3 = 7b. A GS 4 + 3 = 7b was more often associated with a high stage than a 3 + 4 = 7a (p<0.001) (Table III). Of GS 3 + 4 = 7a tumors, 95% were stage pT2, while 79% of  4 + 3 = 7b tumors were stage pT3 or pT4.
   

   
    
Discussion
Over the years, there has been a gradual change in how the Gleason grading system is applied in practice.16 The ISUP consensus meeting in 2005 was organized with the purpose of standardizing both the identification of histologic patterns and the compilation and reporting of the grade information.1 We recently demonstrated that with this modification of the Gleason grading system there was a shift in the most frequent scores from 6 (3 + 3) to 7a (3 + 4) in biopsy specimens.2 A well-known problem with the conventional Gleason grading system is the undergrading of biopsy specimens compared with RP specimens. The agreement of GS between biopsy and RP specimens with the conventional Gleason grading has been reported at ~45%.17 In our series, the overall agreement improved from 58% to 72% (p<0.001) compared with conventional GS, possibly because of a general upgrading of needle biopsies.2 However, as demonstrated in the present study, there is also a considerable upgrading of RP specimens. The clinical implications of this have not yet been evaluated.
    Ideally, grading should reflect the aggressive potential of a tumor. Therefore tumor grade should correlate well with stage. The conventional GS has been shown to correlate with the pT stage of the RP specimens.18 To our knowledge, this study is the first to compare the correlation between pT stage and both conventional and modified Gleason grading.
    The ISUP consensus meeting recommended that the tertiary patterns of higher grades should be included in the GS of needle biopsies, but this recommendation was not extended to RP specimens.1 Hence the upgrading in prostatectomy tumors that we describe in this study can be attributed to changed pattern perception. Notably the definition of Gleason patterns 3 and 4 was modified by the ISUP meeting. For cribriform patterns, Gleason assigned a Gleason pattern 3 or 4, depending on the shape of the cribriform glands.
    There is now an increased awareness that invasive cribriform carcinoma is potentially aggressive. Thus it was recommended that most cribriform carcinomas should be assigned a Gleason pattern 4 rath­er than 3, and the definition of cribriform pattern 3 was restricted to rounded, well-circumscribed cribriform cancerous glands of the same size as normal glands. Furthermore, many medium-sized round atyp­ical cribriform glands are prostatic intraepi­thelial neoplasia rather than invasive carcinoma. Hence pure cribriform Gleason pattern 3 is now con­sidered a rather uncommon finding.
    The ISUP consensus meeting also decided that Gleason pattern 4 should include ill-defined glands with poorly formed glandular lumina, a relatively frequent pattern that was not incorporated in the original definition of pattern 4. It is unclear how this pattern used to be graded, but the incomplete structure of some of the glands may have been overlooked, resulting in their being graded as Gleason pattern 3. Thus, with the ISUP modifications, some cases that once were interpreted as GS 6 are now considered GS 7.
    The major difference that we found in terms of stage distribution among the grades was that in GS 7 tumors pT2 was the most common pathologic stage with modified grading while pT3 was most common with conventional grading. Within stage pT2, there was a marked upgrading from 68% GS 6 to 66% GS 7. Within pT3, the changes were more limited, with GSs 8–9 increasing only marginally from 36–44%. A possible explanation is that the modification of the Gleason grading of RP specimens mainly drives pattern 3 to pattern 4, which increases the number of GS 7 tumors at the expense of GS 6 tumors, while a shift upward of high-grade cases is more uncommon (e.g., from GS 4 + 3 = 7 to GS 4 + 4 = 8).
    The upgrading of prostatic carcinoma in recent years is somewhat problematic because it changes the prognostic significance of the grades. Albertsen et al have referred to this as the Will Rogers phenomenon.19 Will Rogers was a U.S. comedian from Oklahoma who said that “when the Okies moved to California, the IQ of both states went up.” This parallels the effect that reclassification of tumors may have. If the worst GS 6 tumors are moved to GS 7, the prognosis of GS 6 will evidently improve. However, the poor prognosis of GS 7 will also be diluted, and consequently, the prognosis of both grades will improve.
    A modified definition of the GS may also change the previous definitions of insignificant carcinoma. This category has been defined as a minute focus (≤0.5 mm) of carcinoma in only 1 biopsy core, PSA density <0.15 and a GS <7.20 With an upgrading of prostate cancer from GS 6 to 7, insignificant carcinoma will be more uncommon when this definition is used. Furthermore, if as many as 71% of pT2 tumors are assigned a GS of 7 or higher, a biopsy GS of 7 probably does not necessarily imply a poor prognosis.
    Several studies have suggested that GS 4 + 3 = 7b cancers are at a more advanced pathologic stage and have a higher risk of disease progression after prostatectomy than Gleason score 3 + 4 = 7a cancers.21-23 Of all modified GS 7 tumors in this study, a minority (44%) were 3 + 4 = 7a, in contrast with 66%,22 67%23 and 80%21 in previous reports. However, a modified GS 4 + 3 = 7b was still associated with a higher stage than GS 3 + 4 = 7a.
    To be clinically useful, a grading system must be reproducible. To our knowledge, the reproducibility of modified Gleason grading on RP specimens has not yet been investigated. The modified Gleason grading in this study was carried out by a single pathologist (B.H.). Hence the study design did not allow assessment of interobserver variability. It would, unfortunately, have been too time-consuming to have this extensive series (649 cases) reviewed by 2 independent pathologists.
    The conclusion of this study is that the modified Gleason grading correlates very well with the pathologic stage of RP specimens. Its importance for prediction of prognosis remains to be investigated.
     
References
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From the Department of Pathology, General Hospital HBH Kliniken Singen, Academic Hospital of the University of Freiburg, Singen, Germany; and International Agency for Research on Cancer, Lyon, France.

Dr. Helpap is Professor, Department of Pathology, General Hospital HBH Kliniken Singen, Academic Hospital of the University of Freiburg.

Dr. Egevad is Scientist, International Agency for Research on Cancer.

Address correspondence to: Lars Egevad, M.D., Ph.D., Pathology Group (PAT), 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 authors have no connection to any companies or products mentioned in this article.

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