- Email: [email protected]
The Significance of Positive Surgical Margin in Areas of Capsular Incision in Otherwise Organ Confined Disease at Radical Prostatectomy
The Significance of Positive Surgical Margin in Areas of Capsular Incision in Otherwise Organ Confined Disease at Radical Prostatectomy Ai-Ying Chuang, Matthew E. Nielsen, David J. Hernandez, Patrick C. Walsh and Jonathan I. Epstein* From the Department of Pathology, Koo Foundation Sun Yat-Sen Cancer Center, (AYC) and Affiliation of National Yang-Ming University (AYC), Taipei, Taiwan, and Departments of Pathology (AYC, JIE), Urology (MEN, DJH, PCW, JIE) and Oncology (JIE), The Johns Hopkins Hospital, Baltimore, Maryland
Purpose: The significance of capsular incision into tumor at radical prostatectomy with otherwise organ confined tumor is not well understood. Materials and Methods: Inclusion criteria were positive margin in an area of capsular incision, no extraprostatic extension elsewhere, negative seminal vesicles and lymph nodes, entire prostate submitted for examination, and no neoadjuvant therapy. Results: The postoperative progression of 135 cases of radical prostatectomy with capsular incision (1.3% of radical prostatectomies 1993 to 2004) was compared to 10,311 radical prostatectomies without capsular incision. Mean tumor length at the capsular incision site was 2.6 mm. Capsular incision was posterolateral (61.5%), posterior (18.5%), anterior (8.9%), lateral (8.1%) and apical (3%). The 5-year actuarial freedom from biochemical recurrence for tumors with capsular incision was worse (71.3%) than organ confined margin negative tumor (96.7%) (p ⬍0.0001) and focal extraprostatic extension margin negative disease (89.7%) (p ⫽ 0.02), yet better than extensive extraprostatic extension margin positive tumors (58.5%) (p ⬍0.0001). The risks of progression in men with capsular incision, focal extraprostatic extension margin positive and extensive extraprostatic extension margin negative disease were not significantly different. Risk of recurrence correlated with tumor length at the capsular incision site (p ⫽ 0.002). The 5-year risks of biochemical progression were 20.0% and 55% for less than 3 mm and 3 mm or greater of tumor cut across, respectively. Conclusions: Isolated capsular incision into tumor is uncommon in cases of radical prostatectomy performed by experienced urologists, typically Gleason score 6, and most common in the neurovascular bundle region. Isolated capsular incision has a higher recurrence rate than organ confined or focal extraprostatic extension margin negative disease, yet a lower recurrence rate than extensive extraprostatic extension margin positive tumor, and a worse prognosis with greater extent of capsular incision. Key Words: prostate, prostatectomy, survival
he controversy surrounding the importance of capsular incision in men with organ confined disease has been brought into focus with increased interest in less invasive approaches to radical prostatectomy. There is no better way to cure cancer that is localized to the prostate than total surgical removal, and to effectively achieve this goal every attempt must be made to excise all tumor. In the past when patients presented with extensive extraprostatic extension this was often impossible because of the limited amount of soft tissue that surrounds the prostate. However, today when the majority of men have organ confined disease, failure to remove all tumor may occur when there is iatrogenic incision into tumor that is confined to the prostate. This study investigates the impact of capsular incision into cancer on biochemical-free survival.
T
The significance of capsular incision into tumor at radical prostatectomy with otherwise organ confined disease is not well understood. Only a few studies have addressed the outcome of these cases and there is no consensus as to the prognostic significance. Some studies have suggested that capsular incision has no adverse impact while others report an increased risk of postoperative progression.1– 4 We previously reported on this issue in 2001.5 The current study differs from this earlier study in several aspects. We previously analyzed only 70 cases compared to 135 in the current study. The prior study included cases from 1993 to 2004 as opposed to current study period of 1993 to 2006 with longer followup. In contrast to a one-to-one matched pair analysis comparing cases with capsular incision to those with extraprostatic extension, the current work included our entire
Submitted for publication February 22, 2007. Nothing to disclose. * Correspondence: The Johns Hopkins Hospital, The Weinberg Building, Room 2242, 401 N. Broadway St., Baltimore, Maryland 21231 (e-mail: [email protected]).
Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1556 and 1557.
