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Re: Detailed Analysis of Patients with Metastasis to the Prostatic Anterior Fat Pad Lymph Nodes: A Multi-Institutional Study
LETTERS TO THE EDITOR/ERRATA
559
5. Elalouf V, Xylinas E, Klap J et al: Bladder recurrence after radical nephroureterectomy: predictors and impact on oncological outcomes. Int J Urol 2013; 20: 1078. 6. Gandaglia G, Bianchi M, Trinh QD et al: Survival after nephroureterectomy for upper tract urothelial carcinoma: a population-based competing-risks analysis. Int J Urol 2013. Epub ahead of print.
Re: Detailed Analysis of Patients with Metastasis to the Prostatic Anterior Fat Pad Lymph Nodes: A Multi-Institutional Study I. Y. Kim, P. K. Modi, E. Sadimin, Y.-S. Ha, J. H. Kim, D. Skarecky, D. Y. Cha, C. O. Wambi, Y.-C. Ou, B. Yuh, S. Park, E. Llukani, D. M. Albala, T. Wilson, T. Ahlering, K. Badani, H. Ahn, D. I. Lee, M. May, W.-J. Kim and D. H. Lee J Urol 2013; 190: 527e534.
To the Editor: This study is the largest pathological analysis of lymph nodes and lymph node metastases in the prostatic anterior fat pad (PAFP). The authors found that lymph nodes were present in the PAFP in 11.9% of cases at radical prostatectomy (RP), and metastatic lymph nodes were present in 0.94% of cases. Furthermore, they found that the majority of PAFP lymph node metastases (92.5%) were discovered in intermediate or high risk patients. Therefore, they concluded that while the PAFP should be removed in all patients, pathological analysis should be limited to patients with intermediate to high risk disease. The authors should be commended for this important contribution to the urological literature. At our institution removal and pathological analysis of the PAFP is routinely performed in open and robotic RPs. Since 2010, 876 PAFP specimens were obtained at RP, and 87 (9.9%) contained at least 1 lymph node. Of the cases where nodes were found in the PAFP 53 (60.9%) were performed open and 34 (39.1%) were performed using a robotic approach. Metastatic lymph nodes to the PAFP were found in 5 patients (0.57%), of whom 4 had positive nodes only in the PAFP and not in the pelvic lymph nodes. In all 5 patients the dominant nodule had an anterior component, and all patients had Gleason pattern 4 or 5 in the final specimen. Four of these patients (80%) had high or intermediate risk disease preoperatively. Our findings are similar to those of the authors but the difference in surgical approach should be emphasized. The majority of RPs in the present study (95%) were performed robotically, with removal of the PAFP before the pelvic lymph node dissection (PLND). Conceivably the pelvic lymph nodes could be sampled inadvertently during this maneuver, leading to false detection of PAFP nodes. In our study the majority of cases were performed open with PLND performed before removal of the PAFP. By performing the PLND first, the risk of inadvertently sampling obturator or hypogastric nodal tissue during anterior fat pad dissection is nearly eliminated. This suggests that the PAFP does harbor lymphatic tissue in some men, and it may represent drainage of the anterior prostate. Like the authors, we advocate routine removal of the PAFP in all patients undergoing RP. However, given that 10% to 20% of metastatic PAFP nodes occurred in men with low risk disease, we would advocate that all PAFP tissue undergo pathological analysis to accurately stage these patients. Respectfully, Mark W. Ball, Jeffrey K. Mullins, Jonathan I. Epstein, Alan W. Partin and Patrick C. Walsh Department of Urology The James Buchanan Brady Urological Institute & Department of Urology The Johns Hopkins University School of Medicine Baltimore, Maryland
To the Editor: We commend the authors for presenting the most current and largest reported series on metastatic prostate adenocarcinoma to the prostatic anterior fat pad. In this study PAFP nodes were found in 11.9% of cases, of which 0.94% harbored metastatic disease. The
560
LETTERS TO THE EDITOR/ERRATA
majority of those with metastases to the PAFP were of intermediate to high risk (92.5%) and were biochemical recurrence-free (51.8%) after observation or adjuvant therapy. Therefore, the authors concluded that PAFP should be done in all cases of radical prostatectomy but pathological examination should be limited to intermediate to high risk cases. The incidence of PAFP nodes and nodal metastasis in this study are not far from those reported in other studies, which fall in the range of 11.6% to 16.7% and 1.2% to 2.5%, respectively.13 The finding in the present series of PAFP metastasis in higher risk cancers is a recurring theme in other studies done of the PAFP. In addition, cases with metastasis to the PAFP have been associated with higher metastatic rates, more anteriorly located cancer, higher positive margin rates and cancer up-staging.14 The factors predicting PAFP metastasis are not yet known, although it is noteworthy that an earlier study found an association between higher prostate specific antigen levels and PAFP metastasis.5 The number of nodes needed to be removed to detect PAFP metastasis and the longterm effect of PAFP on survival have yet to be established.3 