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A Tertiary Gleason Pattern in the Prostatectomy Specimen and Its Association with Adverse Outcome after Radical Prostatectomy: Results of a Large Contemporary Prostatectomy Series

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A Tertiary Gleason Pattern in the Prostatectomy Specimen and Its Association with Adverse Outcome after Radical Prostatectomy: Results of a Large Contemporary Prostatectomy Series
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  A Tertiary Gleason Pattern in the Prostatectomy Specimenand its Association with Adverse Outcome after RadicalProstatectomy Meike Adam,* Amir Hannah, Lars Bud € aus, Thomas Steuber, Georg Salomon,Uwe Michl, Alexander Haese, Margit Fisch, Corinna Wittmer, Stefan Steurer,Sarah Minner, Hans Heinzer, Hartwig Huland, Markus Graefen, Guido Sauter,Thorsten Schlomm and Hendrik Isbarn From the Martini-Clinic, Prostate Cancer Center Hamburg-Eppendorf (MA, AH, LB, TS, GS, UM, AH, HH, HH, MG, TS, HI) and Departments of Urology (MA, MF, HI) and Pathology (CW, SS, SM, GS), University Medical Center Hamburg-Eppendorf,Hamburg, Germany  Purpose:  The prognostic significance of a tertiary Gleason pattern in the radicalprostatectomy specimen is controversial. We tested the impact of a tertiaryGleason pattern on adverse histopathological features and biochemical recur-rence rates after radical prostatectomy. Materials and Methods:  We assessed data on 11,226 consecutive patientstreated with radical prostatectomy at our institution between June 2007 andFebruary 2013. We compared 2,396 patients with (22.4%) and 8,260 without(77.5%) a tertiary Gleason pattern for adverse histopathological features(extraprostatic extension, seminal vesicle invasion, positive surgical margins andlymph node invasion) using the chi-square test. The effect of a tertiary Gleasonpattern on biochemical recurrence was tested in univariable and multivariablemodels. Subanalyses were then done for different radical prostatectomy Gleasongroups (6 or less, 3  þ  4 and 4  þ  3). Results:  A tertiary Gleason pattern was statistically significantly associated withall evaluated histopathological parameters (each p  < 0.001). It was an indepen-dent predictor of biochemical recurrence (HR 1.43, p  < 0.001). On subanalysisonly a tertiary Gleason pattern independently predicted biochemical recurrencein the patient cohort with a radical prostatectomy Gleason score of 3  þ  4 and4  þ  3. However, it failed to attain independent predictor status in patients witha radical prostatectomy Gleason score of 6 or less. Conclusions:  A tertiary Gleason pattern is a significant and independentpredictor of biochemical recurrence after radical prostatectomy with the stron-gest prognostic effect in cases with Gleason scores 3  þ  4 and 4  þ  3. Therefore,a tertiary Gleason pattern should be recorded in the pathological report. Key Words:  prostate; prostatic neoplasms; prostatectomy;neoplasm recurrence, local; neoplasm grading R  ADICAL  prostatectomy is a standardprocedure for localized or locallyadvanced prostate cancer. 1 The pa-tient risk of BCR after RP issignificantly influenced by preopera-tivePSA,pTstage,lymphnodestatus,surgical margin status and particu- larly prostatectomy Gleason score. 1 e 3 Abbreviationsand Acronyms BCR  ¼  biochemical recurrenceEPE  ¼  extraprostatic extensionLNI  ¼  lymph node invasionPSA  ¼  prostate specific antigenPSM  ¼  positive surgical marginRP  ¼  radical prostatectomySVI  ¼  seminal vesicle invasionTGP  ¼  tertiary Gleason pattern Accepted for publication January 10, 2014.