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Pelvic Lymph Node Dissection in Prostate Cancer: Indication, Extent, and Therapeutic Role in the Contemporary Era 1,2Kwang 2Department 1Department of Urology, Ewha Womans University Mokdong Hospital of Urology, Urologic Science Institute, Yonsei University College of Medicine Abstract Recently, fewer pelvic lymph node dissections (PLNDs) have been performed in the treatment of prostate cancer; this decrease may be attributable to stage migration and an increased use of minimal invasive surgery. Nevertheless, PLND remains the most accurate methods for detecting lymph node metastasis; furthermore, patients with lymph node metastasis who undergo PLND demonstrate favorable long term outcomes. The decision to perform PLND is based on a predictive model. Current models rely upon various nomograms which originate from an extended series of PLNDs. Although recent imaging modalities have demonstrated improved diagnostic accuracy, PLND should not be omitted in patients showing negative results in image studies. To assess the adequacy of PLND, anatomical templates are more important than total Keywords: prostatic neoplasm; prostatectomy; lymph node excision (MeSH) # Dr. Hyun Kim#, 2Sung Joon Hong, 2Koon Ho Rha lymph node counts. It is generally agreed that PLND should be performed in patients with risk of lymph node metastasis using extended templates; these templates include not only the external iliac and obturator area, but also the internal iliac area. Despite improved staging accuracy, removing lymphatic tissue from the presacral area may affect functional outcomes after surgery. Primary lymphatic landing sites also include the common iliac area, which can be a route to the retroperitoneal lymph nodes. A growing body of evidence suggests that PLND improves oncologic outcomes, and a recent randomized controlled trial demonstrated that PLND improves biochemical outcomes in patients with intermediate and high risk prostate cancer. The long term oncologic outcomes of PLND treatment should be investigated in further studies. Introduction The widespread application of the prostate-specific antigen (PSA) test has resulted in early detection of prostate cancer and a decreased incidence of lymph node metastasis. The incidence of lymph node metastasis was 20-40% in patients undergoing surgery before the PSA era, whereas this rate has now decreased to 4-6 %.1-3 Accordingly, fewer patients are undergoing pelvic lymph node dissection (PLND) and fewer lymph nodes have been removed by PLND in recent times.4,5 Moreover, the advent of minimal invasive surgery procedures has also influenced the decision to perform PLND. Data from the Surveillance Epidemiology and End Results Kwang Hyun Kim has been awarded "Eminent Scientist of the Year 2014" of International Research Promotion Council. (www.irpc.org) Correspondence: Koon Ho Rha, M.D., Ph.D., Department of Urology, Urological Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: 82-2-2228-2310, Fax: 82-2-312-2538, E-mail: [email protected] 87 Kwang Hyun Kim (SEER) cancer registry reveals that PLND was five times more likely to be performed on men treated with open surgery compared with men treated with minimal invasive surgery.6 However, the incidence of lymph node metastasis has been reported to be 20-30% in patients with high risk prostate cancer,7,8 and the presence of lymph node metastasis still represents an adverse prognostic factor for disease progression and survival, and portends poorer outcomes.9,10 PLND is still the most accurate method for determining nodal staging. However, PLND is associated with increased morbidity and long operating times; moreover, meticulous surgical technique is required in order for PLND to be effective. Unfortunately, recent sophisticated imaging procedures have shown limited success in accurately identifying nodal involvement, and are limited by their significant costs.11,12 Several nomograms have been developed to better predict the risk of lymph node metastasis,13-15 and some urologists perform PLND based on such nomograms. However, the indication and optimal extent of PLND treatment remains controversial. Furthermore, no consistent conclusion has been reached regarding the beneficial effects of PLND on survival in patients with prostate cancer. The aim of this review is to evaluate the role of PLND in patients with prostate cancer by summarizing issues from the current literature regarding PLND in prostate cancer, including the indication, extent, and therapeutic role of PLND. Current Indication of Pelvic Lymph Node Dissection Even though PLND is the most accurate method for determining lymph node metastasis, PLND is associated with increased morbidity and complications. The benefits of PLND must therefore be weighed against the potential risk of PLND, and the decision to perform PLND is usually based on the characteristics of prostate cancer. Several nomograms have been created to evaluate the risk of lymph node metastasis, using preoperatively available parameters.13-17 However, nomograms should be developed based on results from extended PLND in