These facts, at this point, should caution us from excluding low risk patients in the pathological analysis. Our institutional data on 1,271 robot-assisted radical prostatectomies (RARPs) performed by a single surgeon since 2005 are consistent with those of the authors and previous literature. We found mean SD 1.6 1.09 PAFP nodes in 10.8% of patients (176 of 1,271) and 1.25 0.45 PAFP nodal metastasis in 16 patients (1.2%). Of those with PAFP metastasis 93.8% were high risk. The only patient with PAFP metastasis who was classified as low risk was found to also have pelvic node metastases but is still biochemical recurrence-free after 2 months of followup without further therapy. In 1 of our unpublished studies after mean SD followup 13.1 15.7 months we found that 93.8% of patients with PAFP nodal metastasis had recurrence. Further analysis showed PAFP nodal metastasis as an independent predictor of biochemical recurrence (OR 14.6, CI 1.93e111.54, p ¼ 0.009). Kaplan-Meier analysis showed similar biochemical recurrence-free survival between those with only PAFP nodal metastasis and those with only pelvic nodal metastasis. If we view this finding in light of the finding of Kim et al regarding the majority of PAFP nodes in the middle packet, it seems that PAFP nodes are distinct from pelvic nodes but when they harbor metastasis they behave like pelvic nodes. While we agree with the authors that PAFP node examination should be performed in all prostatectomies for proper staging, we believe that more data are required before we can identify the subset of patients in whom it is most beneficial. Respectfully, Patrick H. Tuliao and Koon Ho Rha Department of Urology Yonsei University College of Medicine Seoul, Republic of Korea 1. Finley DS, Deane L, Rodriguez E et al: Anatomic excision of anterior prostatic fat at radical prostatectomy: implications for pathologic upstaging. Urology 2007; 70: 1000. 2. Yuh B, Wu H, Ruel N et al: Analysis of regional lymph nodes in periprostatic fat following robot-assisted radical prostatectomy. BJU Int 2012; 109: 603. 3. Hansen J, Budaus L, Spethman J et al: Assessment of rates of lymph nodes and lymph node metastases in periprostatic fat pads in a consecutive cohort treated with retropubic radical prostatectomy. Urology 2012; 80: 877. 4. Deng FM, Mendrinos SE, Da K et al: Periprostatic lymph node metastasis in prostate cancer and its clinical significance. Histopathology 2012; 60: 1004. 5. Jeong J, Choi EY, Kang DI et al: Pathologic implications of prostatic anterior fat pad. Urol Oncol 2013; 31: 63.
Reply by Authors: In our study we reviewed 4,261 patients from 8 institutions, and analyzed the preoperative and postoperative features of 40 men with PAFP lymph node metastasis. Based on these findings, we recommended that PAFP be removed during all radical prostatectomies. Although this is the largest known series published to date on this topic, there are weaknesses in our study. First, the overwhelming majority of men in our series underwent robot-assisted
LETTERS TO THE EDITOR/ERRATA
radical prostatectomy. Since pelvic lymph node dissection during RARP is carried out following removal of the prostate, we acknowledge that lymph nodes within the PAFP may be due to incompletely removed obturator nodes. However, lymph node mapping has confirmed that nearly 90% of lymph nodes found in the PAFP are limited to the middle portion of the PAFP, suggesting that lymph nodes within the PAFP are, indeed, distinct from the pelvic lymph nodes. Since the submission of our article, we have performed lymph node mapping of PAFP during RARP in 200 additional patients, and the results are consistent with our reported observations. Another concern raised is our recommendation that pathological analysis of PAFP be limited to patients with intermediate to high risk oncologic features preoperatively. As a matter of oncologic principle, we agree with the view that all PAFP specimens should be analyzed by a pathologist. However, we believe that PAFP pathological analysis in patients with low risk features might not be cost-effective. In our series the overall incidence of PAFP lymph node metastasis in these men was 0.02%. That said, at all 8 institutions participating in the present series detailed pathological examination is still being performed in all PAFP specimens removed during radical prostatectomy. The most important question concerning PAFP remains its oncologic implication. As our initial study suggested, PAFP lymph node metastasis may have better prognosis than pelvic lymph node metastasis. This is in contrast to the unpublished series discussed by Tuliao and Rha. Currently we have expanded the scope of the study and are analyzing the data of more than 80 men with PAFP lymph node metastasis from 11 different institutions. This update will likely yield a more accurate clinical picture of men with PAFP lymph node metastasis. In the meantime we recommend that PAFP be removed in all patients. Although pathological analysis of PAFP is likely more cost-effective in men with intermediate to high risk oncologic features preoperatively, we do not discourage pathological examination of PAFP in men with low risk disease.