* Correspondence: Martini-Clinic, ProstateCancerCenter Hamburg-Eppendorf,Martinistr.52,20246 Hamburg, Germany (e-mail: meikeadam@hotmail.com). 0022-5347/14/1921-0097/0THE JOURNAL OF UROLOGY  ®  ©  2014 by A MERICAN  U ROLOGICAL  A SSOCIATION  E DUCATION AND  R ESEARCH , I NC .http://dx.doi.org/10.1016/j.juro.2014.01.029Vol. 192, 97-102, July 2014Printed in U.S.A.  www.jurology.com  j  97  Traditionally the Gleason score is generated bythe 2 (if more than 1 Gleason pattern is present)most frequently observed Gleason patterns in theprostate. However, in a significant proportion of cases more than 2 Gleason patterns are present. In1992 Gleason reported that TGP could be observedin up to 50% of RP specimens. Since then, othershave retrospectively reported the clinical signifi-cance of TGP in the RP specimen but published studies to date describe conflicting results. 4 e 7 Whilemost reports showed that TGP was significantlyassociated with more advanced disease, the impactof TGP with respect to the probability of BCR afterRP is acknowledged less unanimously. To furtherassess the prognostic relevance of TGP we report theimpact of TGP on adverse histopathological featuresand its impact on the probability of BCR after RP. MATERIALS AND METHODS Patient Cohort We assessed data on 11,226 consecutive patients treatedwith RP between January 2007 and February 2013 atthe Martini-Clinic, Prostate Cancer Center and Univer-sity Medical Center Hamburg-Eppendorf. We excluded554 patients who received neoadjuvant hormonal treat-ment and 16 due to missing data on important histo-pathological parameters, resulting in 10,656 evaluablepatients. For study purposes data on these patients wereretrospectively analyzed. Sufficient followup data wereavailable on 8,014 patients. BCR was defined as post-operative PSA 0.2 ng/ml and increasing. If no adjuvanttherapy was performed, PSA was measured quarterlyin year 1, followed by biannual measurements in year 2and annual measurements in the years thereafter. Histopathology and TGP Assessment  All RP specimens were processed by experienced genito-urinary pathologists using whole mount 3 mm serial stepsections according to the Stanford protocol. 8 Grading wasdone according to the Gleason system. 9 The clinical rele-vance of  tertiary Gleason grade was initially reported byPan etal. 10 Routinely reporting thetertiary Gleason gradewassubsequentlysuggestedin2004byWHO 11 andin2005by ISUP (International Society of Urological Pathology). 12 Lymph node dissection was performed in patients atmoderate or high risk for LNI according to validatedprediction tools. 13 Surgical margins were considered pos-itive when 1 or more cancer cells extended to the inkedprostate surface. For pathological staging the 2002 TNMsystem was used. As previously reported, 14 there were 2 circumstancesunder which Gleason grade was considered tertiary. 1) If a Gleason pattern consisted of less than 5% of the wholecancer volume and there was no secondary Gleasonpattern greater than 5% (eg Gleason score 3  þ  3  ¼  6 andless than 5% tertiary Gleason grade 4), grade was consid-ered tertiary. 