order to better assess the actual risk of lymph node metastasis. Predictive models based on limited PLND are associated with a significant risk of underestimating the risk of nodal metastasis. Thus, Godoy et al14 recently updated their nomogram to include only patients who Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 13, No. 2, April 2014 underwent extended PLND, thereby demonstrating improved calibration of their nomogram, along with a high discriminative accuracy. Briganti et al13 also recently published their updated nomogram, which was based on their extended PLND series. The updated Briganti nomogram was recently validated in a different European cohort, and also demonstrated good performance characteristics.18 However, the characteristics of study cohorts affect the performance of predictive models, and the predictive models developed in Western populations might not be applicable in Asian populations. We have recently developed a nomogram for predicting lymph node metastasis in Asian men with prostate cancer.15 We used data from 541 men who underwent both RALP and PLND, performed by a single surgeon, between 2008 and 2011. The median number of lymph nodes removed was 17; 45 patients (8.3%) exhibited lymph node metastasis. Our nomogram was developed based on the preoperative PSA level, clinical stage, and biopsy Gleason score. This model produced a receiver operating characteristic curve of 0.88, and demonstrated high accuracy in internal validations. We suggest that a value of 4% probability for lymph node invasion is an appropriate cutoff for pursuing PLND. Using our model with a 4% cutoff value, approximately 60% of patients would be spared PLND. Current guidelines also recommend performing PLND based on preexisting nomograms. For instance, the European Association of Urology guidelines recommend performing PLND on patients with a risk of lymph node metastasis greater than 5%, based on the Briganti nomogram.13,19 Similarly, the National Comprehensive Cancer Network (NCCN) uses the nomogram by Cagiannos et al16 and recommends performing PLND on patients with predicted probabilities of lymph node metastasis of 2% or more.20 However, the nomogram used by Cagiannos et al16 originated from a cohort of individuals who underwent limited PLND. As mentioned above, limited PLND is associated with a high rate of false-negative results regarding lymph node invasion. Abdollah et al21 validated the NCCN guideline nomograms in patients treated with extended PLND, and demonstrated that the NCCN nomogram, which was based on a limited PLND template, tends to underestimate the true rate of lymph node invasion. Therefore, this study concluded that the recommended cutoff of 2% might not be appropriate to trigger PLND. The diagnosis of lymph node metastasis with current imaging modalities, such as computed tomography or magnetic resonance imaging (MRI), has limited accuracy in prostate cancer.22 These imaging modalities assess the pp 87 -92 88 Pelvic Lymph Node Dissection in Prostate Cancer: .... presence of lymph node invasion based on size and shape. Therefore, small metastases often remain undetectable, and lymph nodes enlarged by reactive hyperplasia are often misinterpreted as metastatic lesions.23 In prostate cancer, only 30% of lymph node metastases were detected by these imaging modalities, as the sizes of most metastatic lymph nodes were less than 8 mm.22 Lymphotropic ultrasmall superparamagnetic particles of iron oxide (USPIO) can be used as an MRI contrast agent for the detection of metastasis in normal-sized lymph nodes. Meta-analysis has shown that USPIO-enhanced MRI offers higher diagnostic performance than conventional MRI.24 In prostate cancer, combining USPIO-diffusion with weighted MRI was shown to improve the detection of metastasis in normal-sized lymph nodes.25 Currently, USPIO is not commercially available, and further research into other iron nanoparticle-based approaches is needed. Despite their improved diagnostic accuracies, the chance of lymph node metastasis resulting in a negative finding by USPIO MRI is 8-11%.25 Thus, negative USPIO MRI results do not rule out the need for a PLND. Extent of Pelvic Lymph Node Dissection The rate of lymph node metastasis increases linearly with the extent of PLND.14,26 The ideal number of lymph nodes removed has not yet been determined. While an autopsy series suggested that at least 20 lymph nodes should be removed for accurate staging,27 the probability that a patient has been correctly staged as node negative can be predicted based on not only the number of lymph nodes removed, but also the pathologic characteristics of the particular prostate cancer.28 However, meticulous excision within an anatomical template is more important than total lymph node count for defining an adequate PLND. Current guidelines recommend PLND with an extended template in patients with risk of lymph node metastasis.19,20 However, the anatomical boundaries of extended PLND vary among centers, and the terminologies and definitions of extended PLND have not been standardized. Generally, the template of extended PLND includes at least the