Re: Clinical Efficacy, Safety and Tolerability of Collagenase Clostridium Histolyticum for the Treatment of Peyronie Disease in 2 Large Double-Blind, Randomized, Placebo Controlled Phase 3 Studies M. Gelbard, I. Goldstein, W. J. Hellstrom, C. G. McMahon, T. Smith, J. Tursi, N. Jones, G. J. Kaufman and C. C. Carson, III J Urol 2013; 190: 199e207.
To the Editor: This article provides good insight into the role of this novel agent in the treatment of Peyronie disease (PD). Different medical therapies have been tried to date for the treatment of PD. Unfortunately not many have been subjected to double-blind drug testing. This study is unique since it is a placebo controlled, randomized, double-blind study and has renewed interest in the management of PD. However, there are a few points that need to be clarified. The method used for randomization is unclear, as there seems to be a discrepancy in the number of subjects in the collagenase Clostridium histolyticum (CCh) group vs the placebo group. Treatment related adverse effects were higher in the CCh group compared to controls. As both groups underwent penile plaque remodeling, the increased adverse events in the CCh group should be due to the intralesional injection of collagenase per se, which, if true, is a matter of serious concern. It could also be due to the discrepant number of patients in each group, and should be further evaluated. The ecchymotic lesions when healed may also form new plaques. The long-term effect of this ecchymosis needs to be observed. Although this study showed a statistically significant improvement in penile curvature, with mean SD 17.0 14.8 degrees change per subject in the CCh group, this improvement would not have been sufficient to avoid surgery. For example a 17-degree improvement in a subject with a 60 to 70 degrees curvature would have resulted in a final curvature of 43 to 53 degrees, which could preclude normal intercourse. The basis of the interval between the 2 injection sessions is unclear in the article.
561
559
5. Elalouf V, Xylinas E, Klap J et al: Bladder recurrence after radical nephroureterectomy: predictors and impact on oncological outcomes. Int J Urol 2013; 20: 1078. 6. Gandaglia G, Bianchi M, Trinh QD et al: Survival after nephroureterectomy for upper tract urothelial carcinoma: a population-based competing-risks analysis. Int J Urol 2013. Epub ahead of print.
Re: Detailed Analysis of Patients with Metastasis to the Prostatic Anterior Fat Pad Lymph Nodes: A Multi-Institutional Study I. Y. Kim, P. K. Modi, E. Sadimin, Y.-S. Ha, J. H. Kim, D. Skarecky, D. Y. Cha, C. O. Wambi, Y.-C. Ou, B. Yuh, S. Park, E. Llukani, D. M. Albala, T. Wilson, T. Ahlering, K. Badani, H. Ahn, D. I. Lee, M. May, W.-J. Kim and D. H. Lee J Urol 2013; 190: 527e534.