0022-5347/07/1784-1306/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
1306
Vol. 178, 1306-1310, October 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.05.159
POSITIVE SURGICAL MARGIN AND CAPSULAR INCISION AT RADICAL PROSTATECTOMY cohort of men with EPE as the comparison group. Whereas EPE was not subdivided in our initial study we have now subcategorized EPE into focal and extensive. Finally, in the current study each case was critically reviewed histologically using contemporary criteria for capsular incision, deleting cases that did not meet our strict criteria. MATERIALS AND METHODS Cases with capsular incision into tumor were identified from pathology reports at The Johns Hopkins Hospital (1993 to 2004) and histology was reviewed. Prostates were inked to determine the surgical margins and fixed in formalin. The proximal (bladder neck) margin was removed from the proximal urethral area as a 1 mm thin shave margin, and any tumor on the bladder neck margin slice was considered positive. The distal 5 to 8 mm of the prostate was amputated and then sectioned parallel to the urethra in 2 to 3 mm slices. Tumor at the inked perpendicular margins was considered a positive margin. Cases in which tumor extended to the inked margins in the same plane where benign prostatic acini also extended to the inked margins were considered to have a positive margin due to capsular incision. At the apex, if tumor unassociated with benign acini was seen at the inked edge, the tumor was considered to show extraprostatic extension with a positive margin. Following removal of the apical distal and proximal margins, the remaining prostate was sectioned at 2 to 3 mm intervals and entirely submitted for histological examination. Margin positivity in the remaining prostate was diagnosed when tumor extended to the inked edge of the tissue. All pelvic lymph nodes were submitted for pathological examination. Only cases meeting all of the criteria were included in this study, meaning only positive margin was in an area of capsular incision; elsewhere there was no EPE, seminal vesicle invasion or lymph node spread; the entire prostate was submitted for pathological examination; and there was no neoadjuvant therapy. We recorded tumor length at the capsular incision site, total length of tumor and benign prostate glands that extended to the ink in an area of capsular incision, capsular incision location overall Gleason score for the entire prostate carcinoma and the Gleason score of tumor at the area of capsular incision. In the uncommon case where tumor in an area of capsular incision was noncontiguous, tumor length was measured from one cancer focus to the other including intervening tissue. In cases with more than 1 focus of capsular incision, statistical analyses were based on the largest area of capsular incision. Any case with equivocal capsular incision vs EPE was excluded from study. Cases with capsular incision were compared to other previously defined pathological groups in our database during the same period, such as Gleason score 6 or 7 tumor which was organ confined margin negative (7,531), FEPE margin negative (1,223), FEPE margin positive (289), extensive EPE margin negative (835) and EEPE margin positive (433). The 135 radical prostatectomies with capsular incision represented 1.3% of the radical prostatectomies performed during this period with Gleason score 6 –7 and 1.8% of the radical prostatectomies with otherwise organ confined tumor during this period. Disease progression was defined as prostate specific antigen 0.2 ng/ml or greater. No patient in the capsular incision group underwent adjuvant therapy before recurrence.
1307
The probability of freedom from disease progression was estimated using the Kaplan-Meier method. Cases with or without capsular incision were compared using the Cox analysis. RESULTS Patients with capsular incision ranged from 43 to 70 years old (mean 57.5, median 58). Most patients (128, 94.8%) only had 1 area of capsular incision. Six patients had 2 different areas of capsular incision and one had 3 areas of capsular incision. The mean and median lengths of tumor at the capsular incision site were 2.6 and 2 mm, respectively (range less than 0.5 to 24 mm). The mean and median total lengths of tumor and benign prostate glands that extended to the ink in an area of capsular incision were 3.4 and 2.1 mm, respectively (range less than 0.5 to 47.5 mm). The location of capsular incision was posterolateral (61.5%), posterior (18.5%), anterior (8.9%), lateral (8.1%) and apical (3%). The overall grade in the capsular incision group was Gleason score 6 (98, 72.6%) and Gleason score 7 (37, 27.4%), similar to the proportion of cases without capsular incision with Gleason score 6 (6,716, 68.9%) and Gleason score 7 (3,037, 31.1%). The Gleason score at the capsular incision site was 6 (129, 95.6%) and 7 (6, 4.4%). A total of 113 patients had available followup information and all men without progression were followed for more than 1 year. There were 58 (51.3%) men with more than 3 years of followup and 20 (17.7%) with more than 5 years of followup. The 5-year actuarial freedom from recurrence was 96.7% for OC M⫺, 89.7% for FEPE M⫺, 78.6% for FEPE M⫹, 74% for EEPE M⫺, 71.3% for capsular incision into tumor and 58.5% for EEPE M⫹ (fig. 1). Men with capsular incision had a higher likelihood of progression than men with OC M⫺ (p ⬍0.0001) and FEPE M⫺ (p ⫽ 0.02). The risks of progression for men with capsular incision, FEPE M⫹ and EEPE M⫺ were not significantly different. Tumors with capsular incision had a greater likelihood of freedom from recurrence than tumors with EEPE M⫹ (p ⬍0.0001).
FIG. 1. Kaplan-Meier 5-year actuarial freedom from recurrence by pathological group. Short dash, organ confined margin negative. Long dash-dot, focal extraprostatic extension margin negative. Solid line, focal extraprostatic extension margin positive. Dots, extensive extraprostatic extension margin negative. Short dash-dot, capsular incision into tumor. Long dash, extraprostatic extension margin positive.
1308
POSITIVE SURGICAL MARGIN AND CAPSULAR INCISION AT RADICAL PROSTATECTOMY
FIG. 2. Kaplan-Meier 5-year actuarial freedom from recurrence by less than 3 mm (solid line) and 3 mm or greater (dash) of tumor at capsular incision site.
