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Should the involvement of skeletal muscle by prostatic adenocarcinoma be reported on biopsies?
Should the Involvement of Skeletal Muscle by Prostatic Adenocarcinoma be Reported on Biopsies? Evita T. Sadimin MD, Huihui Ye MD, Jonathan I. Epstein MD PII: DOI: Reference:
S0046-8177(15)00440-2 doi: 10.1016/j.humpath.2015.10.010 YHUPA 3742
To appear in:
Human Pathology
Received date: Revised date: Accepted date:
2 September 2015 9 October 2015 16 October 2015
Please cite this article as: Sadimin Evita T., Ye Huihui, Epstein Jonathan I., Should the Involvement of Skeletal Muscle by Prostatic Adenocarcinoma be Reported on Biopsies?, Human Pathology (2015), doi: 10.1016/j.humpath.2015.10.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
SHOULD THE INVOLVEMENT OF SKELETAL MUSCLE BY PROSTATIC ADENOCARCINOMA BE REPORTED ON BIOPSIES?
1
RI P
T
Evita T. Sadimin, MD1, Huihui Ye, MD2, Jonathan I. Epstein, MD1 Department of Pathology, Urology and Oncology
2
SC
The Johns Hopkins Medical Institutions, Baltimore, MD Department of Pathology
NU
Beth Israel Deaconess Medical Center, Boston, MA
MA
Running title: Prostatic adenocarcinoma involving skeletal muscle
CE
Corresponding author:
PT
ED
Keywords: prostatic adenocarcinoma; skeletal muscle; positive apical margin; distal apex; anterior apex
Jonathan I. Epstein, MD
AC
Department of Pathology
The Johns Hopkins Hospital 401 N Broadway St, Weinberg Rm 2242 Baltimore, MD 21231 Phone: (410) 955-5043 Fax: (443) 287-3818 e-mail: [email protected]
Conflicts of interest: The authors declare no conflict of interest associated with this work. Funding disclosures: The authors have no relevant financial relationships to disclose.
ACCEPTED MANUSCRIPT 2
ABSTRACT Skeletal muscle is seen at the distal part of the prostate apex, where benign glands may reside as
RI P
T
part of normal anatomy and histology, and extends more proximally anteriorly. At times, prostatic adenocarcinoma can be seen admixed with skeletal muscle, raising the question of
SC
extraprostatic extension. While there has been increased attention regarding biopsy sampling of the distal apex to guide the performing of the apical dissection on radical prostatectomy, the
NU
finding of skeletal muscle involvement by prostatic adenocarcinoma has not been consistently
MA
reported by pathologists on biopsies. We searched our database spanning 12 years from 2000 to 2012 for all patients who had prostatic adenocarcinoma Gleason score 3+3=6 involving skeletal
ED
muscle on biopsy. We identified 220 patients who met the criteria. Of the 220 patients, 101 underwent prostatectomy which comprised the “study group”. Prostatectomy reports from these
PT
patients were compared with those of a “control group”, which consisted of 201
CE
contemporaneous patients with Gleason score 3+3=6 prostatic adenocarcinoma on biopsy without skeletal muscle involvement. The results showed a significantly higher percentage of
AC
positive margins in the study group compared to the control group (p=0.006). The study group also had a higher percent of positive margins at the apex admixed with skeletal muscle (p=0.008). In summary, the findings in this study support that pathologists should report the involvement of skeletal muscle by tumor, and recommended that urologists performing radical prostatectomies on these patients try to ensure adequate excision in the apical area to avoid positive apical margin.
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INTRODUCTION The human prostate is composed of a complex arrangement of glandular epithelium and
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T
fibromuscular stroma. At the posterior part of the prostate, there is a distinct border between the fibromuscular stroma and the extraprostatic fibroadipose tissue. In contrast, there is no distinct
SC
boundary at the anterior part of the prostate, where smooth muscle of the prostate merges with the extraprostatic tissue. The skeletal muscle fibers of the urogenital diaphragm are present from
NU
the distal apex up to the mid anterior area of the prostate, where at the distal apex they can be
MA
seen admixed with benign prostate glands (figure 1A,B) [1]. While biopsy of the mid prostate usually does not contain skeletal muscle fibers because they are far too anterior, they can often
ED
be seen on apical biopsy.