internal iliac region, in addition to the obturator and external iliac areas.19,20,29 Many researchers have demonstrated that up to 50% of all positive lymph nodes are found at the internal iliac area.29-31 However, some authors include removal of the presacral area,32,33 and other authors advocate the additional removal of common iliac nodes, at least up to the ureteric crossing, based on imaging studies.34,35 To define the primary landing lymphatic drainage sites, Mattei et al34 used SPECT techniques, comprising intraprostatic injection of technetium (Tc-99m) nanocolloid, in 34 patients with organ-confined prostate cancer. They demonstrated that only 63% of all primary landing sites were located in a region including the external iliac, obturator, and internal iliac vessels, and proposed a new extended PLND template including the common iliac area up to the ureter crossing. Application of new PLND templates removed close to 75% of all primary landing sites. A recent study examining nodal metastasis using molecular techniques detected considerable numbers of positive lymph nodes in the common iliac area.35 Moreover, this study noted that the common iliac area was the only positive region in 11% of patients with nodal metastasis. Regarding retroperitoneal lymph nodes, the level to which the template should be extended is currently unknown. In a prospective study of 19 very high risk prostate cancer patients, PLND was performed with a template including the retroperitoneal area up to the aortic bifurcation.36 In very high risk patients, positive retroperitoneal lymph nodes were found in 14 (77.8%) patients, and no patients with negative common iliac lymph nodes had positive retroperitoneal lymph nodes. These results suggest that retroperitoneal lymph nodes might not represent primary lymphatic landing sites, and that the lymphatic spread ascends through common iliac lymph nodes in prostate cancer. The necessity of performing PLND in the presacral area also has been controversial. Joniau et al32 used a multimodality technique, encompassing SPECT and Tc99m nanocolloid approaches, for mapping pelvic lymph node metastasis in prostate cancer patients. This study included 74 patients at risk of lymph node metastasis or clinical T3 tumors, and proposed a new template including the presacral area. The authors emphasized the importance of removing all metastatic lymph nodes. By adding the presacral area to the template, the rate of patients in whom all metastatic lymph nodes were removed increased from 88% to 97% while the rate of correctly staged patients increased from 94% to 97%. Nevertheless, the benefits of PLND must also be balanced against the associated morbidity. Lymph node dissection in presacral area is associated with injury to the pelvic plexus, particularly the superior hypogastric nerves, which form the superior hypogastric plexus at the level of the sacral promontory. Injuries to these plexuses may affect functional outcomes.37 In rectal cancer literature, an association between the extent of lateral Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 13, No. 2, April 2014 pp 87 -92 89 Kwang Hyun Kim pelvic lymphadenectomy and functional outcome has been demonstrated.38 Although the impact of PLND on functional outcome has not been clearly demonstrated in prostate cancer, surgeons should acknowledge the possible adverse impact on functional outcome during dissection of the presacral region.39,40 Therapeutic Role of Pelvic Lymph Node Dissection The therapeutic benefit of PLND has remained as a contentious issue in the prostate cancer field. Many researchers did not find improved oncologic outcomes with extended PLND treatment, even in patients with higher risk disease.41-44 On the other hand, some authors have suggested that PLND may improve prostate cancer outcomes by eliminating micrometastatic nodal disease that might otherwise progress to systemic dissemination. In a retrospective analysis of 4,611 patients, Masterson et al45 reported that an increased number of removed lymph nodes was significantly associated with biochemical-free survival. The data obtained from 13,020 men in the SEER program also revealed improved prostate cancerspecific survival in patients with increased numbers of removed lymph nodes.46 While these improved oncologic outcomes were obtained from patients without lymph node involvement, Allaf et al47 reported that extended PLND treatment improved biochemical-free survival in patients with lymph node-positive disease. However, these results were based on retrospective analyses and non-randomized designs. In a non-randomized observational study, the template of PLND is selected based on the features of the particular cancer; thus, biases can occur in the analysis of oncologic outcomes. Moreover, extended PLND provides more accurate staging information, affecting the pathological nodal staging. For example, patients with lymph node metastasis diagnosed by extended PLND may be classified as lymph node metastasis-free, if only limited PLND is performed on them. This phenomenon is a well-known statistical artifact known as the ‘Will Rogers