1 2011 Vol: 14(4):307-312. DOI: 10.1038/pcan.2011.15

The clinical significance of in-depth pathological assessment of extraprostatic extension and margin status in radical prostatectomies for prostate cancer

Despite recent Level 1 evidence on the benefits of adjuvant radiotherapy for locally advanced prostate cancer (PCa), the timing and decision to administer adjuvant radiotherapy post-radical prostatectomy (post-RP) remains debatable, particularly for patients with focal extraprostatic extension (EPE) and/or focal positive surgical margins (PSMs). In this study, we assess the utility of detailed pathological assessment of EPE and PSM, as this may influence the criteria for instituting adjuvant radiotherapy. A total of 148 RP cases (1993–2001) were identified retrospectively as having EPE and/or PSM. All slides were re-reviewed, incorporating recent proposals by the Collage of American Pathologists (CAP) for the reporting of EPE and PSM, and correlated with clinical data. Both EPE and PSM were found to be independent predictors of biochemical failure (BCF); however, only EPE was associated with metastasis and death. BCF was also more likely to be associated with cases that had non-focal EPE than focal EPE. Similarly, non-focal PSM cases had a significantly higher risk of BCF than focal cases. Our study confirms the value of detailed pathological assessment of EPE and PSM post-RP. The results support the concept of selective adjuvant radiotherapy in patients with EPE and PSM, based on focality and extent.

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Figures
Figure 1: Measurement of positive surgical margin at 100 × using Spot Advanced Imaging Software (H and E section). Figure 2: Kaplan–Meier curves for biochemical failure-free survival analysis for the four groups. EPE, extraprostatic extension. Figure 3: Kaplan–Meier curves for biochemical failure (BCF)-free survival analysis for positive surgical margin (PSM) <0.1 and 0.1 mm. BCF rates were significantly higher in cases with PSM 0.1 mm than cases with PSM <0.1 mm, (b) Kaplan–Meier curves for BCF-free survival analysis for PSM <0.1 mm, 0.1–1.0 mm and >0.1 mm. No significant difference in BCF was found between the 0.1–1.0 mm and >1.0 mm groups.
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References
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    • . . . For example, although some studies1, 2, 3, 4 have found that immediate adjuvant treatment decreased the risk of biochemical failure (BCF) in patients with PSM and extracapsular tumor extension, it is not entirely clear what its effects are on distant metastasis and survival, in spite of one recent report (SWOG 8794 study) indicating a statistical advantage for early adjuvant radiotherapy . . .
    • . . . Three randomized multi-centre trials comparing adjuvant radiotherapy versus no adjuvant treatment for post-RP patients who had either EPE, PSM, SVI, or a combination thereof, showed fewer and/or later BCF, metastasis development and longer progression-free survival for those who received adjuvant radiotherapy.1, 2, 3, 23 The Southwest Oncology Group (SWOG) study by Thompson et al.,2 with longer follow-up, recently also showed an overall survival benefit with adjuvant radiotherapy compared with the ‘wait and see’ approach . . .
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    • . . . For example, although some studies1, 2, 3, 4 have found that immediate adjuvant treatment decreased the risk of biochemical failure (BCF) in patients with PSM and extracapsular tumor extension, it is not entirely clear what its effects are on distant metastasis and survival, in spite of one recent report (SWOG 8794 study) indicating a statistical advantage for early adjuvant radiotherapy . . .
    • . . . Three randomized multi-centre trials comparing adjuvant radiotherapy versus no adjuvant treatment for post-RP patients who had either EPE, PSM, SVI, or a combination thereof, showed fewer and/or later BCF, metastasis development and longer progression-free survival for those who received adjuvant radiotherapy.1, 2, 3 . . .
    • . . . Three randomized multi-centre trials comparing adjuvant radiotherapy versus no adjuvant treatment for post-RP patients who had either EPE, PSM, SVI, or a combination thereof, showed fewer and/or later BCF, metastasis development and longer progression-free survival for those who received adjuvant radiotherapy.1, 2, 3, 23 The Southwest Oncology Group (SWOG) study by Thompson et al.,2 with longer follow-up, recently also showed an overall survival benefit with adjuvant radiotherapy compared with the ‘wait and see’ approach . . .