Approximately 20-26% of prostatic adenocarcinoma is found in the apical area, defined as the
PT
distal one third of the prostate [2–4]. At times, it can be seen extending into the skeletal muscle
CE
in the distal or anterior apex (figure 1C,D). In prostatectomy specimens, positive apical margins
AC
can be seen in these areas where cancer is admixed with skeletal muscle at the inked margin (figure 1E) in contrast to more proximally or posteriorly where cancer extends to the inked margin without being admixed with skeletal muscle (figure 1F). The significance of skeletal muscle involvement by prostatic adenocarcinoma on biopsy has only rarely been studied from the pathologic point of view, and only in cases involving a limited amount of tumor on biopsy [5]. Consequently, most pathologists do not include this finding routinely on prostate biopsy reports. On the other hand, urologists have recognized the distal apical area as a challenging area in obtaining biopsies and in surgical dissection during prostatectomy. Biopsy of the distal apex especially anteriorly is associated with further
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advancement of the biopsy needle and more pain and discomfort [6]. Apical dissection during radical prostatectomy is challenging due to variation in the shapes of the prostate apex, the rich
T
neurovascular supply and the intermingling muscle layers [7], leading to a dilemma between
RI P
risking positive margin by attempting to preserve the neurovascular bundle in this area or
SC
significant incontinence by doing more extensive apical dissection.
In this study, we analyzed radical prostatectomy findings of patients whose prior biopsies
NU
showed prostatic adenocarcinoma Gleason score 3+3=6 involving skeletal muscle, reviewed and
MA
compared all the positive apical margins in both the control and study groups, and discussed the
ED
importance of including this finding on biopsy reports.
PT
MATERIALS AND METHODS
CE
This study was performed under the approval of Johns Hopkins institutional review board (IRB). We searched the database of both our routine in-house and consult cases spanning 12
AC
years from 2000 to 2012 and identified 220 patients with prostatic adenocarcinoma Gleason score 3+3=6 involving skeletal muscle on the biopsy. This study was limited to only include those with low grade prostatic adenocarcinoma to avoid potential adverse findings bias that could be attributed to the more aggressive behavior of high grade cancer rather than the skeletal muscle involvement. Of the 220 patients, 101 underwent prostatectomy, 41 underwent radiation therapy, 3 underwent androgen deprivation therapy and 29 were lost to follow up. We focused on the 101 patients who underwent prostatectomy. These patients were designated as the “study group”. For the “control group”, we obtained the prostatectomy reports of 201 routine in-house
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consecutive cases whose biopsies showed prostatic adenocarcinoma Gleason score 3+3=6 without skeletal muscle involvement.
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The pathology reports for both groups were retrieved and the findings tabulated. All cases with positive apical margins on prostatectomy were retrieved and reviewed. Final Gleason score,
SC
margins status, presence of extraprostatic extension, seminal vesicle involvement and lymph node involvement in the two groups were compared. The apex was defined as the distal one-third
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of the prostate distal to the verumontanum. In cases with positive apical margins, we recorded
MA
whether the margin was positive in the area where skeletal muscle fibers were present.
ED
RESULTS
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The distributions of percent number of positive cores in the study group and the control
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group were similar (figure 2). Comparison of the prostatectomy findings of the 101 patients in the study group and the 201 patients in the control group revealed a significantly higher
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percentage of positive margins in the study group compared to the control group (p=0.006). There was no significant difference in the distribution of final Gleason score and the presence of extraprostatic extension (table 1). The majority of patients with prostatic adenocarcinoma Gleason score 3+3=6 in the biopsy had the same final Gleason score on prostatectomy. Six patients were found to have no residual cancer. In both groups most patients had organ confined disease (table 1). Additionally, only 1% of patients in the study group and 1.5% of patients in the control group had seminal vesicle involvement. None of the patients had lymph node involvement.
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When assessing extraprostatic extension of tumor in the apical area, only tumor in the fat was considered as extraprostatic extension. In cases where the tumor was transected in the area of the
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skeletal muscle, it was considered uncertain whether the disease was still organ confined due to
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ambiguities of the boundary of the prostate at this site, hence their designation as ambiguous (pT2x) A higher percentage of ambiguous cases were seen in the study group (10.9%) compared
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to the control group (1.0%) (table 1).
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Positive margins were more commonly seen in the apex in both groups (table 2). Although a
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higher percentage of positive apical margins were observed in the study group, the difference in the overall distribution of the positive margins was not significant. Review of all the cases with
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positive apical margins showed that in the study group 78.6% of the positive apical margins are at the most distal apex with admixed skeletal muscle fibers compared to the control group where
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77.8% of the positive margins were in the posterior apex (p=0.008) (table 3). The biopsies prior
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to the prostatectomy of the two patients in the control group who had positive apical margins
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admixed with skeletal muscle did not have cancer present in the apex on the biopsy.