2) If the primary and secondary Gleasongrades were different, the third most prevalent Gleasonpattern was considered tertiary if it was worse than theprimary and secondary Gleason grades regardless of itspercent or differentiation (eg 50% Gleason 4, 30% Gleason3 and 20% Gleason 5 considered Gleason score 4  þ  3  ¼  7with TGP 5). Any Gleason pattern indicating worsedifferentiation than the primary and secondary Gleasonpatterns was considered tertiary. Statistics The association of TGP with EPE, tumor SVI, PSMsand LNI was analyzed by the chi-square test. The effectof TGP on the BCR risk was assessed in univariable(Kaplan-Meier) and multivariable (Cox regression)models.CovariatesinmultivariableCoxregressionmodelsconsisted of preoperative PSA (continuously coded), age(continuously coded), RP Gleason score (6 or less vs 3 þ 4vs 4 þ 3 vs 8 or greater), pT stage (pT2 vs pT3a vs pT3b orgreater), pN stage (pN0 vs pN1 vs pNX) and surgicalmargin status (positive vs negative). Because only 2 pa-tients had pT4 disease, they were added to the group withevidence of SVI (pT3b). All analyses were also reanalyzedin the 3 most relevant Gleason subgroups (6 or less, 3 þ 4and 4  þ  3). The 539 patients who received adjuvant radi-ationtherapywerefirstconsideredtohaveBCR.However,since this might have overestimated the true BCR rate,we repeated multivariable analysis after excluding the549 patients exposed to adjuvant radiation therapy.Statistical significance was considered at p  < 0.05.Statistical analysis was done with JMP  , version 9.0.2. RESULTS Supplementary table 1 (http://jurology.com/ ) listsstudy cohort descriptive characteristics. Median ageat surgery was 65 years (range 37 to 81) and medianpreoperative PSA was 6.7 ng/ml (range 0.1 to 290).Of the patients 68.4% had organ confined diseaseat RP, 31.6% had evidence of extraprostatic disease,11.6% had SVI or pT4 disease and 7% had evidenceof LNI. The prostatectomy Gleason score was 6 orless in 16.7% of cases, 3 þ 4 in 60.2%, 4 þ 3 in 17.1%and 8 or greater in 6.0%. Of the patients 17% hadPSMs and 2,396 (22.4%) had TGP.Supplementary table 2 (http://jurology.com/ )shows the association between TGP and adversehistopathological features in the entire cohort andin the subgroups with Gleason score 6 or less, 3 þ 4and 4 þ 3. In the entire cohort TGP was statisticallysignificantly associated with all evaluated endpoints (each p  < 0.001). Specifically, the EPE ratewas 60.2% in patients with TGP vs 23.4% in pa-tients without TGP. For TGP vs no TGP estimateswere 33.1% vs 5.4% for SVI, 24.3% vs 4.5% for LNIand 30.1% vs 12.1% for PSM. Comparable resultswere observed in all subanalyses except the SVIrate in patients with Gleason score 3  þ  3 probablydue to the small number of events (0.3% vs 0.1%).Median followup in censored patients was 24.3months and in all patients it was 24.5 months.Figure 1 shows the Kaplan-Meier plot of BCR-free 98  TERTIARY GLEASON PATTERN IN PROSTATECTOMY SPECIMEN AND ADVERSE OUTCOME  survival rates in the entire cohort stratified by TGP.The 3-year biochemical free survival rate was 64.5%in patients with TGP vs 80.7% in those withoutworst differentiated TGP (p  ¼  0.001). Subanalysisrevealed that only patients with RP Gleason score3  þ  4 and 4  þ  3 showed statistically significantlydifferent BCR rates while BCR rates did not differsignificantly in patients with RP Gleason score 6 orless (fig. 2).Table 1 shows the multivariable model for BCRprediction after RP. In the entire cohort TGP againhad a significant impact on the probability of BCRand achieved independent predictor status. TGPwas associated with a 43% increased probability of BCR (p  < 0.01) compared to counterparts withoutTGP. PSA, pT stage, prostatectomy Gleason scoreand surgical margin status were further indepen-dent predictors of BCR. Results did not significantlychange when patients exposed to adjuvant radiationtherapy were excluded from analysis (table 1).However, on multivariable analysis a significantinfluence of TGP on the probability