Abstract
Aim. To investigate the reliability of a sentinel node (SN) procedure for nodal staging in prostate cancer (PCa) patients at high risk for lymph node (LN) involvement.
Material and methods. Seventy-four patients with localized prostate adenocarcinoma, who were clinically node-negative and had a risk of LN involvement of ≥ 10% (Partin tables), were prospectively enrolled. Upon intraprostatic 99mTc-nanocolloid injection, they underwent planar scintigraphy and SPECT imaging. Surgical removal of the SN, located by means of a gamma probe, was completed with a superextended LN dissection (seLND) as a reference and followed by radical prostatectomy.
Results. In total, 470 SN (median 6, IQR 3–9) were scintigraphically detected of which 371 (median 4, IQR 2–6) were located by gamma probe and selectively removed during surgery (79%). Histopathology confirmed LN metastases in 37 patients (50%) having 106 affected LN in total (median number per patient 2, IQR 1–4). Twenty-eight patients were node positive (N+) based on the analysis of the resected SN. However, the seLND that was performed as a reference revealed nine additional N+ patients resulting in a sensitivity of 76% (28/37). In total, 15 of 37 patients (41%) had metastases in SN only and could have been spared seLND to remove all affected nodes.
Conclusion. We found a relatively low sensitivity when addressing the SN procedure for nodal staging in PCa patients at high risk for LN involvement. Importantly, only less than half of the N+ patients could have been spared a seLND to remove all affected lymphoid tissue.
According to current guidelines, pelvic lymph node dissection (LND) remains the most reliable staging method given the significant limitations of preoperative imaging in the detection of small metastases (< 5 mm) in prostate cancer (PCa) [Citation1]. The only suitable alternative to extended (e)LND that has been proposed until now is a sentinel node (SN) procedure [Citation2]. This concept was first introduced by Morton et al. in malignant melanoma in 1992 and was further explored in other cancer types, such as early-stage breast cancer [Citation3].
By injecting a lymphotrophic tracer into the tumor, the potential dissemination pattern can be visualized. The first draining lymph node (LN) situated on a lymphatic vessel that has taken up the tracer is called the SN and it is assumed that if this node is free from cancer cells, the next draining echelons will be negative as well. As PCa is known to be notoriously multifocal within the gland and the tumor itself is frequently poorly visible on transrectal ultrasound, injections are performed in a standardized fashion distributed over the entire prostate.
Different institutions have already demonstrated the feasibility of the procedure with acceptable false negative (FN) rates. This FN rate represents the percentage of node positive (N ×) patients that would have been incorrectly staged as node negative when performing a SN procedure without backup LND. A review by Sadeghi and colleagues reported a pooled sensitivity of 94% for 16 studies [Citation4]. The reasoning to prefer this procedure over an eLND is the lower morbidity rate. It has been demonstrated that even in the hands of experienced urologists, an eLND is associated with higher complication rates and longer hospital stay than when a limited (l)LND is performed [Citation5]. If nodal status could be reliably predicted by a SN procedure alone, a large number of patients with intermediate and high-risk PCa could be spared an eLND and associated risk of complications.
The objective of this study was to investigate the reliability of a SN procedure in clinically node negative PCa patients at high risk for lymph node involvement (LNI) according to the Partin tables [Citation6].
Material and methods
Patients
This study is part of a prospective imaging study designed to assess the reliability of 11C-choline positron emission tomography (PET)-computed tomography (CT) and diffusion-weighted magnetic resonance imaging (MRI) for nodal staging [Citation7]. The local ethics committee approved the study and written informed consents were obtained.
Between February 2008 and February 2011, 74 consecutive patients with localized, biopsy-proven prostate adenocarcinoma were scheduled for radical retropubic prostatectomy (RRP) and superextended (se)LND, removing all LN surrounding the common iliac, external and internal iliac vessels, LN in the obturator fossa and presacral areas. The primary tumor was staged by digital rectal examination and transrectal ultrasound. Only patients with a risk of ≥ 10% for LN metastases (Partin tables) were included [Citation6]. Further selection criteria were no pelvic LNI on contrast-enhanced CT (i.e. no LN ≥ 8 mm in transverse dimension), no bone metastasis on bone scan, WHO performance status < 2, no previous hormonal therapy, radiotherapy or prostatectomy and no previous/other malignancy.