To the Editor: This study is the largest pathological analysis of lymph nodes and lymph node metastases in the prostatic anterior fat pad (PAFP). The authors found that lymph nodes were present in the PAFP in 11.9% of cases at radical prostatectomy (RP), and metastatic lymph nodes were present in 0.94% of cases. Furthermore, they found that the majority of PAFP lymph node metastases (92.5%) were discovered in intermediate or high risk patients. Therefore, they concluded that while the PAFP should be removed in all patients, pathological analysis should be limited to patients with intermediate to high risk disease. The authors should be commended for this important contribution to the urological literature. At our institution removal and pathological analysis of the PAFP is routinely performed in open and robotic RPs. Since 2010, 876 PAFP specimens were obtained at RP, and 87 (9.9%) contained at least 1 lymph node. Of the cases where nodes were found in the PAFP 53 (60.9%) were performed open and 34 (39.1%) were performed using a robotic approach. Metastatic lymph nodes to the PAFP were found in 5 patients (0.57%), of whom 4 had positive nodes only in the PAFP and not in the pelvic lymph nodes. In all 5 patients the dominant nodule had an anterior component, and all patients had Gleason pattern 4 or 5 in the final specimen. Four of these patients (80%) had high or intermediate risk disease preoperatively. Our findings are similar to those of the authors but the difference in surgical approach should be emphasized. The majority of RPs in the present study (95%) were performed robotically, with removal of the PAFP before the pelvic lymph node dissection (PLND). Conceivably the pelvic lymph nodes could be sampled inadvertently during this maneuver, leading to false detection of PAFP nodes. In our study the majority of cases were performed open with PLND performed before removal of the PAFP. By performing the PLND first, the risk of inadvertently sampling obturator or hypogastric nodal tissue during anterior fat pad dissection is nearly eliminated. This suggests that the PAFP does harbor lymphatic tissue in some men, and it may represent drainage of the anterior prostate. Like the authors, we advocate routine removal of the PAFP in all patients undergoing RP. However, given that 10% to 20% of metastatic PAFP nodes occurred in men with low risk disease, we would advocate that all PAFP tissue undergo pathological analysis to accurately stage these patients. Respectfully, Mark W. Ball, Jeffrey K. Mullins, Jonathan I. Epstein, Alan W. Partin and Patrick C. Walsh Department of Urology The James Buchanan Brady Urological Institute & Department of Urology The Johns Hopkins University School of Medicine Baltimore, Maryland
To the Editor: We commend the authors for presenting the most current and largest reported series on metastatic prostate adenocarcinoma to the prostatic anterior fat pad. In this study PAFP nodes were found in 11.9% of cases, of which 0.94% harbored metastatic disease. The
560
LETTERS TO THE EDITOR/ERRATA
majority of those with metastases to the PAFP were of intermediate to high risk (92.5%) and were biochemical recurrence-free (51.8%) after observation or adjuvant therapy. Therefore, the authors concluded that PAFP should be done in all cases of radical prostatectomy but pathological examination should be limited to intermediate to high risk cases. The incidence of PAFP nodes and nodal metastasis in this study are not far from those reported in other studies, which fall in the range of 11.6% to 16.7% and 1.2% to 2.5%, respectively.13 The finding in the present series of PAFP metastasis in higher risk cancers is a recurring theme in other studies done of the PAFP. In addition, cases with metastasis to the PAFP have been associated with higher metastatic rates, more anteriorly located cancer, higher positive margin rates and cancer up-staging.14 The factors predicting PAFP metastasis are not yet known, although it is noteworthy that an earlier study found an association between higher prostate specific antigen levels and PAFP metastasis.5 The number of nodes needed to be removed to detect PAFP metastasis and the longterm effect of PAFP on survival have yet to be established.3 These facts, at this point, should caution us from excluding low risk patients in the pathological analysis. Our institutional data on 1,271 robot-assisted radical prostatectomies (RARPs) performed by a single surgeon since 2005 are consistent with those of the authors and previous literature. We found mean SD 1.6 1.09 PAFP nodes in 10.8% of patients (176 of 1,271) and 1.25 0.45 PAFP nodal metastasis in 16 patients (1.2%). Of those with PAFP metastasis 93.8% were high risk. The only patient with PAFP metastasis who was classified as low risk was found to also have pelvic node metastases but is still biochemical recurrence-free after 2 months of followup without further therapy. In 1 of our unpublished studies after mean SD followup 13.1 15.7 months we found