of BCR in thesubgroups with Gleason score 6 or less, 3  þ  4 and4  þ  3 was again only observed for patients withGleason score 3  þ  4 (HR 1.7, p  < 0.001) and 4  þ  3(HR 1.3, p ¼ 0.004, table 2). Similar results with thesame significant inference were observed when pa-tients with adjuvant radiation therapy were againexcluded from analysis (table 2). DISCUSSION Gleason score represents a highly important prog-nostic variable in the RP specimen. However, untilrecently the prognostic significance of TGP was un-known. In 2000 Pan et al first reported the correla-tion of TGP with histopathological features. 10 Intheir study of 114 RP specimens TGP was statisti-cally significantly associated with more advancedstageandahigherprogressionrateafterRP.Severalfurther studies corroborated the adverse effect of TGP on histopathological parameters. Moreover,consideration of a TGP at prostate biopsy shows asubstantially better correlation between the biopsyand prostatectomy Gleason scores compared to thetraditionalGleasonsystem.Therefore,considerationof the TGP is associated with a significantly lowerproportion of upgrading and downgrading betweenbiopsy and prostatectomy specimens. 15 However,although virtually all published studies of the prog-nostic significance of TGP show that it is associatedwith more advanced disease, its impact on theBCR risk is controversial. In some studies TGPachieved independent predictor status for the BCR risk in multivariable models 4,5,16 e 19 while otherstudies showed contradictory results. 6,7 The current study was based on data on 10,656recent consecutive patients not exposed to anyform of neoadjuvant androgen deprivation therapywho were treated with RP from January 2007 toFebruary 2013. TGP was statistically significantlyassociated with higher rates of EPE, SVI, LNI, PSMand BCR after RP. Three-year BCR-free survivalestimates were 79% in patients with TGP vs 85% inthose without TGP (p ¼ 0.001). Moreover, TGP wasan independent predictor of BCR when adjusted forpreoperative PSA, patient age, RP Gleason score, pTstage, pN stage and surgical margin status.Furthermore, TGP did not uniformly predictadverse outcomes when various RP Gleason scores Figure 1.  Kaplan-Meier plot shows BCR-free survival ratesafter RP by worst differentiated TGP presence or absence (logrank p  < 0.0001). Figure 2.  Kaplan-Meier plot shows BCR-free survival rates after RP by worst differentiated TGP presence or absence in patientsubgroups with RP Gleason score ( GS  ) 6 or less, 3  þ  4 or 4  þ  3. TERTIARY GLEASON PATTERN IN PROSTATECTOMY SPECIMEN AND ADVERSE OUTCOME  99  were independently considered. After stratifyingpatients into 3 Gleason groups (Gleason score 6 orless, 3  þ  4 and 4  þ  3) an association with BCR wasonly observed for Gleason scores 3  þ  4 and 4  þ  3.This lack of significance in patients with a RPGleason score of 6 or less might be explained bythe fact that only 1 patient had a TGP of 5 and allother TGPs were Gleason grade 4. Since themagnitude of TGP 4 in patients with a Gleasonscore of 6 or less must be smaller than 5% (other-wise it would be Gleason score 3  þ  4), we speculatethat such a small amount of Gleason pattern 4 doesnot significantly impact the patient prognosis.Comparable results were reported by others. Ina sample of 151 patients Servoll et al observedTGP pattern 5 was associated with clinical pro-gression only in patients with Gleason score 3 þ 4. 