Comparing Gleason score 6 vs 7 at the capsular incision site was not significant (p ⫽ 0.05), yet there were only 6 men with Gleason score 7 at the capsular incision site. Risk of recurrence correlated with tumor length at the capsular incision site (p ⫽ 0.002). If there was less than 3 mm tumor at the capsular incision site, the 5-year risk of biochemical progression was 20.0% compared to 55% if there was 3 mm or more tumor cut across (fig. 2). The 5-year actuarial probability of local recurrence was 3.1%, and of the 3 men in whom local recurrence developed all had undetectable prostate specific antigen levels following radiotherapy. Distant metastases did not develop in any patients. DISCUSSION The percentage of positive surgical margins resulting from capsular incision into tumor varies widely (0% to 61%).6 –10 The data regarding the prognostic significance are also conflicting (see table).1– 4 Surgical procedures as well as the skill and experience of the urologist may also contribute to the highly variable incidence rate of capsular incision. However, one of the most important reasons for this variable rate relates to differences in histological assessment of capsular incision among pathologists. Varying definitions of capsular incision have been reported. As in the current study, some reports have defined it
as margin positive organ confined (pT2) disease, where the surgeon inadvertently developed the resection plane within rather than exterior to the prostate such that capsular incision was not only across tumor but also across adjacent benign prostate glands.1,3,6,11 Others have included capsular incision within a group of other equivocal margins including those that were artifactually positive.2,9 In addition, it is sometimes difficult to distinguish capsular incision into tumor from a positive margin with extraprostatic tumor. Some pathologists require identifying tumor in adipose tissue before being able to diagnose extraprostatic extension. However, prostate carcinoma often extends out of the prostate posteriorly and posterolaterally with an associated fibrotic reaction such that extraprostatic tumor is seen in fibrous rather than adipose tissue. Consequently pathologists may over diagnose capsular incision for what is really a positive margin associated with EPE and an associated desmoplastic response. In this study we carefully distinguished between these situations because of the well-known poor prognosis of EPE with positive margins.1– 4 A unique problem in distinguishing capsular incision from margin positivity with EPE is at the apex where the histological boundaries of the prostate are vague and benign prostate glands are seen admixed with skeletal muscle. When tumor is seen on the inked tissue edge at the apex, it can be subjective whether pathologists consider the tumor to be still within the prostate (ie capsular incision). Our approach has been that if tumor is seen extending to the inked tissue edge at the apex where benign glands are not cut across, we diagnose a positive margin in an area of EPE.12 The frequency with which capsular incision into tumor is diagnosed at the apex may also vary depending on the method used to section the apex. With a shave margin the most apical portion of the prostate is removed as a thin slice of tissue perpendicular to the urethra, where the entire slice is considered the margin. Because tumor often extends apically it is not uncommon to see benign glands next to tumor in this shave margin, resulting in a diagnosis of positive margin in an area of capsular incision. The preferred method of assessing apical margins is with perpendicular margins, where only tumor extending to the ink is considered a positive margin.12 With perpendicular margins many cases that would have been called capsular incision on a shave margin are in fact organ confined tumor with negative margins when analyzed with perpendicular margins. Because there is scant extraprostatic soft tissue surrounding many areas of a radical prostatectomy specimen,
Comparison of studies on capsular incision into tumor
Study yrs No. men in analysis No. capsular incisions into tumor Biochemical failure (ng/ml) Progression-free risk (yr) % Actuarial risk with capsular incision % Actuarial risk OC M⫺ % Actuarial risk EPE M⫺: Focal Nonfocal % Actuarial risk EPE M⫹: Focal Nonfocal
Ohori et al1
Boccon-Gibod et al4
Cheng et al3
Shuford et al2
Current Study
1983–1993 478 23 Greater than 0.4 5 100
1991–1996 94 19 Greater than 0.1 3 63
1986–1993 298 72 Greater than 0.2 5 78
1998–2000 200 18 Greater than 0.2 3 65
1993–2004 10,446 135 Greater than 0.2 5 71.3
95
100
90
96
96.7
84 —
⬇85 —
90 —
91 —
89.7 74
59 —
⬇40 —
55 —
58 —
78.6 58.5
POSITIVE SURGICAL MARGIN AND CAPSULAR INCISION AT RADICAL PROSTATECTOMY another difficulty in interpreting capsular incision is in distinguishing it from organ confined margin negative cancer where the tumor extends close to the inked edge of the prostate. Pathologists may over diagnose capsular incision in this setting. Only if tumor is seen on the inked irregular tissue edge of the prostate do we diagnose positive margins. To our knowledge the current study is the largest series to examine in detail tumor pathology at capsular incision. Most patients (128, 94.8%) only had 1 area of capsular incision, typically measuring a few millimeters in length. Isolated capsular incision into tumor in our study most commonly occurred in the neurovascular bundle region (61.5%), where urologists try to preserve potency and risk incision into the prostate. This anatomical region has also been noted by others to have the highest incidence of capsular incision.2,7 In our study the apex (3%) was the least common site of capsular incision. Other authors have reported a high incidence of capsular incision into tumor at the apex, although as stated the definition of capsular incision into tumor at the apex can vary significantly