Scintigraphy
Patients were intraprostatically injected with 99mTc-nanocolloid (Nanocoll®; GE Healthcare, Amersham Health, USA) under transrectal ultrasound guidance on the day of surgery. Three applications of 20 MBq each (0.5 mL) were performed per lobe with a Chiba needle (0.95 × 220 mm). Injections were performed in the basal, middle and apical portion of the prostate in both lobes in a standard fashion [Citation8].
Approximately two hours post-injection, patients underwent planar scintigraphy and single-photon emission computed tomography (SPECT) imaging on a Trionix BIAD dual-headed gamma camera (Biad Trionix Research Laboratories, Twinsburg, OH, USA). To facilitate anatomic SN localization, SPECT images were fused with the staging CT-scan using MIM Vista software (MIM Software Inc, Cleveland, OH, USA).
The last 17 patients were imaged on a Symbia 16 SPECT/CT (Siemens, Erlangen, Germany) dual-headed gamma camera.
Lead shielding was used for the prostate to minimize interference and the patient was asked to empty his bladder before the scan. Foci of activity that were significantly higher than background activity on visual inspection that could not be attributed to the injection site, bladder, rectum, bone marrow, kidneys nor liver were considered draining LN. All scans were analyzed by an experienced nuclear medicine physician (C.M.D.).
Surgery
Surgery was performed by one experienced urologist (S.J.). Guided by the SPECT/CT images, all pelvic lymphatic drainage regions were systematically screened with a hand-held gamma-detection probe (Neo2000® Gamma Detection System; Neoprobe Corp, Dublin, OH, USA) before lymphadenectomy. When a high intensity signal was located, it was isolated and mapped separately on a standardized map. Care was taken to ascertain good contact between the tip of the probe and the lymphatic tissue, and to always point away from the prostate region whilst doing so in order to avoid signal interference. Following this procedure, a backup bilateral seLND was performed as defined earlier. All lymphatic tissue from this seLND was screened ex vivo for any remaining radioactivity and laid out on a second map. SN visualized on the SPECT/CT images but located outside the seLND template were only resected if technically feasible. In some cases, all presacral nodes were removed through a right-sided approach, as the left common iliac vein prohibited a safe left-sided approach. Therefore, the presacral area was considered as one region. Finally, an open RRP was performed according to the technique previously described [Citation9].
Histological examination
All labeled specimens were delivered to the pathology department on the standardized maps. LN were fixed overnight in 6% formalin. All stations were examined by palpation, visual inspection and sectioning. The lamellated (1 mm sections) LN were then embedded in paraffin and were serially sectioned. Every 300 μ one 5 μ section was immunohistochemically stained for pankeratin [monoclonal Ab, clone AE1/AE3, Ready-to-Use, Dako, Denmark - automatical staining (Dako PT Link, Dako, Denmark)]. All slides were microscopically evaluated for the presence of metastases by an experienced uropathologist (E.L.). The maximal diameter of each metastasis was noted and categorized in macrometastases (≥ 2 mm), micrometastases (> 0.2 mm and < 2 mm) and isolated tumor cells (ITC) (≤ 0.2 mm) [Citation10].
Prostatectomy specimens were entirely embedded and handled according to the International Society of Urological Pathology (ISUP) guidelines [Citation11]. Gleason scores were determined and tumors were pathologically staged (2002 TNM classification). In addition, tumor volume was calculated as follows: sum of all tumor areas on the slides (cm²) * slice thickness (0.3 cm) * 1.33 (shrinkage factor due to fixation) [Citation12].
Statistics
Data are presented as percentage or median + range or interquartile range (IQR) for continuous variables, and rates + percentage in the case of discrete variables.
Results
Patient and disease characteristics are depicted in . SN were retrieved during surgery in 71 of 74 patients. In one patient, no SN was detected on the SPECT images nor intraoperatively and in two patients, the SN on the SPECT images could not be retrieved during surgery.