phenomenon’.48 Thus, extended PLND treatment might result in improved oncologic outcomes, according to the stage migration results. Multivariate analysis, adjusting the status of lymph node involvement, would also not completely overcome this artifact. To overcome the limitations of retrospective analysis and eliminate bias caused by stage migration, we utilized propensity score matching to adjust for preoperative variables associated with either lymph node metastasis or the performance of PLND.26 Our analysis included 170 Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 13, No. 2, April 2014 patients treated with extended PLND, and 294 patients treated with limited PLND, for intermediate or high risk prostate cancer. Propensity score matching placed 141 patients into each group, with no significant differences between the groups regarding their clinicopathological characteristics, except the incidence of lymph node metastasis. Although we were unable to demonstrate improved biochemical outcomes in the extended PLND group, the hazard ratio trend was inverted in favor of extended PLND (3 year biochemical-free survival rates, 77.8% and 73.5%, hazard ratio 0.85, p=0.497) in the matched cohort. However, the median follow up period was only 36 months; this period is too short to draw meaningful conclusions regarding oncologic outcomes. Thus, it would be extremely interesting to update our cohort results at 5 or 7 years. In addition, a large series of patients treated with PLND has shown that a considerable subset of men with lymph node metastasis remained free of disease at long term follow up. Furthermore, their oncologic outcomes were not necessarily poor. In a series of 122 patients with lymph node metastasis, the median cancer-specific survival at year 10 was 60.1%, and patients with 2 or less positive nodes had favorable long term results.49 Another large series of 703 node-positive patients also revealed that patients with up to 2 positive nodes experienced excellent cancer-specific survival rates, compared with patients with more than 2 positive lymph nodes.50 A recent study investigated the natural histories of 369 patients with lymph node metastasis, who were not treated with routine adjuvant hormonal treatment.51 The overall and cancer-specific survival rates at year 10 were 60% and 72%, respectively. This study also found significant differences in oncologic outcomes, according to the extent of nodal invasion. Given the high rate of cancer control and the different outcomes according to their nodal metastatic burdens, we speculate that lymph node-positive prostate cancers are not systemic diseases in all cases; therefore, PLND might have a curative effect in patients with minimal nodal invasion. Recently, the first prospective randomized trial examining the impact of the extent of PLND was published from China. 52 This study included 360 patients, randomized to receive either extended PLND or standard PLND. The median follow up time was 74 months; extended PLND was found to be associated with improved biochemical outcomes in patients with both intermediate and high risk prostate cancer. Although this initial evidence is informative, cancer-specific survival was not described in this study. Currently, randomized pp 87 -92 90 Pelvic Lymph Node Dissection in Prostate Cancer: .... trials comparing extended versus limited PLND are ongoing in Europe (NCT#01555086); these trials will evaluate the impact of PLND on long term outcomes in terms of both cancer-specific and overall survival rates. Conclusions In this review, we focused on the indication, extent, and efficacy of PLND in treating prostate cancer. The decision to perform PLND is based on a predictive model. Currently, several nomograms are available, which originated from an extended PLND series. Clinicians should choose the nomogram derived from the population which most closely resembles their patient population. In patients with risk of lymph node metastasis, PLND should be performed with an extended template. The benefit from removing lymphatic tissue in the presacral or common iliac area must be balanced against the associated morbidity. Although the therapeutic benefit of PLND has been debated, a growing body of evidence, including a recent randomized controlled trial, indicates that PLND is of therapeutic benefit. REFERENCES 1. Fowler JE, Whitmore WF. The incidence and extent of pelvic lymph node metastases in apparently localized prostatic cancer. Cancer. 1981;47:2941-2945. 2. Petros JA, Catalona WJ. Lower incidence of unsuspected lymph node metastases in 521 consecutive patients with clinically localized prostate cancer. J Urol. 1992;147:1574-1575. 3. Joung JY, Cho I, Lee KH. Role of pelvic lymph node dissection in prostate cancer treatment. Korean J Urol. 2011;52:437-445. 4. Abdollah F, Sun M, Thuret R et al. Decreasing rate and extent of lymph node staging in patients undergoing radical prostatectomy may undermine the rate of diagnosis of lymph node metastases in prostate cancer. Eur Urol. 2010;58:882-892. 5. Kawakami J, Meng MV, Sadetsky N et al. 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