among pathologists and the diagnosis of capsular incision can depend on how the apex was processed histologically.8,9,13,14 In our study men with capsular incision had a worse likelihood of cure than men with OC M⫺ disease (p ⬍0.0001). Although Ohori et al suggested that the prognosis between capsular incision and OC M⫺ was not different, others have found similar adverse affects of capsular incision (see table).1– 4 In our study men with capsular incision had a better likelihood of cure than men with EEPE M⫹ (p ⬍0.0001). Although Shuford et al suggested the prognostic significance of capsular incision was similar to that of EPE M⫹,2 other studies supported our findings that there was a significantly lower risk of recurrence in cases with capsular incision compared to those with EPE M⫹.1– 4,9 To our knowledge the current study is the first to analyze cases with capsular incision into tumor in comparison to cases in which EPE has been subdivided into focal and more extensive EPE. We found that the risks of progression for men with capsular incision into tumor, FEPE M⫹ and EEPE M⫺ were not significantly different. The overall grade in our cases with capsular incision was Gleason score 6 (98, 72.6%) and Gleason score 7 (37, 27.4%). Only one other study has noted the overall Gleason score of tumors with capsular incision (ranging from 5 to 8).2 In our review cases with higher grade prostate cancer (Gleason score 8 –10) which showed capsular incision had other confounding adverse features such as EPE or positive margins in an area away from the site of capsular incision, or seminal vesicle invasion or lymph node metastases. We found only 1 case with Gleason score 4 ⫹ 5 ⫽ 9 with isolated capsular incision into tumor, which we excluded from analysis because it was a unique case that would not be comparable to the other cases. The Gleason score of tumor at the capsular incision site was 6 (129, 95.6%) and 7 (6, 4.4%) in our study. Comparing Gleason score 6 vs 7 tumor at the capsular incision site barely missed statistical significance (p ⫽ 0.05), yet there were only 6 men with Gleason score 7 tumor at the capsular incision site. With a larger number of cases, tumor grade at the capsular incision site may prove to be predictive. This issue has not been previously studied. To our knowledge our study is also the only one to demonstrate that the risk of recurrence correlated with tumor length at the capsular incision site (p ⫽ 0.002). If there was less than 3
1309
mm of tumor at the capsular incision site, the 5-year risk of biochemical progression was 20.0% compared to 55% if there was 3 mm or greater of tumor cut across. These data suggest that some indication in the pathology report as to the extent of capsular incision is warranted. CONCLUSIONS Isolated capsular incision into tumor is uncommon in radical prostatectomy specimens performed by experienced urologists and most commonly occurs in the neurovascular bundle region. Most men with capsular incision and otherwise OC disease typically have Gleason score 6 tumor. Men with isolated capsular incision have a significantly higher recurrence rate than patients with OC M⫺ and FEPE M⫺, yet a significantly lower recurrence rate than patients with EEPE M⫹. This information along with the extent of capsular incision can be factored in when counseling men with capsular incision in terms of postoperative chance of cure and consideration of adjuvant therapy.
Abbreviations and Acronyms EEPE EPE FEPE M⫹ M⫺ OC
⫽ ⫽ ⫽ ⫽ ⫽ ⫽
nonfocal extraprostatic extension extraprostatic extension focal extraprostatic extension margin positive margin negative organ confined
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
Ohori M, Wheeler TM, Kattan MW, Goto Y and Scardino PT: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1995; 154: 1818. Shuford MD, Cookson MS, Chang SS, Shintani AK, Tsiatis A, Smith JA Jr et al: Adverse prognostic significance of capsular incision with radical retropubic prostatectomy. J Urol 2004; 172: 119. Cheng L, Darson MF, Bergstralh EJ, Slezak J, Myers RP and Bostwick DG: Correlation of margin status and extraprostatic extension with progression of prostate carcinoma. Cancer 1999; 86: 1775. Boccon-Gibod L, Ravery V, Vordos D, Toublanc M, Delmas V and Boccon-Gibod L: Radical prostatectomy for prostate cancer: the perineal approach increases the risk of surgically induced positive margins and capsular incisions. J Urol 1998; 160: 1383. Barocas DA, Han M, Epstein JI, Chan DY, Trock BJ, Walsh PC et al: Does capsular incision at radical retropubic prostatectomy affect disease-free survival in otherwise organ-confined prostate cancer? Urology 2001; 58: 746. van den Ouden D, Bentvelsen FM, Boeve ER and Schroder FH: Positive margins after radical prostatectomy: correlation with local recurrence and distant progression. Br J Urol 1993; 72: 489. Rosen MA, Goldstone L, Lapin S, Wheeler T and Scardino PT: Frequency and location of extracapsular extension and positive surgical margins in radical prostatectomy specimens. J Urol 1992; 148: 331. Stamey TA, Villers AA, McNeal JE, Link PC and Freiha FS: Positive surgical margins at radical prostatectomy: importance of the apical dissection. J Urol 1990; 143: 1166. Watson RB, Civantos F and Soloway MS: Positive surgical margins with radical prostatectomy: detailed pathological analysis and prognosis. Urology 1996; 48: 80.
1310 10.
11.
12.
POSITIVE SURGICAL MARGIN AND CAPSULAR INCISION AT RADICAL PROSTATECTOMY
Weldon VE, Tavel FR, Neuwirth H and Cohen R: Patterns of positive specimen margins and detectable prostate specific antigen after radical perineal prostatectomy. J Urol 1995; 153: 1565. Epstein JI: Incidence and significance of positive margins in radical prostatectomy specimens. Urol Clin North Am 1996; 23: 651. Epstein JI, Amin M, Boccon-Gibod L, Egevad L, Humphrey PA, Mikuz G et al: Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic
13.