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    • . . . For example, although some studies1, 2, 3, 4 have found that immediate adjuvant treatment decreased the risk of biochemical failure (BCF) in patients with PSM and extracapsular tumor extension, it is not entirely clear what its effects are on distant metastasis and survival, in spite of one recent report (SWOG 8794 study) indicating a statistical advantage for early adjuvant radiotherapy . . .
    • . . . Three randomized multi-centre trials comparing adjuvant radiotherapy versus no adjuvant treatment for post-RP patients who had either EPE, PSM, SVI, or a combination thereof, showed fewer and/or later BCF, metastasis development and longer progression-free survival for those who received adjuvant radiotherapy.1, 2, 3, 23 The Southwest Oncology Group (SWOG) study by Thompson et al.,2 with longer follow-up, recently also showed an overall survival benefit with adjuvant radiotherapy compared with the ‘wait and see’ approach . . .
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    • . . . EPE is simply defined as tumor outside the normal confines of the prostate,6, 7 however, the pathological reporting of EPE is far from simple particularly with the incorporation of new recommendations by the College of American Pathologists (CAP) . . .
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    • . . . First, the CAP has suggested that EPE be subdivided into focal and non-focal types as multiple studies have indicated that focal EPE is associated with a better prognosis.8, 9, 10, 11 It remains unresolved, however, as to which of the many definitions for EPE focality should be incorporated into the decision-making algorithm on adjuvant radiotherapy . . .
    • . . . Focal EPE was defined in three ways: (1) Epstein et al.8 definition: a few neoplastic glands exterior to the prostate, (2) Wheeler et al.9 definition: tumor outside the prostate involving less than one high-power field in 1–2 sections, and (3) a simplified definition introduced by our group for the purpose of this study: ‘EPE confined to one slide only’ . . .
    • . . . Multiple studies, including our own, have shown that focal EPE has a much better prognosis than non-focal EPE.8, 9 As there is no consensus definition established for focal EPE, our study compared Epstein's8 and Wheeler's8, 9 criteria and introduced a third definition for focal EPE as ‘EPE confined to one slide only’ . . .
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    • . . . First, the CAP has suggested that EPE be subdivided into focal and non-focal types as multiple studies have indicated that focal EPE is associated with a better prognosis.8, 9, 10, 11 It remains unresolved, however, as to which of the many definitions for EPE focality should be incorporated into the decision-making algorithm on adjuvant radiotherapy . . .
    • . . . Focal EPE was defined in three ways: (1) Epstein et al.8 definition: a few neoplastic glands exterior to the prostate, (2) Wheeler et al.9 definition: tumor outside the prostate involving less than one high-power field in 1–2 sections, and (3) a simplified definition introduced by our group for the purpose of this study: ‘EPE confined to one slide only’ . . .
    • . . . Multiple studies, including our own, have shown that focal EPE has a much better prognosis than non-focal EPE.8, 9 As there is no consensus definition established for focal EPE, our study compared Epstein's8 and Wheeler's8 . . .
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    • . . . First, the CAP has suggested that EPE be subdivided into focal and non-focal types as multiple studies have indicated that focal EPE is associated with a better prognosis.8, 9, 10, 11 It remains unresolved, however, as to which of the many definitions for EPE focality should be incorporated into the decision-making algorithm on adjuvant radiotherapy . . .
    • . . . Several studies have found that patients with focal/short PSM possess a better prognosis than patients with non-focal/longer PSM,10, 15, 16, 17, 18, 19, 20 though definitions for PSM focality are highly variable with no consensus. . . .
    • . . . To refine the decision-making process on adjuvant therapy based on PSM, some have suggested triaging patients based on the total linear extent of the PSM.10, 15, 16, 17, 18, 19, 20 Suggested PSM cutoff points have ranged from 115 to 3 mm10, 16, 17, 20 to 618 to 10 mm19 . . .
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    • . . . First, the CAP has suggested that EPE be subdivided into focal and non-focal types as multiple studies have indicated that focal EPE is associated with a better prognosis.8, 9, 10, 11 It remains unresolved, however, as to which of the many definitions for EPE focality should be incorporated into the decision-making algorithm on adjuvant radiotherapy . . .
  12. Epstein JI, Sauvageot J. Do close but negative margins in radical prostatectomy specimens increase the risk of postoperative progression? J Urol 1997; 157: 241-243 , .