17 However, they could not exclude the possibility thatthisfindingmighthavebeenduetotheirsmallstudycohort.Ina study cohortof 214 patients others noteda statistically significant correlation with BCR butit was limited to Gleason score 3  þ  4 tumors. Incontrast, in 3,230 patients Trock et al observed thatTGP pattern 5 was associated with biochemicalfailure regardless of the assessed Gleason score (3 þ 4 or 4  þ  3). 5 Based on their findings they recom-mended that TGP be directly factored into theGleason grading system since to date treatmentdecision making has usually been based on riskcalculators that do not consider TGP presence orabsence. Our results support this suggestion and wealso suggest that future nomograms addressingcancer control outcomes after RP consider TGP. Table 1.  Univariable and multivariable Cox regression models of TGP effect on BCR probability after RP overall and after excluding adjuvant radiation  Univariable* MultivariableHR (95% CI) HR (95% CI) p Value Overall  TGP 2.1 (1.9 e 2.4) 1.43 (1.3 e 1.6)  < 0.001Age (continuous) 1.02 (1.02 e 1.03) 1.0 (0.7 e 1.4) 1.0PSA (continuous) 1.01 (1.01 e 1.02) 1.0 (1.0 e 1.0) 0.004pT stage:  < 0.001pT3a vs pT2 4.6 (4.1 e 5.3) 2.5 (2.2 e 2.9)  < 0.001pT3b or greater vs pT2 14.3 (12.6 e 16.3) 3.2 (2.7 e 3.9)  < 0.001pN stage:  < 0.001pN1 vs pN0 6.4 (5.7 e 7.3) 1.5 (1.3 e 1.8)  < 0.001pNX vs pN0 0.3 (0.3 e 0.4) 0.9 (0.6 e 0.8)  < 0.001Prostatectomy Gleason score:  < 0.0013  þ  4 vs 6 or Less 3.3 (2.6 e 4.3) 2.1 (1.6 e 2.8)  < 0.0014  þ  3 vs 6 or Less 14.3 (11.0 e 18.8) 4.1 (3.1 e 5.5)  < 0.0018 or Greater vs 6 or less 31.3 (24.9 e 41.5) 5.8 (4.2 e 8.2)  < 0.001Surgical margin status(pos vs neg)5.4 (4.9 e 6.0) 2.4 (2.2 e 2.7) 0.007 Excluding adjuvant radiation  TGP 2.1 (1.9 e 2.4) 1.5 (1.3 e 1.8)  < 0.001Age (continuous) 1.01 (0.93 e 1.1) 1.0 (0.99 e 1.01) 0.7PSA (continuous) 1.01 (1.01 e 1.02) 1.0 (1.0 e 1.0)  < 0.001pT stage:  < 0.001pT3a vs pT2 3.5 (3.0 e 4.0) 1.9 (1.6 e 2.2)  < 0.001pT3b or greater vs pT2 9.6 (8.2 e 11.2) 2.3 (1.9 e 2.9)  < 0.001pN stage:  < 0.001pN1 vs pN0 6.2 (5.2 e 7.4) 1.7 (1.4 e 2.1)  < 0.001pNX vs pN0 0.3 (0.3 e 0.4) 0.6 (0.5 e 0.8)  < 0.001Prostatectomy Gleason score:  < 0.0013  þ  4 vs 6 or Less 2.8 (2.2 e 3.8) 2.1 (1.6 e 2.9)  < 0.0014  þ  3 vs 6 or Less 11.7 (8.9 e 15.7) 4.8 (3.5 e 6.6)  < 0.0018 or Greater vs 6 or less 23.4 (17.4 e 32.2) 7.1 (4.9 e 10.3)  < 0.001Surgical margin status(pos vs neg)2.8 (2.4 e 3.2) 1.4 (1.2 e 1.7)  < 0.001*Each p  < 0.001. Table 2.  Multivariable Cox regression models of TGP effect on BCR probability after RP by Gleason score group overall and after excluding adjuvant radiation  Gleason Score 6 or Less Gleason Score 3  þ  4 Gleason Score 4  þ  3HR (95% CI) p Value HR (95% CI) p Value HR (95% CI) p Value Overall  TGP (higher vs lower) 1.1 (0.63 e 0.67) 0.6 1.7 (1.4 e 2.1)  < 0.001 1.3 (1.1 e 1.5) 0.004Age 1.0 (1.0 e 1.05) 0.6 1.0 (1.0 e 1.02) 0.8 0.99 (0.98 e 1.0) 0.5PSA 1.03 (1.0 e 1.07) 0.1 1.0 (1.01 e 1.02)  < 0.001 1.0 (1.0 e 1.0) 0.0001pT stage:pT3a vs pT2 3.1 (1.4 e 6.3) 0.005 2.2 (1.8 e 2.7)  < 0.001 2.1 (1.6 e 2.7)  < 0.001pT3b or greater vs pT2 31.6 (4.5 e 139.9) 0.002 4.1 (3.1 e 5.5)  < 0.001 2.5 (1.9 e 3.3)  < 0.001pN stage:pN1 vs pN0 No data  e  2.7 (1.9 e 3.8)  < 0.001 1.6 (1.3 e 2.0)  < 0.001pNX vs pN0 0.4 (0.2 e 0.6)  < 0.001 0.8 (0.6 e 1.0) 0.03 0.7 (0.5 e 1.0) 0.03Surgical margin status (pos vs neg) 6.0 (3.3 e 10.7)  < 0.001 3.2 (2.7 e 3.9)  < 0.001 2.1 (1.7 e 2.5)  < 0.001 Excluding adjuvant radiation  TGP (higher vs lower) 0.8 (0.5 e 1.5) 0.5 1.7 (1.4 e 2.3)  < 0.001 1.4 (1.2 e 1.8)  < 0.001Age 1.0 (1.0 e 1.06) 0.4 1.0 (0.99 e 1.01) 0.7 1.0 (0.98 e 1.0) 0.9PSA 1.04 (1.1 e 1.08) 0.1 1.0 (1.01 e 1.03)  < 0.001 1.02 (1.01 e 1.02)  < 