DISCUSSION
Our study demonstrated that skeletal muscle involvement by prostatic adenocarcinoma in biopsies was associated with an overall increased risk of having positive margin in the corresponding radical prostatectomy specimen and especially at the distal apical area at prostatectomy though most patients still had organ confined disease with negative margins and no lymph node involvements. The upgrading rate on prostatectomy seen in our study is consistent with previous studies and reflects the undersampling of higher grade cancer on biopsy
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[8]. The positive surgical margins in both groups were mostly found at the apex, similar to the findings in another study[9]. Patients with positive surgical margin in the radical prostatectomy
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have been shown to have higher risk for disease progression compared to those with negative
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margins [10,11]. This risk was also observed specifically with positive surgical margin at the apex [12]. Furthermore, in some studies, positive apical surgical margin showed association with
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worse prognosis [13,14]. These studies, however, did not specify whether the positive apical
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surgical margin involved the distal or anterior apical areas admixed with skeletal muscle or the
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more posterior region of the apex.
The distal and anterior apex of the prostate where the skeletal muscle is located is often not
ED
consistently biopsied. Several studies looking into the standard 12 core biopsy showed that the this area of the prostate was often undersampled [15,16]. When adequately sampled, patients
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with normal DRE have been found to have a higher cancer detection rate in this site [16–18].
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Further supporting the importance of adequate sampling, the anterior apical biopsies have been shown to have the highest yield of cancer compared to all of the cores from other sites [19,20].
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Some studies have found that increased sampling of the anterior apical biopsy improved overall prostate cancer detection [6,21]. The American Urological Association recently recommended that a 12-core prostate biopsy should incorporate apical area, including distal and anterior apex [22,23]. Consequently, as seen in two of our control cases, undersampling of the apex may have caused an underestimation of the number of patients in our study group as these two cases would have been part of our study group if their biopsies included the distal or anterior apex. With increased awareness and therefore increased sampling of this area, it would be reasonable for pathologists to expect to see more prostatic adenocarcinoma involving skeletal muscle in biopsy specimens.
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Tumors residing in the anterior apex are less likely to be palpable, and not readily identifiable on traditional MRI, increasing the challenge of adequate sampling. There have been suggestions to
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utilize imaging such as multiparametric MRI or MRI/ultrasound fusion to guide biopsies of this
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area [24]. Tumors at the anterior apical area have similar clinical significance compared to tumors from other sites, again emphasizing the importance of detecting cancers in this area [4].
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Additionally, non-surgical treatments may be less effective for distal apical tumors. One study
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showed that residual cancer after high-intensity focused ultrasonography (HIFU) ablation was
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mostly found in the distal apex [3].
By reporting the presence of tumor in the skeletal muscle, pathologists could help urologists
ED
make decisions whether specific attention would be necessary for the apical area. Urologists may decide to extend the apical dissection during prostatectomy [5,9] when there is tumor in the
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skeletal muscle on biopsy, while they may not otherwise. Furthermore, utilizing MRI to plan the
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apical dissection in prostatectomy may be beneficial in being able to avoid a positive apical margin [25]. Dissection of the apical area is recognized as a challenging task, with more
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experience surgeons having fewer patients with positive apical surgical margins compared to the less experience surgeons. This difference was not observed in non-apical margins [26]. In our control group, skeletal muscles were not consistently present, reflecting that the anterior or distal apical region was often not sampled. Some urologists at our institution who saw reports with skeletal muscle involvement by tumor on the biopsy took the extra precaution on dissecting the apical area, preventing a positive margin in an otherwise what could have been a positive margin. These factors may have lessened the significance of the relationship between having tumor involving skeletal muscle in the prostate biopsy with having positive margin in the prostatectomy in the area of the distal or anterior apex in our study.
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One previous study showed a similar finding that apical positivity on biopsy corresponded to increased likelihood of having positive margin in the prostatectomy [27]. In this prior study it did
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not specify the involvement of skeletal muscle and if the positive margins were associated with
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the presence of tumor within the skeletal muscle. In our study, there was a significant difference in the location of the positive apical margins between the two groups, where in the study group
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they were at the distal apex with admixed skeletal muscle, and in the control group they were at
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the more proximal apex. Additionally, the percentage of positive apical margins at the more proximal apex in both groups were similar, 3 cases out of 101 total number of cases (2.9%) in the
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study group versus 7 cases out of 201 total number of cases (3.5%) in the control group. This showed that the overall increased number of positive apical margins in the study group could
ED
only be attributed to the presence of tumor in the skeletal muscle.
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In summary, the findings in this study highlight the importance of distal or anterior apical
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sampling in prostate biopsies, suggested that pathologists should report the involvement of skeletal muscle by tumor, and recommended that urologists performing radical prostatectomies
margin.
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on these patients try to ensure adequate excision in the apical area to avoid positive apical
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LEGENDS Figure 1. Benign prostatic glands in skeletal muscle on core biopsy (A) and on prostatectomy (B)
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as part of normal anatomy and histology. Prostatic adenocarcinoma in skeletal muscle on core biopsy (C) and on prostatectomy (D). Positive apical margin at the anterior prostate involving
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skeletal muscle (E) and at the lateral prostate lacking skeletal muscles (F). Hematoxylin and
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eosin, original magnifications x10.