    • . . . Presently, a margin is only considered positive if there is a tumor in actual contact with the resection margin.6, 12 Although, previous studies have shown that the presence of a PSM carries with it prognostic significance,13, 14 it is not entirely clear which patients with PSM should receive adjuvant therapy . . .
  13. Eastham JA, Kuroiwa K, Ohori M, Serio AM, Gorbonos A, Maru N et al. Prognostic significance of location of positive margins in radical prostatectomy specimens. Urology 2007; 70: 965-969 , .
    • . . . Presently, a margin is only considered positive if there is a tumor in actual contact with the resection margin.6, 12 Although, previous studies have shown that the presence of a PSM carries with it prognostic significance,13, 14 it is not entirely clear which patients with PSM should receive adjuvant therapy . . .
  14. Karakiewicz PI, Eastham JA, Graefen M, Cagiannos I, Stricker PD, Klein E et al. Prognostic impact of positive surgical margins in surgically treated prostate cancer: Multi-institutional assessment of 5831 patients. Urology 2005; 66: 1245-1250 , .
    • . . . Presently, a margin is only considered positive if there is a tumor in actual contact with the resection margin.6, 12 Although, previous studies have shown that the presence of a PSM carries with it prognostic significance,13, 14 it is not entirely clear which patients with PSM should receive adjuvant therapy . . .
  15. Shikanov S, Song J, Royce C, Al-Ahmadie H, Zorn K, Steinberg G et al. Length of positive surgical margin after radical prostatectomy as a predictor of biochemical recurrence. J Urol 2009; 182: 139-144 , .
    • . . . Several studies have found that patients with focal/short PSM possess a better prognosis than patients with non-focal/longer PSM,10, 15, 16, 17, 18, 19, 20 though definitions for PSM focality are highly variable with no consensus. . . .
    • . . . To refine the decision-making process on adjuvant therapy based on PSM, some have suggested triaging patients based on the total linear extent of the PSM.10, 15, 16, 17, 18, 19, 20 Suggested PSM cutoff points have ranged from 115 to 3 mm10, 16, 17, 20 to 618 to 10 mm19 . . .
  16. Babaian RJ, Troncoso P, Bhadkamkar VA, Johnston DA. Analysis of clinicopathologic factors predicting outcome after radical prostatectomy. Cancer 2001; 91: 1414-1422 , .
    • . . . Several studies have found that patients with focal/short PSM possess a better prognosis than patients with non-focal/longer PSM,10, 15, 16, 17, 18, 19, 20 though definitions for PSM focality are highly variable with no consensus. . . .
    • . . . To refine the decision-making process on adjuvant therapy based on PSM, some have suggested triaging patients based on the total linear extent of the PSM.10, 15, 16, 17, 18, 19, 20 Suggested PSM cutoff points have ranged from 115 to 3 mm10 . . .
  17. Ochiai A, Sotelo T, Troncoso P, Bhadkamkar V, Babaian RJ. Natural history of biochemical progression after radical prostatectomy based on length of a positive margin. Urology 2008; 71: 308-312 , .
    • . . . Several studies have found that patients with focal/short PSM possess a better prognosis than patients with non-focal/longer PSM,10, 15, 16, 17, 18, 19, 20 though definitions for PSM focality are highly variable with no consensus. . . .
    • . . . To refine the decision-making process on adjuvant therapy based on PSM, some have suggested triaging patients based on the total linear extent of the PSM.10, 15, 16, 17, 18, 19, 20 Suggested PSM cutoff points have ranged from 115 to 3 mm10, 16 . . .
  18. Saether T, Sorlien LT, Viset T, Lydersen S, Angelsen A. Are positive surgical margins in radical prostatectomy specimens an independent prognostic marker? Scand J Urol Nephrol 2008; 42: 514-521 , .
    • . . . Several studies have found that patients with focal/short PSM possess a better prognosis than patients with non-focal/longer PSM,10, 15, 16, 17, 18, 19, 20 though definitions for PSM focality are highly variable with no consensus. . . .
    • . . . To refine the decision-making process on adjuvant therapy based on PSM, some have suggested triaging patients based on the total linear extent of the PSM.10, 15, 16, 17, 18, 19, 20 Suggested PSM cutoff points have ranged from 115 to 3 mm10, 16, 17, 20 to 618 to 10 mm19 . . .