Table I. Patient and disease characteristics.
In total, 470 SN were located on SPECT/CT fusion images (median 6, IQR 3–9) of which 371 SN could be resected (median 4, IQR 2–6). As SN located outside the seLND template were only resected if technically feasible (e.g. SN above the level of the aortic bifurcation) and not all SN visualized on the preoperative images could be located during surgery, a 79% (371/470) resection rate was obtained. demonstrates the localization of SN that were scintigraphically detected and surgically removed as well as the total number of (affected) LN removed per region. Fifty-six percent (262/470) of SN were located within the standard eLND template (i.e. obturator region, external and internal iliac region) and 82% (385/470) within the seLND template (i.e. eLND template plus presacral and common iliac region). Next to that, 85 SN (18%) were also visualized in regions outside the seLND template: paraaortic (49/470), aortic bifurcation (17/470), pararectal (14/470), paravesical (2/470), mesenteric fat (2/470) and inguinal (1/470). Resected LN outside the seLND template were located in the pararectal region (6/371), paraaortic region (3/371), mesenteric fat (2/371), aortic bifurcation region and paravesical region (both 1/371).
Table II. Localization of SN that were scintigraphically detected and surgically retrieved and the number of (affected) LN removed (SN + seLND) when completing the SN procedure with a seLND.
In total, 106 affected LN (median 2, IQR 1–4) were detected, which were predominantly located within the standard eLND template (n = 91, 86%). Forty-seven (44%) of the positive nodes were classified as macrometastases, 47 (44%) as micrometastases and 12 (11%) as ITC. Fifty metastatic LN were SN (47%). Six of these metastatic LN were found in SN outside the standard eLND template, of which one was retrieved even outside the seLND template (i.e. in the aortic bifurcation region).
shows an overview of the results of the SN procedure and consecutive seLND on patient level. Histopathology confirmed LN metastases in 37 patients (50%). Twenty-eight patients were N+ based on the analysis of the resected SN. However, the seLND that was performed as a reference revealed nine additional N+ patients resulting in a sensitivity of 76% (28/37). When considering the complete patient group, this translates into 63/74 patients that were staged correctly (i.e. 85% accuracy).
An overview of the N+ patients is presented in Supplementary Table I (to be found online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2014.987354) demonstrating Gleason scores, number of affected nodes, details on LN regions and performance of the procedure. In total, 15 of 37 patients (41%) had metastases in SN only and could have been spared seLND to remove all affected LN. In the 22 patients with residual disease after the SN dissection 56 affected LN would have been left behind of which the majority was > 0.2 mm (Supplementary Table II, to be found online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2014.987354). An additional obturator LND, lLND (i.e. obturator and external iliac region), eLND and seLND would have been necessary to remove all affected LN in respectively three, six, seven and six patients.
Discussion
Based on the advantages in other cancer types, such as breast cancer, several groups investigated the SN procedure as an alternative to (e)LND for nodal evaluation in PCa as it is associated with lower morbidity rates [Citation13].
We found the SN procedure to be technically and logistically feasible. Planar imaging was completed with SPECT/CT imaging to improve detection of SN [Citation14]. As for the distribution of SN on the images, our results were in accordance with earlier mapping studies [Citation15,Citation16]. In spite of the availability of preoperative images, only 79% of the nodes visualized on scintigraphy could be retrieved. The main reason for this was that SN located outside the seLND template were only resected if technically feasible.
The FN rate determines the sensitivity of the technique and is used to assess its reliability for nodal staging. The Augsburg group started performing radioguided LNDs on PCa patients in 1999 and has meanwhile gained the largest experience in over 2000 patients [Citation17]. Despite this very large number of patients, it has to be stressed that the majority of patients did not undergo an additional LND nor were long-term oncological data reported for these patients. Of 187 N+ men who did undergo a backup LND, they only found 11 patients who presented with positive nodes while the SN were negative (i.e. 5.9% FN rate). Although no recommendation has been made on the ‘acceptable’ FN rate for PCa, they report their results to be within the limits set by national and international guidelines for breast cancer [Citation17–19]. The aforementioned meta-analysis added 15 other although smaller studies to these results, thereby reaching a FN rate of only 6%. Although only studies in which a backup LND was performed were included to assess sensitivity, templates differed and were sometimes limited to LN in the obturator fossa and external iliac region. In contrast, we found a FN rate of 24% (9/37) which is higher than most data in literature but at the same time, the backup seLND we used as a reference was the most extensive.