0.001pT stage:pT3a vs pT2 2.9 (1.4 e 6.3) 0.005 1.7 (1.3 e 2.1)  < 0.001 1.9 (1.5 e 2.5)  < 0.001pT3b or greater vs pT2 31.6 (4.5 e 139.9) 0.002 2.7 (1.8 e 3.8)  < 0.001 2.2 (1.6 e 3.0)  < 0.001pN stage:pN1 vs pN0 No data  e  3.4 (2.0 e 5.3)  < 0.001 1.6 (1.2 e 2.1) 0.003pNX vs pN0 0.4 (0.2 e 0.6)  < 0.001 0.8 (0.6 e 1.0) 0.03 0.7 (0.4 e 1.0) 0.04Surgical margin status (pos vs neg) 6.0 (3.3 e 10.7)  < 0.001 1.7 (1.4 e 2.2)  < 0.001 1.2 (1.6 e 1.1) 0.1 100  TERTIARY GLEASON PATTERN IN PROSTATECTOMY SPECIMEN AND ADVERSE OUTCOME  Differences between findings of the current studyand previous studies in which TGP failed to achieveindependent predictor status might be explained bydifferences in cohort size. Previous reports included277 to 3,230 patients and, thus, they were sub-stantially smaller than our patient cohort. There-fore, an absent independent predictor status of TGP might be related to a type 2 error derivedfrom insufficiently powered sample sizes.We included the role of adjuvant therapy in pa-tients after RP in the absence of BCR to investigatethe prognostic role of TGP. If these patients wereconsidered not to have received adjuvant treatment,the BCR rate might have been underestimated. If exposure to adjuvant radiation therapy wereconsidered an event in each case, the BCR ratewould be potentially overestimated. We addressedthis issue by considering adjuvant radiation therapya BCR event and subsequently repeating analysisafter excluding patients with adjuvant radiotherapywho showed no significantly different results.Ourstudyisnotdevoidoflimitations,ofwhichoneis its retrospective study design, a feature that ourstudy shares with all previous reports of TGP. Nonetheless, TGP presence or absence wasprospectively evaluated in all RP specimens, whichmight at least partly attenuate this limitation.However, RP specimens were not reevaluated forstudy purposes. Moreover, the median followup of 24 months is relatively short and we cannot ruleout the possibility that longer followup might havechanged the results. However, most BCR eventsafterRPdevelopwithinthefirst2yearsoffollowup. 20  Apart from these limitations our study also hasstrengths. 1) The study inclusion interval wasrelatively short. Thus, our study was probably notinfluenced by factors such as changes in surgicalmodalities or treatment patterns in general, orother subjects along the same lines which mightaffect the results. 2) All RP specimens were evalu-ated by highly experienced pathologists and all RPswere performed by high volume RP surgeons.Therefore, surgical or pathological variability didnot significantly affect the current report. CONCLUSIONS TGP is a significant and independent predictor of BCR after RP in patients with Gleason score 3  þ  4and 4  þ  3. This study underlines the requirementthat the presence or absence of TGP should conse-quently be reported in the pathological RP report. REFERENCES 1. Heidenreich A, Aus G, Bolla M et al: EAUguidelines on prostate cancer. Eur Urol 2008;  53: 68.2. Walz J, Chun FK, Klein EA et al: Nomogrampredicting the probability of early recurrenceafter radical prostatectomy for prostate cancer.J Urol 2009;  181:  601.3. Stephenson AJ, Scardino PT, Eastham JA et al:Postoperative nomogram predicting the 10-yearprobability of prostate cancer recurrence afterradicalprostatectomy.JClinOncol2005; 23: 7005.4. Sim HG, Telesca D, Culp SH et al: TertiaryGleason pattern 5 in Gleason 7 prostate cancerpredicts pathological stage and biochemicalrecurrence. J Urol 2008;  179:  1775.5. 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