14.
lymphadenectomy specimens. Scand J Urol Nephrol, suppl., 2005; 216: 34. Ackerman DA, Barry JM, Wicklund RA, Olson N and Lowe BA: Analysis of risk factors associated with prostate cancer extension to the surgical margin and pelvic node metastasis at radical prostatectomy. J Urol 1993; 150: 1845. Blute ML, Bostwick DG, Bergstralh EJ, Slezak JM, Martin SK, Amling CL et al: Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on outcome after radical prostatectomy. Urology 1997; 50: 733.
Purpose: The significance of capsular incision into tumor at radical prostatectomy with otherwise organ confined tumor is not well understood. Materials and Methods: Inclusion criteria were positive margin in an area of capsular incision, no extraprostatic extension elsewhere, negative seminal vesicles and lymph nodes, entire prostate submitted for examination, and no neoadjuvant therapy. Results: The postoperative progression of 135 cases of radical prostatectomy with capsular incision (1.3% of radical prostatectomies 1993 to 2004) was compared to 10,311 radical prostatectomies without capsular incision. Mean tumor length at the capsular incision site was 2.6 mm. Capsular incision was posterolateral (61.5%), posterior (18.5%), anterior (8.9%), lateral (8.1%) and apical (3%). The 5-year actuarial freedom from biochemical recurrence for tumors with capsular incision was worse (71.3%) than organ confined margin negative tumor (96.7%) (p ⬍0.0001) and focal extraprostatic extension margin negative disease (89.7%) (p ⫽ 0.02), yet better than extensive extraprostatic extension margin positive tumors (58.5%) (p ⬍0.0001). The risks of progression in men with capsular incision, focal extraprostatic extension margin positive and extensive extraprostatic extension margin negative disease were not significantly different. Risk of recurrence correlated with tumor length at the capsular incision site (p ⫽ 0.002). The 5-year risks of biochemical progression were 20.0% and 55% for less than 3 mm and 3 mm or greater of tumor cut across, respectively. Conclusions: Isolated capsular incision into tumor is uncommon in cases of radical prostatectomy performed by experienced urologists, typically Gleason score 6, and most common in the neurovascular bundle region. Isolated capsular incision has a higher recurrence rate than organ confined or focal extraprostatic extension margin negative disease, yet a lower recurrence rate than extensive extraprostatic extension margin positive tumor, and a worse prognosis with greater extent of capsular incision. Key Words: prostate, prostatectomy, survival
he controversy surrounding the importance of capsular incision in men with organ confined disease has been brought into focus with increased interest in less invasive approaches to radical prostatectomy. There is no better way to cure cancer that is localized to the prostate than total surgical removal, and to effectively achieve this goal every attempt must be made to excise all tumor. In the past when patients presented with extensive extraprostatic extension this was often impossible because of the limited amount of soft tissue that surrounds the prostate. However, today when the majority of men have organ confined disease, failure to remove all tumor may occur when there is iatrogenic incision into tumor that is confined to the prostate. This study investigates the impact of capsular incision into cancer on biochemical-free survival.
T
The significance of capsular incision into tumor at radical prostatectomy with otherwise organ confined disease is not well understood. Only a few studies have addressed the outcome of these cases and there is no consensus as to the prognostic significance. Some studies have suggested that capsular incision has no adverse impact while others report an increased risk of postoperative progression.1– 4 We previously reported on this issue in 2001.5 The current study differs from this earlier study in several aspects. We previously analyzed only 70 cases compared to 135 in the current study. The prior study included cases from 1993 to 2004 as opposed to current study period of 1993 to 2006 with longer followup. In contrast to a one-to-one matched pair analysis comparing cases with capsular incision to those with extraprostatic extension, the current work included our entire
Submitted for publication February 22, 2007. Nothing to disclose. * Correspondence: The Johns Hopkins Hospital, The Weinberg Building, Room 2242, 401 N. Broadway St., Baltimore, Maryland 21231 (e-mail: [email protected]).
Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1556 and 1557.