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Figure 2. Distribution of cases with percent number of positive cores in both groups.
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REFERENCES
Fine SW, Al-Ahmadie H a, Gopalan A, et al. Anatomy of the anterior prostate and extraprostatic space: A contemporary surgical pathology analysis. Adv. Anat. Pathol. 2007;14:401–407.
2.
Haffner J, Potiron E, Bouyé S, et al. Peripheral zone prostate cancers: Location and intraprostatic patterns of spread at histopathology. Prostate 2009;69:276–282.
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Boutier R, Girouin N, Cheikh A Ben, et al. Location of residual cancer after transrectal high-intensity focused ultrasound ablation for clinically localized prostate cancer. BJU Int. 2011;108:1776–1781.
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Al-Ahmadie HA, Tickoo SK, Olgac S, et al. Anterior-predominant prostatic tumors: Zone of origin and pathologic outcomes at radical prostatectomy. Am. J. Surg. Pathol. 2008;32:229–235.
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Ye H, Walsh PC, Epstein JI. Skeletal muscle involvement by limited Gleason score 6 adenocarcinoma of the prostate on needle biopsy is not associated with adverse findings at radical prostatectomy. J. Urol. 2010;184:2308–2312.
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Moussa AS, Meshref A, Schoenfield L, et al. Importance of additional “extreme” anterior apical needle biopsies in the initial detection of prostate cancer. Urology 2010;75:1034– 1039.
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Walz J, Burnett AL, Costello AJ, et al. A critical analysis of the current knowledge of surgical anatomy related to optimization of cancer control and preservation of continence and erection in candidates for radical prostatectomy. Eur. Urol. 2010;57:179–192.
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Epstein JI, Feng Z, Trock BJ, et al. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: Incidence and predictive factors using the modified gleason grading system and factoring in tertiary grades. Eur. Urol. 2012;61:1019–1024. doi:10.1016/j.eururo.2012.01.050.
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Borin JF, Skarecky DW, Narula N, et al. Impact of urethral stump length on continence and positive surgical margins in robot-assisted laparoscopic prostatectomy. Urology 2007;70:173–177. doi:10.1016/j.urology.2007.03.050.
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Swindle P, Eastham J a, Ohori M, et al. Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J. Urol. 2008;179:S47– S51.
11.
Blute ML, Bergstralh EJ, Iocca A, et al. Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. J. Urol. 2001;165:119–125.
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1.
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Connolly SS, O’Toole GC, O’Malley KJ, et al. Positive apical surgical margins after radical retropubic prostatectomy, truth or artefact? Scand. J. Urol. Nephrol. 2004;38:26– 31.
13.
Dev HS, Wiklund P, Patel V, et al. Surgical margin length and location affect recurrence rates after robotic prostatectomy. Urol. Oncol. Semin. Orig. Investig. 2015;33:109.e7– 109.e13.
14.
Sooriakumaran P, Ploumidis A, Nyberg T, et al. The impact of length and location of positive margins in predicting biochemical recurrence after robot-assisted radical prostatectomy with a minimum follow-up of 5 years. BJU Int. 2015;115:106–113.
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Iremashvili V, Pelaez L, Jorda M, et al. Prostate sampling by 12-core biopsy: Comparison of the biopsy results with tumor location in prostatectomy specimens. Urology 2012;79:37–42.
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Meng M V., Franks JH, Presti JC, et al. The utility of apical anterior horn biopsies in prostate cancer detection. Urol. Oncol. Semin. Orig. Investig. 2003;21:361–365.
17.
Orikasa K, Ito A, Ishidoya S, et al. Anterior apical biopsy: Is it useful for prostate cancer detection? Int. J. Urol. 2008;15:900–904.
18.
Takashima R, Egawa S, Kuwao S, et al. Anterior distribution of stage T1c nonpalpable tumors in radical prostatectomy specimens. Urology 2002;59:692–697.
19.
Wright JL, Ellis WJ. Improved prostate cancer detection with anterior apical prostate biopsies. Urol. Oncol. Semin. Orig. Investig. 2006;24:492–495.
20.
Eskicorapci SY, Baydar DE, Akbal C, et al. An extended 10-core transrectal ultrasonography guided prostate biopsy protocol improves the detection of prostate cancer. Eur. Urol. 2004;45:444–449.
21.
Elshafei A, Kartha G, Li Y, et al. Low risk patients benefit from extreme anterior apical sampling on initial biopsy for prostate cancer diagnosis. Prostate 2014;74:1183–1188.