  19. van Oort IM, Bruins HM, Kiemeney LA, Knipscheer BC, Witjes JA, Hulsbergen-van de Kaa CA. The length of positive surgical margins correlates with biochemical recurrence after radical prostatectomy. Histopathology 2010; 56: 464-471 , .
    • . . . Several studies have found that patients with focal/short PSM possess a better prognosis than patients with non-focal/longer PSM,10, 15, 16, 17, 18, 19, 20 though definitions for PSM focality are highly variable with no consensus. . . .
    • . . . To refine the decision-making process on adjuvant therapy based on PSM, some have suggested triaging patients based on the total linear extent of the PSM.10, 15, 16, 17, 18, 19, 20 Suggested PSM cutoff points have ranged from 115 to 3 mm10, 16, 17, 20 to 618 to 10 mm19 . . .
  20. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 1993; 71: 3582-3593 , .
    • . . . Several studies have found that patients with focal/short PSM possess a better prognosis than patients with non-focal/longer PSM,10, 15, 16, 17, 18, 19, 20 though definitions for PSM focality are highly variable with no consensus. . . .
    • . . . To refine the decision-making process on adjuvant therapy based on PSM, some have suggested triaging patients based on the total linear extent of the PSM.10, 15, 16, 17, 18, 19, 20 Suggested PSM cutoff points have ranged from 115 to 3 mm10, 16, 17 . . .
  21. Cheng L, Darson MF, Bergstralh EJ, Slezak J, Myers RP, Bostwick DG. Correlation of margin status and extraprostatic extension with progression of prostate carcinoma. Cancer 1999; 86: 1775-1782 , .
    • . . . Finally, although, assessment of the independent and additive prognostic significance of PSM and EPE has been evaluated previously by researchers such as by Cheng et al.,21 no study has re-evaluated this significance after incorporating the new CAP recommendations. . . .
    • . . . Our results concur with findings by Cheng et al.21 who reported a 5-year progression free survival of 55% for +EPE+Margin cases and 90% for −EPE−Margin cases . . .
    • . . . The presence of both EPE and PSM in RP is known to be associated with a poor prognosis.21 Theoretically, having these two features at the same location may portend a worse prognosis versus different locations . . .
  22. Epstein JI, Allsbrook WC, Amin MB, Egevad LL. The 2005 international society of urological pathology (ISUP) consensus conference on gleason grading of prostatic carcinoma. Am J Surg Pathol 2005; 29: 1228-1242 , .
    • . . . The following pathologic features were determined: Gleason score based on the 2005 ISUP guidelines,22 seminal vesicle invasion (SVI), lymphovascular invasion, lymph node metastasis, tumor volume in percentage (assessed by visual inspection), margin status and presence or absence of EPE . . .
  23. Nielsen ME, Trock BJ, Walsh PC. Salvage or adjuvant radiation therapy: counseling patients on the benefits. J Natl Compr Canc Netw 2010; 8: 228-237 , .
    • . . . Three randomized multi-centre trials comparing adjuvant radiotherapy versus no adjuvant treatment for post-RP patients who had either EPE, PSM, SVI, or a combination thereof, showed fewer and/or later BCF, metastasis development and longer progression-free survival for those who received adjuvant radiotherapy.1, 2, 3, 23 The Southwest Oncology Group (SWOG) study by Thompson et al.,2 with longer follow-up, recently also showed an overall survival benefit with adjuvant radiotherapy compared with the ‘wait and see’ approach . . .
  24. Lake AM, He C, Wood Jr DP. Focal positive surgical margins decrease disease-free survival after radical prostatectomy even in organ-confined disease. Urology 2010; 76: 1212-1216 , .
    • . . . Lake et al.24 found that focal positive margin after RP conferred a decreased disease free survival even in patients with otherwise organ-confined disease . . .
  25. Swindle P, Eastham JA, Ohori M, Kattan MW, Wheeler T, Maru N et al. Do margins matter? the prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 2008; 179: S47-S51 , .
    • . . . Similarly, Swindle et al. 25 argued that removal of cases with adjuvant therapy may distort recurrence rates by excluding cases at higher risk of recurrence . . .
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