0022-5347/07/1784-1306/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
1306
Vol. 178, 1306-1310, October 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.05.159
POSITIVE SURGICAL MARGIN AND CAPSULAR INCISION AT RADICAL PROSTATECTOMY cohort of men with EPE as the comparison group. Whereas EPE was not subdivided in our initial study we have now subcategorized EPE into focal and extensive. Finally, in the current study each case was critically reviewed histologically using contemporary criteria for capsular incision, deleting cases that did not meet our strict criteria. MATERIALS AND METHODS Cases with capsular incision into tumor were identified from pathology reports at The Johns Hopkins Hospital (1993 to 2004) and histology was reviewed. Prostates were inked to determine the surgical margins and fixed in formalin. The proximal (bladder neck) margin was removed from the proximal urethral area as a 1 mm thin shave margin, and any tumor on the bladder neck margin slice was considered positive. The distal 5 to 8 mm of the prostate was amputated and then sectioned parallel to the urethra in 2 to 3 mm slices. Tumor at the inked perpendicular margins was considered a positive margin. Cases in which tumor extended to the inked margins in the same plane where benign prostatic acini also extended to the inked margins were considered to have a positive margin due to capsular incision. At the apex, if tumor unassociated with benign acini was seen at the inked edge, the tumor was considered to show extraprostatic extension with a positive margin. Following removal of the apical distal and proximal margins, the remaining prostate was sectioned at 2 to 3 mm intervals and entirely submitted for histological examination. Margin positivity in the remaining prostate was diagnosed when tumor extended to the inked edge of the tissue. All pelvic lymph nodes were submitted for pathological examination. Only cases meeting all of the criteria were included in this study, meaning only positive margin was in an area of capsular incision; elsewhere there was no EPE, seminal vesicle invasion or lymph node spread; the entire prostate was submitted for pathological examination; and there was no neoadjuvant therapy. We recorded tumor length at the capsular incision site, total length of tumor and benign prostate glands that extended to the ink in an area of capsular incision, capsular incision location overall Gleason score for the entire prostate carcinoma and the Gleason score of tumor at the area of capsular incision. In the uncommon case where tumor in an area of capsular incision was noncontiguous, tumor length was measured from one cancer focus to the other including intervening tissue. In cases with more than 1 focus of capsular incision, statistical analyses were based on the largest area of capsular incision. Any case with equivocal capsular incision vs EPE was excluded from study. Cases with capsular incision were compared to other previously defined pathological groups in our database during the same period, such as Gleason score 6 or 7 tumor which was organ confined margin negative (7,531), FEPE margin negative (1,223), FEPE margin positive (289), extensive EPE margin negative (835) and EEPE margin positive (433). The 135 radical prostatectomies with capsular incision represented 1.3% of the radical prostatectomies performed during this period with Gleason score 6 –7 and 1.8% of the radical prostatectomies with otherwise organ confined tumor during this period. Disease progression was defined as prostate specific antigen 0.2 ng/ml or greater. No patient in the capsular incision group underwent adjuvant therapy before recurrence.
1307
The probability of freedom from disease progression was estimated using the Kaplan-Meier method. Cases with or without capsular incision were compared using the Cox analysis. RESULTS Patients with capsular incision ranged from 43 to 70 years old (mean 57.5, median 58). Most patients (128, 94.8%) only had 1 area of capsular incision. Six patients had 2 different areas of capsular incision and one had 3 areas of capsular incision. The mean and median lengths of tumor at the capsular incision site were 2.6 and 2 mm, respectively (range less than 0.5 to 24 mm). The mean and median total lengths of tumor and benign prostate glands that extended to the ink in an area of capsular incision were 3.4 and 2.1 mm, respectively (range less than 0.5 to 47.5 mm). The location of capsular incision was posterolateral (61.5%), posterior (18.5%), anterior (8.9%), lateral (8.1%) and apical (3%). The overall grade in the capsular incision group was Gleason score 6 (98, 72.6%) and Gleason score 7 (37, 27.4%), similar to the proportion of cases without capsular incision with Gleason score 6 (6,716, 68.9%) and Gleason score 7 (3,037, 31.1%). The Gleason score at the capsular incision site was 6 (129, 95.6%) and 7 (6, 4.4%). A total of 113 patients had available followup information and all men without progression were followed for more than 1 year. There were 58 (51.3%) men with more than 3 years of followup and 20 (17.7%) with more than 5 years of followup. The 5-year actuarial freedom from recurrence was 96.7% for OC M⫺, 89.7% for FEPE M⫺, 78.6% for FEPE M⫹, 74% for EEPE M⫺, 71.3% for capsular incision into tumor and 58.5% for EEPE M⫹ (fig. 1). Men with capsular incision had a higher likelihood of progression than men with OC M⫺ (p ⬍0.0001) and FEPE M⫺ (p ⫽ 0.02). The risks of progression for men with capsular incision, FEPE M⫹ and EEPE M⫺ were not significantly different. Tumors with capsular incision had a greater likelihood of freedom from recurrence than tumors with EEPE M⫹ (p ⬍0.0001).
FIG. 1. Kaplan-Meier 5-year actuarial freedom from recurrence by pathological group. Short dash, organ confined margin negative. Long dash-dot, focal extraprostatic extension margin negative. Solid line, focal extraprostatic extension margin positive. Dots, extensive extraprostatic extension margin negative. Short dash-dot, capsular incision into tumor. Long dash, extraprostatic extension margin positive.
1308
POSITIVE SURGICAL MARGIN AND CAPSULAR INCISION AT RADICAL PROSTATECTOMY
FIG. 2. Kaplan-Meier 5-year actuarial freedom from recurrence by less than 3 mm (solid line) and 3 mm or greater (dash) of tumor at capsular incision site.