22.
Bjurlin MA, Carter HB, Schellhammer P, et al. Optimization of initial prostate biopsy in clinical practice: Sampling, labeling and specimen processing. J. Urol. 2013;189:2039– 2046.
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Taneja SS, Bjurlin MA, Carter HB, et al. Optimal techniques of prostate biopsy and specimen handling. Am. Urol. Assoc. 2013:1–29.
24.
Nix JW, Turkbey B, Hoang A, et al. Very distal apical prostate tumours: Identification on multiparametric MRI at 3 Tesla. BJU Int. 2012;110:E694–E700.
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12.
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Yao A, Iwamoto H, Masago T, et al. The role of staging MRI in predicting apical margin positivity for robot-assisted laparoscopic radical prostatectomy. Urol. Int. 2014;93:182– 188.
26.
Tsivian M, Zilberman DE, Ferrandino MN, et al. Apical surgical margins status in robotassisted laparoscopic radical prostatectomy does not depend on disease characteristics. J. Endourol. 2012;26:361–365.
27.
Choo MS, Cho SY, Jeong CW, et al. Predictors of positive surgical margins and their location in Korean men undergoing radical prostatectomy. Int. J. Urol. 2014;21:894–898.
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25.
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Table 1. Comparison of findings on prostatectomy of the study group and the control group. *Six cases had no residual tumor. +In calculating the p value, ambiguous extension was not taken into consideration. Control group
≤ 3 + 3*
81 (80.2%)
143 (71.1%)
3+4
16 (15.8%)
4+3
3 (3.0%)
4+4
1 (1.0%)
>4+4
0 (0%)
Extension
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9 (4.5%)
0 (0%)
166 (82.6%)
12 (11.9%)
33 (16.4%)
11 (10.9%)
2 (1.0%)
83 (82.2%)
186 (92.5%)
Positive
18 (17.8%)
15 (7.5%)
101
201
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AC
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Number of cases
0.41
3 (1.5%)
Negative Margin
P value
46 (22.9%)
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78 (77.2%)
ED
Ambiguous+
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Organ confined Not organ confined
MA
Final Gleason score
T
Study group
0.48
0.006
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Table 2. Location of positive margins in the study group and the control group. Control group
Apex
14 (77.8%)
9 (60.0%)
Mid
1 (5.5%)
5 (33.3%)
Base
3 (16.7%)
1 (6.7%)
Number of cases
18
15
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SC NU MA ED PT CE AC
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Study group
P Value
0.10
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Table 3. Location of positive apical margins in the study group and the control group.
11 (78.6%)
2 (22.2%)
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3 (21.4%)
7 (77.8%)
14
9
AC
CE
PT
ED
MA
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Number of cases
T
Control group
SC
Distal apex with admixed skeletal muscle More proximal apex
Study group
P value
0.008
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17
Figure 1
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Figure 2
S0046-8177(15)00440-2 doi: 10.1016/j.humpath.2015.10.010 YHUPA 3742
To appear in:
Human Pathology
Received date: Revised date: Accepted date:
2 September 2015 9 October 2015 16 October 2015
Please cite this article as: Sadimin Evita T., Ye Huihui, Epstein Jonathan I., Should the Involvement of Skeletal Muscle by Prostatic Adenocarcinoma be Reported on Biopsies?, Human Pathology (2015), doi: 10.1016/j.humpath.2015.10.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
SHOULD THE INVOLVEMENT OF SKELETAL MUSCLE BY PROSTATIC ADENOCARCINOMA BE REPORTED ON BIOPSIES?
1
RI P
T
Evita T. Sadimin, MD1, Huihui Ye, MD2, Jonathan I. Epstein, MD1 Department of Pathology, Urology and Oncology
2
SC
The Johns Hopkins Medical Institutions, Baltimore, MD Department of Pathology
NU
Beth Israel Deaconess Medical Center, Boston, MA
MA
Running title: Prostatic adenocarcinoma involving skeletal muscle
CE
Corresponding author:
PT
ED
Keywords: prostatic adenocarcinoma; skeletal muscle; positive apical margin; distal apex; anterior apex
Jonathan I. Epstein, MD
AC
Department of Pathology
The Johns Hopkins Hospital 401 N Broadway St, Weinberg Rm 2242 Baltimore, MD 21231 Phone: (410) 955-5043 Fax: (443) 287-3818 e-mail: [email protected]
Conflicts of interest: The authors declare no conflict of interest associated with this work. Funding disclosures: The authors have no relevant financial relationships to disclose.