A possible explanation for FN SN as suggested by Weckermann and colleagues could be blockage of LN channels by (macro)metastases thereby directing the tracer towards a false first LN or even completely interrupting its flow [Citation20]. Holl et al. postulated that the FN rate should therefore be proportional to the Gleason score as higher Gleason scores are correlated to a higher risk of LN metastases. Accordingly, they found a higher FN rate with increasing Gleason score, with a FN rate of up to 14% in the group of Gleason score > 8 [Citation17]. It should be noted that all of the six FN patients in this specific subgroup had LN metastases ≥ 10 mm. In our study, the relatively low patient number on the one hand but especially the handled inclusion criteria on the other hand could have prevented us from observing a comparable correlation. When we looked at the size of tumor deposits in our FN patients we found metastases ≥ 2 mm in only four of nine patients.
A second hypothesis that has been reported as a potential cause of FN SN is a too low count rate for intraoperative detection. Brenot-Rossi and colleagues demonstrated that an injected activity of at least 200 MBq resulted into a 92.9% detection rate compared to 69.4% with 60 MBq [Citation21]. In this study an activity of 120 MBq was administered and surgery was performed on the same day which is different from the procedure reported in most other articles where 200 MBq was applied and surgery was performed 20–24 hours after injection. However, the fact that eight of nine FN patients did show a SN in another region than the N+ region is an argument against this hypothesis as well as our 96% detection rate (i.e. at least one SN in 71/74 patients) which is in accordance with literature [Citation4].
It has also been demonstrated that the tracer injection technique influences the number and location of the SNs. Although performed in a standardized fashion, it is not unimaginable that some tracer may have leaked out of the peripheral zones or may not have reached the index lesion resulting in a somewhat different drainage pattern than that specific for the tumor location [Citation22].
Although the sensitivity of a SN technique is not convincing based on our data, it is still a manifest improvement compared to currently used imaging techniques [Citation1]. However, we consider the 24% FN rate a high price to pay given the invasiveness and extent of the procedure. As results of non-invasive strategies for nodal staging, such as functional imaging [Citation7] or blood-based markers [Citation23] have been disappointing so far, the quest for reliable methods for pelvic LN staging thus remains [Citation24,Citation25].
Importantly, our data also corroborate earlier findings that when it is aspired to remove all pelvic LN metastases, a SN procedure should be performed along with an eLND [Citation20]. In our study only 15 N+ patients appeared to be free from nodal disease after SN dissection with significant residual nodal tumor load in most of the other 22 patients, stressing the need for a backup LND. In no less than a quarter of these patients, only a seLND would have been sufficient for ‘curative intention’. The fact that as many as half of the patients appeared to have positive LN also warrants for a more intensive, multi-modality treatment approach for patients at high risk for LNI. During the past years, it has become clear that local treatment of the prostate in conjunction with androgen deprivation therapy (ADT) in patients with LN positive disease is beneficial [Citation26]. Emerging evidence suggests even that these patients should be offered a trimodality treatment, consisting of radical prostatectomy with eLND followed by adjuvant radiotherapy in combination with ADT [Citation27,Citation28].
The most important merits of this study are the high event rate (50% N+ patients), its prospective design and meticulous histopathological workup that was carried out to assure that every positive node was recorded. Moreover, the seLND that was performed as a reference in all patients was not only highly standardized but also more extensive compared to other studies, making this dataset unique in its kind. The explanation for our relatively high FN rates compared to other reports might be inherent to the major strengths of this study, i.e. the extensive backup LND and detailed histological examination of every LN.