Comparing Gleason score 6 vs 7 at the capsular incision site was not significant (p ⫽ 0.05), yet there were only 6 men with Gleason score 7 at the capsular incision site. Risk of recurrence correlated with tumor length at the capsular incision site (p ⫽ 0.002). If there was less than 3 mm tumor at the capsular incision site, the 5-year risk of biochemical progression was 20.0% compared to 55% if there was 3 mm or more tumor cut across (fig. 2). The 5-year actuarial probability of local recurrence was 3.1%, and of the 3 men in whom local recurrence developed all had undetectable prostate specific antigen levels following radiotherapy. Distant metastases did not develop in any patients. DISCUSSION The percentage of positive surgical margins resulting from capsular incision into tumor varies widely (0% to 61%).6 –10 The data regarding the prognostic significance are also conflicting (see table).1– 4 Surgical procedures as well as the skill and experience of the urologist may also contribute to the highly variable incidence rate of capsular incision. However, one of the most important reasons for this variable rate relates to differences in histological assessment of capsular incision among pathologists. Varying definitions of capsular incision have been reported. As in the current study, some reports have defined it
as margin positive organ confined (pT2) disease, where the surgeon inadvertently developed the resection plane within rather than exterior to the prostate such that capsular incision was not only across tumor but also across adjacent benign prostate glands.1,3,6,11 Others have included capsular incision within a group of other equivocal margins including those that were artifactually positive.2,9 In addition, it is sometimes difficult to distinguish capsular incision into tumor from a positive margin with extraprostatic tumor. Some pathologists require identifying tumor in adipose tissue before being able to diagnose extraprostatic extension. However, prostate carcinoma often extends out of the prostate posteriorly and posterolaterally with an associated fibrotic reaction such that extraprostatic tumor is seen in fibrous rather than adipose tissue. Consequently pathologists may over diagnose capsular incision for what is really a positive margin associated with EPE and an associated desmoplastic response. In this study we carefully distinguished between these situations because of the well-known poor prognosis of EPE with positive margins.1– 4 A unique problem in distinguishing capsular incision from margin positivity with EPE is at the apex where the histological boundaries of the prostate are vague and benign prostate glands are seen admixed with skeletal muscle. When tumor is seen on the inked tissue edge at the apex, it can be subjective whether pathologists consider the tumor to be still within the prostate (ie capsular incision). Our approach has been that if tumor is seen extending to the inked tissue edge at the apex where benign glands are not cut across, we diagnose a positive margin in an area of EPE.12 The frequency with which capsular incision into tumor is diagnosed at the apex may also vary depending on the method used to section the apex. With a shave margin the most apical portion of the prostate is removed as a thin slice of tissue perpendicular to the urethra, where the entire slice is considered the margin. Because tumor often extends apically it is not uncommon to see benign glands next to tumor in this shave margin, resulting in a diagnosis of positive margin in an area of capsular incision. The preferred method of assessing apical margins is with perpendicular margins, where only tumor extending to the ink is considered a positive margin.12 With perpendicular margins many cases that would have been called capsular incision on a shave margin are in fact organ confined tumor with negative margins when analyzed with perpendicular margins. Because there is scant extraprostatic soft tissue surrounding many areas of a radical prostatectomy specimen,
Comparison of studies on capsular incision into tumor
Study yrs No. men in analysis No. capsular incisions into tumor Biochemical failure (ng/ml) Progression-free risk (yr) % Actuarial risk with capsular incision % Actuarial risk OC M⫺ % Actuarial risk EPE M⫺: Focal Nonfocal % Actuarial risk EPE M⫹: Focal Nonfocal
Ohori et al1
Boccon-Gibod et al4
Cheng et al3
Shuford et al2
Current Study
1983–1993 478 23 Greater than 0.4 5 100
1991–1996 94 19 Greater than 0.1 3 63
1986–1993 298 72 Greater than 0.2 5 78
1998–2000 200 18 Greater than 0.2 3 65
1993–2004 10,446 135 Greater than 0.2 5 71.3
95
100
90
96
96.7
84 —
⬇85 —
90 —
91 —
89.7 74
59 —
⬇40 —
55 —
58 —
78.6 58.5
POSITIVE SURGICAL MARGIN AND CAPSULAR INCISION AT RADICAL PROSTATECTOMY another difficulty in interpreting capsular incision is in distinguishing it from organ confined margin negative cancer where the tumor extends close to the inked edge of the prostate. Pathologists may over diagnose capsular incision in this setting. Only if tumor is seen on the inked irregular tissue edge of the prostate do we diagnose positive margins. To our knowledge the current study is the largest series to examine in detail tumor pathology at capsular incision. Most patients (128, 94.8%) only had 1 area of capsular incision, typically measuring a few millimeters in length. Isolated capsular incision into tumor in our study most commonly occurred in the neurovascular bundle region (61.5%), where urologists try to preserve potency and risk incision into the prostate. This anatomical region has also been noted by others to have the highest incidence of capsular incision.2,7 In our study the apex (3%) was the least common site of capsular incision. Other authors have reported a high incidence of capsular incision into tumor at the apex, although as stated the definition of capsular incision into tumor at the apex can vary significantly among pathologists and the diagnosis of capsular incision can depend on how the apex was processed histologically.8,9,13,14 In our study men with capsular incision had a worse likelihood of cure than men with OC M⫺ disease (p ⬍0.0001). Although