ACCEPTED MANUSCRIPT 2
ABSTRACT Skeletal muscle is seen at the distal part of the prostate apex, where benign glands may reside as
RI P
T
part of normal anatomy and histology, and extends more proximally anteriorly. At times, prostatic adenocarcinoma can be seen admixed with skeletal muscle, raising the question of
SC
extraprostatic extension. While there has been increased attention regarding biopsy sampling of the distal apex to guide the performing of the apical dissection on radical prostatectomy, the
NU
finding of skeletal muscle involvement by prostatic adenocarcinoma has not been consistently
MA
reported by pathologists on biopsies. We searched our database spanning 12 years from 2000 to 2012 for all patients who had prostatic adenocarcinoma Gleason score 3+3=6 involving skeletal
ED
muscle on biopsy. We identified 220 patients who met the criteria. Of the 220 patients, 101 underwent prostatectomy which comprised the “study group”. Prostatectomy reports from these
PT
patients were compared with those of a “control group”, which consisted of 201
CE
contemporaneous patients with Gleason score 3+3=6 prostatic adenocarcinoma on biopsy without skeletal muscle involvement. The results showed a significantly higher percentage of
AC
positive margins in the study group compared to the control group (p=0.006). The study group also had a higher percent of positive margins at the apex admixed with skeletal muscle (p=0.008). In summary, the findings in this study support that pathologists should report the involvement of skeletal muscle by tumor, and recommended that urologists performing radical prostatectomies on these patients try to ensure adequate excision in the apical area to avoid positive apical margin.
ACCEPTED MANUSCRIPT 3
INTRODUCTION The human prostate is composed of a complex arrangement of glandular epithelium and
RI P
T
fibromuscular stroma. At the posterior part of the prostate, there is a distinct border between the fibromuscular stroma and the extraprostatic fibroadipose tissue. In contrast, there is no distinct
SC
boundary at the anterior part of the prostate, where smooth muscle of the prostate merges with the extraprostatic tissue. The skeletal muscle fibers of the urogenital diaphragm are present from
NU
the distal apex up to the mid anterior area of the prostate, where at the distal apex they can be
MA
seen admixed with benign prostate glands (figure 1A,B) [1]. While biopsy of the mid prostate usually does not contain skeletal muscle fibers because they are far too anterior, they can often
ED
be seen on apical biopsy.
Approximately 20-26% of prostatic adenocarcinoma is found in the apical area, defined as the
PT
distal one third of the prostate [2–4]. At times, it can be seen extending into the skeletal muscle
CE
in the distal or anterior apex (figure 1C,D). In prostatectomy specimens, positive apical margins
AC
can be seen in these areas where cancer is admixed with skeletal muscle at the inked margin (figure 1E) in contrast to more proximally or posteriorly where cancer extends to the inked margin without being admixed with skeletal muscle (figure 1F). The significance of skeletal muscle involvement by prostatic adenocarcinoma on biopsy has only rarely been studied from the pathologic point of view, and only in cases involving a limited amount of tumor on biopsy [5]. Consequently, most pathologists do not include this finding routinely on prostate biopsy reports. On the other hand, urologists have recognized the distal apical area as a challenging area in obtaining biopsies and in surgical dissection during prostatectomy. Biopsy of the distal apex especially anteriorly is associated with further
ACCEPTED MANUSCRIPT 4
advancement of the biopsy needle and more pain and discomfort [6]. Apical dissection during radical prostatectomy is challenging due to variation in the shapes of the prostate apex, the rich
T
neurovascular supply and the intermingling muscle layers [7], leading to a dilemma between
RI P
risking positive margin by attempting to preserve the neurovascular bundle in this area or
SC
significant incontinence by doing more extensive apical dissection.
In this study, we analyzed radical prostatectomy findings of patients whose prior biopsies
NU
showed prostatic adenocarcinoma Gleason score 3+3=6 involving skeletal muscle, reviewed and
MA
compared all the positive apical margins in both the control and study groups, and discussed the
ED
importance of including this finding on biopsy reports.
PT
MATERIALS AND METHODS
CE
This study was performed under the approval of Johns Hopkins institutional review board (IRB). We searched the database of both our routine in-house and consult cases spanning 12
AC
years from 2000 to 2012 and identified 220 patients with prostatic adenocarcinoma Gleason score 3+3=6 involving skeletal muscle on the biopsy. This study was limited to only include those with low grade prostatic adenocarcinoma to avoid potential adverse findings bias that could be attributed to the more aggressive behavior of high grade cancer rather than the skeletal muscle involvement. Of the 220 patients, 101 underwent prostatectomy, 41 underwent radiation therapy, 3 underwent androgen deprivation therapy and 29 were lost to follow up. We focused on the 101 patients who underwent prostatectomy. These patients were designated as the “study group”. For the “control group”, we obtained the prostatectomy reports of 201 routine in-house
ACCEPTED MANUSCRIPT 5
consecutive cases whose biopsies showed prostatic adenocarcinoma Gleason score 3+3=6 without skeletal muscle involvement.