Some limitations of this study have to be pointed out. First, we did not define a threshold nor quantify activity uptake in SN so that secondary nodes could have been included. The use of a more dynamic imaging approach could also have helped to identify the true first echelon nodes. However, the number of SN detected was generally in accordance with other studies and does not impact the FN rate [Citation4]. Second, it is possible that not all SN were removed in the exact region they were preoperatively located. Nevertheless, with the backup seLND and ex vivo screening of all tissue, we believe we attained adequate coverage to assess the efficacy of the procedure. Finally, pathologic information on SN at the aortic bifurcation or higher is lacking but as demonstrated by other groups and supported by our own findings on mapping of pelvic LN metastases, we believe that the number of patients with positive node in these regions is negligible [Citation29–31].
In conclusion, we found a relatively low sensitivity when addressing the SN procedure for nodal staging in PCa patients at high risk for LN involvement. Importantly, only less than half of the N+ patients could have been spared a seLND to remove all affected lymphoid tissue.
Supplementary material available online
Supplementary Tables I–II to be found online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2014.987354.
ionc_a_987354_sm2670.pdf
Download PDF (160.2 KB)Acknowledgments
This work was supported through a research grant of the IWT – Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT TBM 060793), the National Cancer Plan Action 29 (KPC_29_037) – Belgium and the ‘Stichting Emmanuel van der Schueren’ from the Flemish League against Cancer. K.H. is a fundamental clinical researcher of the Research Foundation – Flanders (FWO). E.L. and C.M.D. are supported by a grant from the ‘Klinisch Onderzoeksfonds (KOF)’ – University Hospitals Leuven.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Hovels AM, Heesakkers RA, Adang EM, Jager GJ, Strum S, Hoogeveen YL, et al. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: A meta-analysis. Clin Radiol 2008;63: 387–95.
- Heidenreich A, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V, et al. EAU guidelines on prostate cancer. Part 1: Screening, diagnosis, and treatment of clinically localised disease. Eur Urol 2011;59:61–71.
- Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127: 392–9.
- Sadeghi R, Tabasi KT, Bazaz SM, Kakhki VR, Massoom AF, Gholami H, et al. Sentinel node mapping in the prostate cancer. Meta-analysis. Nuklearmedizin 2011;50:107–15.
- Briganti A, Chun FK, Salonia A, Suardi N, Gallina A, Da Pozzo LF, et al. Complications and other surgical outcomes associated with extended pelvic lymphadenectomy in men with localized prostate cancer. Eur Urol 2006;50: 1006–13.
- Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 2001;58:843–8.
- Budiharto T, Joniau S, Lerut E, Van den Bergh L, Mottaghy F, Deroose CM, et al. Prospective evaluation of 11C-choline positron emission tomography/computed tomography and diffusion-weighted magnetic resonance imaging for the nodal staging of prostate cancer with a high risk of lymph node metastases. Eur Urol 2011;60:125–30.
- Beri A, Janetschek G. Technology insight: Radioguided sentinel lymph node dissection in the staging of prostate cancer. Nat Clin Pract Urol 2006;3:602–10.
- Hsu C-Y, Joniau S, Van Poppel H. Radical prostatectomy for locally advanced prostate cancer: Technical aspects of radical prostatectomy. EAU Update Series 2005;90–7.
- Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 2002;20:3628–36.
- Samaratunga H, Montironi R, True L, Epstein JI, Griffiths DF, Humphrey PA, et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 1: specimen handling. Mod Pathol 2011;24: 6–15.
- Greene DR, Wheeler TM, Egawa S, Dunn JK, Scardino PT. A comparison of the morphological features of cancer arising in the transition zone and in the peripheral zone of the prostate. J Urol 1991;146:1069–76.
- Winter A, Vogt C, Weckermann D, Wawroschek F. [Complications of pelvic lymphadenectomy in clinically localised prostate cancer: Different techniques in comparison and dependency on the number of removed lymph nodes]. Aktuelle Urol 2011;42:179–83.
- Vermeeren L, Valdes Olmos RA, Meinhardt W, Bex A, van der Poel HG, Vogel WV, et al. Value of SPECT/CT for detection and anatomic localization of sentinel lymph nodes before laparoscopic sentinel node lymphadenectomy in prostate carcinoma. J Nucl Med 2009;50:865–70.