Ohori et al suggested that the prognosis between capsular incision and OC M⫺ was not different, others have found similar adverse affects of capsular incision (see table).1– 4 In our study men with capsular incision had a better likelihood of cure than men with EEPE M⫹ (p ⬍0.0001). Although Shuford et al suggested the prognostic significance of capsular incision was similar to that of EPE M⫹,2 other studies supported our findings that there was a significantly lower risk of recurrence in cases with capsular incision compared to those with EPE M⫹.1– 4,9 To our knowledge the current study is the first to analyze cases with capsular incision into tumor in comparison to cases in which EPE has been subdivided into focal and more extensive EPE. We found that the risks of progression for men with capsular incision into tumor, FEPE M⫹ and EEPE M⫺ were not significantly different. The overall grade in our cases with capsular incision was Gleason score 6 (98, 72.6%) and Gleason score 7 (37, 27.4%). Only one other study has noted the overall Gleason score of tumors with capsular incision (ranging from 5 to 8).2 In our review cases with higher grade prostate cancer (Gleason score 8 –10) which showed capsular incision had other confounding adverse features such as EPE or positive margins in an area away from the site of capsular incision, or seminal vesicle invasion or lymph node metastases. We found only 1 case with Gleason score 4 ⫹ 5 ⫽ 9 with isolated capsular incision into tumor, which we excluded from analysis because it was a unique case that would not be comparable to the other cases. The Gleason score of tumor at the capsular incision site was 6 (129, 95.6%) and 7 (6, 4.4%) in our study. Comparing Gleason score 6 vs 7 tumor at the capsular incision site barely missed statistical significance (p ⫽ 0.05), yet there were only 6 men with Gleason score 7 tumor at the capsular incision site. With a larger number of cases, tumor grade at the capsular incision site may prove to be predictive. This issue has not been previously studied. To our knowledge our study is also the only one to demonstrate that the risk of recurrence correlated with tumor length at the capsular incision site (p ⫽ 0.002). If there was less than 3
1309
mm of tumor at the capsular incision site, the 5-year risk of biochemical progression was 20.0% compared to 55% if there was 3 mm or greater of tumor cut across. These data suggest that some indication in the pathology report as to the extent of capsular incision is warranted. CONCLUSIONS Isolated capsular incision into tumor is uncommon in radical prostatectomy specimens performed by experienced urologists and most commonly occurs in the neurovascular bundle region. Most men with capsular incision and otherwise OC disease typically have Gleason score 6 tumor. Men with isolated capsular incision have a significantly higher recurrence rate than patients with OC M⫺ and FEPE M⫺, yet a significantly lower recurrence rate than patients with EEPE M⫹. This information along with the extent of capsular incision can be factored in when counseling men with capsular incision in terms of postoperative chance of cure and consideration of adjuvant therapy.
Abbreviations and Acronyms EEPE EPE FEPE M⫹ M⫺ OC
⫽ ⫽ ⫽ ⫽ ⫽ ⫽
nonfocal extraprostatic extension extraprostatic extension focal extraprostatic extension margin positive margin negative organ confined
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
Ohori M, Wheeler TM, Kattan MW, Goto Y and Scardino PT: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1995; 154: 1818. Shuford MD, Cookson MS, Chang SS, Shintani AK, Tsiatis A, Smith JA Jr et al: Adverse prognostic significance of capsular incision with radical retropubic prostatectomy. J Urol 2004; 172: 119. Cheng L, Darson MF, Bergstralh EJ, Slezak J, Myers RP and Bostwick DG: Correlation of margin status and extraprostatic extension with progression of prostate carcinoma. Cancer 1999; 86: 1775. Boccon-Gibod L, Ravery V, Vordos D, Toublanc M, Delmas V and Boccon-Gibod L: Radical prostatectomy for prostate cancer: the perineal approach increases the risk of surgically induced positive margins and capsular incisions. J Urol 1998; 160: 1383. Barocas DA, Han M, Epstein JI, Chan DY, Trock BJ, Walsh PC et al: Does capsular incision at radical retropubic prostatectomy affect disease-free survival in otherwise organ-confined prostate cancer? Urology 2001; 58: 746. van den Ouden D, Bentvelsen FM, Boeve ER and Schroder FH: Positive margins after radical prostatectomy: correlation with local recurrence and distant progression. Br J Urol 1993; 72: 489. Rosen MA, Goldstone L, Lapin S, Wheeler T and Scardino PT: Frequency and location of extracapsular extension and positive surgical margins in radical prostatectomy specimens. J Urol 1992; 148: 331. Stamey TA, Villers AA, McNeal JE, Link PC and Freiha FS: Positive surgical margins at radical prostatectomy: importance of the apical dissection. J Urol 1990; 143: 1166. Watson RB, Civantos F and Soloway MS: Positive surgical margins with radical prostatectomy: detailed pathological analysis and prognosis. Urology 1996; 48: 80.
1310 10.
11.
12.
POSITIVE SURGICAL MARGIN AND CAPSULAR INCISION AT RADICAL PROSTATECTOMY
Weldon VE, Tavel FR, Neuwirth H and Cohen R: Patterns of positive specimen margins and detectable prostate specific antigen after radical perineal prostatectomy. J Urol 1995; 153: 1565. Epstein JI: Incidence and significance of positive margins in radical prostatectomy specimens. Urol Clin North Am 1996; 23: 651. Epstein JI, Amin M, Boccon-Gibod L, Egevad L, Humphrey PA, Mikuz G et al: Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic
13.
14.
lymphadenectomy specimens. Scand J Urol Nephrol, suppl., 2005; 216: 34. Ackerman DA, Barry JM, Wicklund RA, Olson N and Lowe BA: Analysis of risk factors associated with prostate cancer extension to the surgical margin and pelvic node metastasis at radical prostatectomy. J Urol 1993; 150: 1845. Blute ML, Bostwick DG, Bergstralh EJ, Slezak JM, Martin SK, Amling CL et al: Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on outcome after radical prostatectomy. Urology 1997; 50: 733.