RI P
T
The pathology reports for both groups were retrieved and the findings tabulated. All cases with positive apical margins on prostatectomy were retrieved and reviewed. Final Gleason score,
SC
margins status, presence of extraprostatic extension, seminal vesicle involvement and lymph node involvement in the two groups were compared. The apex was defined as the distal one-third
NU
of the prostate distal to the verumontanum. In cases with positive apical margins, we recorded
MA
whether the margin was positive in the area where skeletal muscle fibers were present.
ED
RESULTS
PT
The distributions of percent number of positive cores in the study group and the control
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group were similar (figure 2). Comparison of the prostatectomy findings of the 101 patients in the study group and the 201 patients in the control group revealed a significantly higher
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percentage of positive margins in the study group compared to the control group (p=0.006). There was no significant difference in the distribution of final Gleason score and the presence of extraprostatic extension (table 1). The majority of patients with prostatic adenocarcinoma Gleason score 3+3=6 in the biopsy had the same final Gleason score on prostatectomy. Six patients were found to have no residual cancer. In both groups most patients had organ confined disease (table 1). Additionally, only 1% of patients in the study group and 1.5% of patients in the control group had seminal vesicle involvement. None of the patients had lymph node involvement.
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When assessing extraprostatic extension of tumor in the apical area, only tumor in the fat was considered as extraprostatic extension. In cases where the tumor was transected in the area of the
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skeletal muscle, it was considered uncertain whether the disease was still organ confined due to
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ambiguities of the boundary of the prostate at this site, hence their designation as ambiguous (pT2x) A higher percentage of ambiguous cases were seen in the study group (10.9%) compared
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to the control group (1.0%) (table 1).
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Positive margins were more commonly seen in the apex in both groups (table 2). Although a
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higher percentage of positive apical margins were observed in the study group, the difference in the overall distribution of the positive margins was not significant. Review of all the cases with
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positive apical margins showed that in the study group 78.6% of the positive apical margins are at the most distal apex with admixed skeletal muscle fibers compared to the control group where
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77.8% of the positive margins were in the posterior apex (p=0.008) (table 3). The biopsies prior
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to the prostatectomy of the two patients in the control group who had positive apical margins
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admixed with skeletal muscle did not have cancer present in the apex on the biopsy.
DISCUSSION
Our study demonstrated that skeletal muscle involvement by prostatic adenocarcinoma in biopsies was associated with an overall increased risk of having positive margin in the corresponding radical prostatectomy specimen and especially at the distal apical area at prostatectomy though most patients still had organ confined disease with negative margins and no lymph node involvements. The upgrading rate on prostatectomy seen in our study is consistent with previous studies and reflects the undersampling of higher grade cancer on biopsy
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[8]. The positive surgical margins in both groups were mostly found at the apex, similar to the findings in another study[9]. Patients with positive surgical margin in the radical prostatectomy
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have been shown to have higher risk for disease progression compared to those with negative
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margins [10,11]. This risk was also observed specifically with positive surgical margin at the apex [12]. Furthermore, in some studies, positive apical surgical margin showed association with
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worse prognosis [13,14]. These studies, however, did not specify whether the positive apical
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surgical margin involved the distal or anterior apical areas admixed with skeletal muscle or the
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more posterior region of the apex.
The distal and anterior apex of the prostate where the skeletal muscle is located is often not
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consistently biopsied. Several studies looking into the standard 12 core biopsy showed that the this area of the prostate was often undersampled [15,16]. When adequately sampled, patients
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with normal DRE have been found to have a higher cancer detection rate in this site [16–18].
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Further supporting the importance of adequate sampling, the anterior apical biopsies have been shown to have the highest yield of cancer compared to all of the cores from other sites [19,20].
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Some studies have found that increased sampling of the anterior apical biopsy improved overall prostate cancer detection [6,21]. The American Urological Association recently recommended that a 12-core prostate biopsy should incorporate apical area, including distal and anterior apex [22,23]. Consequently, as seen in two of our control cases, undersampling of the apex may have caused an underestimation of the number of patients in our study group as these two cases would have been part of our study group if their biopsies included the distal or anterior apex. With increased awareness and therefore increased sampling of this area, it would be reasonable for pathologists to expect to see more prostatic adenocarcinoma involving skeletal muscle in biopsy specimens.
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Tumors residing in the anterior apex are less likely to be palpable, and not readily identifiable on traditional MRI, increasing the challenge of adequate sampling. There have been suggestions to
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utilize imaging such as multiparametric MRI or MRI/ultrasound fusion to guide biopsies of this
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area [24]. Tumors at the anterior apical area have similar clinical significance compared to tumors from other sites, again emphasizing the importance of detecting cancers in this area [4].