- Ganswindt U, Schilling D, Muller AC, Bares R, Bartenstein P, Belka C. Distribution of prostate sentinel nodes: A SPECT-derived anatomic atlas. Int J Radiat Oncol Biol Phys 2011; 79:1364–72.
- Mattei A, Fuechsel FG, Bhatta DN, Warncke SH, Thalmann GN, Krause T, et al. The template of the primary lymphatic landing sites of the prostate should be revisited: Results of a multimodality mapping study. Eur Urol 2008; 53:118–25.
- Holl G, Dorn R, Wengenmair H, Weckermann D, Sciuk J. Validation of sentinel lymph node dissection in prostate cancer: experience in more than 2,000 patients. Eur J Nucl Med Mol Imaging 2009;36:1377–82.
- Lyman GH, Giuliano AE, Somerfield MR, Benson AB, III, Bodurka DC, Burstein HJ, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 2005; 23:7703–20.
- Rousseau C, Rousseau T, Bridji B, Pallardy A, Lacoste J, Campion L, et al. Laparoscopic sentinel lymph node (SLN) versus extensive pelvic dissection for clinically localized prostate carcinoma. Eur J Nucl Med Mol Imaging 2012; 39:291–9.
- Weckermann D, Dorn R, Holl G, Wagner T, Harzmann R. Limitations of radioguided surgery in high-risk prostate cancer. Eur Urol 2007;51:1549–56.
- Brenot-Rossi I, Rossi D, Esterni B, Brunelle S, Chuto G, Bastide C. Radioguided sentinel lymph node dissection in patients with localised prostate carcinoma: Influence of the dose of radiolabelled colloid to avoid failure of the procedure. Eur J Nucl Med Mol Imaging 2008;35:32–8.
- Buckle T, Brouwer OR, Valdes Olmos RA, van der Poel HG, van Leeuwen FW. Relationship between intraprostatic tracer deposits and sentinel lymph node mapping in prostate cancer patients. J Nucl Med 2012;53:1026–33.
- Isebaert S, Haustermans K, Van den Bergh L, Joniau S, Dirix P, Oyen R, et al. Identification and characterization of nodal metastases in prostate cancer patients at high risk for lymph node involvement. Acta Oncol 2013;52:1336–44.
- Joniau S, Van den Bergh L, Peeters C, Haustermans K, Spahn M. Nodal staging in prostate cancer: Still an unresolved issue. Eur Urol 2012;61:1139–41.
- Malmstrom PU. Lymph node staging in prostatic carcinoma revisited. Acta Oncol 2005;44:593–8.
- Verhagen PC, Schroder FH, Collette L, Bangma CH. Does local treatment of the prostate in advanced and/or lymph node metastatic disease improve efficacy of androgen-deprivation therapy? A systematic review. Eur Urol 2010; 58:261–9.
- Abdollah F, Karnes RJ, Suardi N, Cozzarini C, Gandaglia G, Fossati N, et al. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer. J Clin Oncol Epub 2014 Sep 22.
- Briganti A, Karnes RJ, Da Pozzo LF, Cozzarini C, Capitanio U, Gallina A, et al. Combination of adjuvant hormonal and radiation therapy significantly prolongs survival of patients with pT2-4 pN+ prostate cancer: Results of a matched analysis. Eur Urol 2011;59:832–40.
- Briganti A, Suardi N, Capogrosso P, Passoni N, Freschi M, di Trapani E, et al. Lymphatic spread of nodal metastases in high-risk prostate cancer: The ascending pathway from the pelvis to the retroperitoneum. Prostate 2012;72:186–92.
- Joniau S, Van den Bergh L, Lerut E, Deroose CM, Haustermans K, Oyen R, et al. Mapping of pelvic lymph node metastases in prostate cancer. Eur Urol 2013;63:450–8.
- Meinhardt W, van der Poel HG, Valdes Olmos RA, Bex A, Brouwer OR, Horenblas S. Laparoscopic sentinel lymph node biopsy for prostate cancer: The relevance of locations outside the extended dissection area. Prostate Cancer 2012;2012:751753.