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Additionally, non-surgical treatments may be less effective for distal apical tumors. One study
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showed that residual cancer after high-intensity focused ultrasonography (HIFU) ablation was
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mostly found in the distal apex [3].
By reporting the presence of tumor in the skeletal muscle, pathologists could help urologists
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make decisions whether specific attention would be necessary for the apical area. Urologists may decide to extend the apical dissection during prostatectomy [5,9] when there is tumor in the
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skeletal muscle on biopsy, while they may not otherwise. Furthermore, utilizing MRI to plan the
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apical dissection in prostatectomy may be beneficial in being able to avoid a positive apical margin [25]. Dissection of the apical area is recognized as a challenging task, with more
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experience surgeons having fewer patients with positive apical surgical margins compared to the less experience surgeons. This difference was not observed in non-apical margins [26]. In our control group, skeletal muscles were not consistently present, reflecting that the anterior or distal apical region was often not sampled. Some urologists at our institution who saw reports with skeletal muscle involvement by tumor on the biopsy took the extra precaution on dissecting the apical area, preventing a positive margin in an otherwise what could have been a positive margin. These factors may have lessened the significance of the relationship between having tumor involving skeletal muscle in the prostate biopsy with having positive margin in the prostatectomy in the area of the distal or anterior apex in our study.
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One previous study showed a similar finding that apical positivity on biopsy corresponded to increased likelihood of having positive margin in the prostatectomy [27]. In this prior study it did
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not specify the involvement of skeletal muscle and if the positive margins were associated with
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the presence of tumor within the skeletal muscle. In our study, there was a significant difference in the location of the positive apical margins between the two groups, where in the study group
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they were at the distal apex with admixed skeletal muscle, and in the control group they were at
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the more proximal apex. Additionally, the percentage of positive apical margins at the more proximal apex in both groups were similar, 3 cases out of 101 total number of cases (2.9%) in the
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study group versus 7 cases out of 201 total number of cases (3.5%) in the control group. This showed that the overall increased number of positive apical margins in the study group could
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only be attributed to the presence of tumor in the skeletal muscle.
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In summary, the findings in this study highlight the importance of distal or anterior apical
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sampling in prostate biopsies, suggested that pathologists should report the involvement of skeletal muscle by tumor, and recommended that urologists performing radical prostatectomies
margin.
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on these patients try to ensure adequate excision in the apical area to avoid positive apical
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LEGENDS Figure 1. Benign prostatic glands in skeletal muscle on core biopsy (A) and on prostatectomy (B)
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as part of normal anatomy and histology. Prostatic adenocarcinoma in skeletal muscle on core biopsy (C) and on prostatectomy (D). Positive apical margin at the anterior prostate involving
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skeletal muscle (E) and at the lateral prostate lacking skeletal muscles (F). Hematoxylin and
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eosin, original magnifications x10.
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Figure 2. Distribution of cases with percent number of positive cores in both groups.
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Yao A, Iwamoto H, Masago T, et al. The role of staging MRI in predicting apical margin positivity for robot-assisted laparoscopic radical prostatectomy. Urol. Int. 2014;93:182– 188.
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25.
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Table 1. Comparison of findings on prostatectomy of the study group and the control group. *Six cases had no residual tumor. +In calculating the p value, ambiguous extension was not taken into consideration. Control group
≤ 3 + 3*
81 (80.2%)
143 (71.1%)
3+4
16 (15.8%)
4+3
3 (3.0%)
4+4
1 (1.0%)
>4+4
0 (0%)
Extension
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9 (4.5%)
0 (0%)
166 (82.6%)
12 (11.9%)
33 (16.4%)
11 (10.9%)
2 (1.0%)
83 (82.2%)
186 (92.5%)
Positive
18 (17.8%)
15 (7.5%)
101
201
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Number of cases
0.41
3 (1.5%)
Negative Margin
P value
46 (22.9%)
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78 (77.2%)
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Ambiguous+
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Organ confined Not organ confined
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Final Gleason score
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Study group
0.48
0.006
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Table 2. Location of positive margins in the study group and the control group. Control group
Apex
14 (77.8%)
9 (60.0%)
Mid
1 (5.5%)
5 (33.3%)
Base
3 (16.7%)
1 (6.7%)
Number of cases
18
15
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Study group
P Value
0.10
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Table 3. Location of positive apical margins in the study group and the control group.
11 (78.6%)
2 (22.2%)
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3 (21.4%)
7 (77.8%)
14
9
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PT
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Number of cases
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Control group
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Distal apex with admixed skeletal muscle More proximal apex
Study group
P value
0.008
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Figure 1
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Figure 2