that 93.8% of patients with PAFP nodal metastasis had recurrence. Further analysis showed PAFP nodal metastasis as an independent predictor of biochemical recurrence (OR 14.6, CI 1.93e111.54, p ¼ 0.009). Kaplan-Meier analysis showed similar biochemical recurrence-free survival between those with only PAFP nodal metastasis and those with only pelvic nodal metastasis. If we view this finding in light of the finding of Kim et al regarding the majority of PAFP nodes in the middle packet, it seems that PAFP nodes are distinct from pelvic nodes but when they harbor metastasis they behave like pelvic nodes. While we agree with the authors that PAFP node examination should be performed in all prostatectomies for proper staging, we believe that more data are required before we can identify the subset of patients in whom it is most beneficial. Respectfully, Patrick H. Tuliao and Koon Ho Rha Department of Urology Yonsei University College of Medicine Seoul, Republic of Korea 1. Finley DS, Deane L, Rodriguez E et al: Anatomic excision of anterior prostatic fat at radical prostatectomy: implications for pathologic upstaging. Urology 2007; 70: 1000. 2. Yuh B, Wu H, Ruel N et al: Analysis of regional lymph nodes in periprostatic fat following robot-assisted radical prostatectomy. BJU Int 2012; 109: 603. 3. Hansen J, Budaus L, Spethman J et al: Assessment of rates of lymph nodes and lymph node metastases in periprostatic fat pads in a consecutive cohort treated with retropubic radical prostatectomy. Urology 2012; 80: 877. 4. Deng FM, Mendrinos SE, Da K et al: Periprostatic lymph node metastasis in prostate cancer and its clinical significance. Histopathology 2012; 60: 1004. 5. Jeong J, Choi EY, Kang DI et al: Pathologic implications of prostatic anterior fat pad. Urol Oncol 2013; 31: 63.
Reply by Authors: In our study we reviewed 4,261 patients from 8 institutions, and analyzed the preoperative and postoperative features of 40 men with PAFP lymph node metastasis. Based on these findings, we recommended that PAFP be removed during all radical prostatectomies. Although this is the largest known series published to date on this topic, there are weaknesses in our study. First, the overwhelming majority of men in our series underwent robot-assisted
LETTERS TO THE EDITOR/ERRATA
radical prostatectomy. Since pelvic lymph node dissection during RARP is carried out following removal of the prostate, we acknowledge that lymph nodes within the PAFP may be due to incompletely removed obturator nodes. However, lymph node mapping has confirmed that nearly 90% of lymph nodes found in the PAFP are limited to the middle portion of the PAFP, suggesting that lymph nodes within the PAFP are, indeed, distinct from the pelvic lymph nodes. Since the submission of our article, we have performed lymph node mapping of PAFP during RARP in 200 additional patients, and the results are consistent with our reported observations. Another concern raised is our recommendation that pathological analysis of PAFP be limited to patients with intermediate to high risk oncologic features preoperatively. As a matter of oncologic principle, we agree with the view that all PAFP specimens should be analyzed by a pathologist. However, we believe that PAFP pathological analysis in patients with low risk features might not be cost-effective. In our series the overall incidence of PAFP lymph node metastasis in these men was 0.02%. That said, at all 8 institutions participating in the present series detailed pathological examination is still being performed in all PAFP specimens removed during radical prostatectomy. The most important question concerning PAFP remains its oncologic implication. As our initial study suggested, PAFP lymph node metastasis may have better prognosis than pelvic lymph node metastasis. This is in contrast to the unpublished series discussed by Tuliao and Rha. Currently we have expanded the scope of the study and are analyzing the data of more than 80 men with PAFP lymph node metastasis from 11 different institutions. This update will likely yield a more accurate clinical picture of men with PAFP lymph node metastasis. In the meantime we recommend that PAFP be removed in all patients. Although pathological analysis of PAFP is likely more cost-effective in men with intermediate to high risk oncologic features preoperatively, we do not discourage pathological examination of PAFP in men with low risk disease.
Re: Clinical Efficacy, Safety and Tolerability of Collagenase Clostridium Histolyticum for the Treatment of Peyronie Disease in 2 Large Double-Blind, Randomized, Placebo Controlled Phase 3 Studies M. Gelbard, I. Goldstein, W. J. Hellstrom, C. G. McMahon, T. Smith, J. Tursi, N. Jones, G. J. Kaufman and C. C. Carson, III J Urol 2013; 190: 199e207.
To the Editor: This article provides good insight into the role of this novel agent in the treatment of Peyronie disease (PD). Different medical therapies have been tried to date for the treatment of PD. Unfortunately not many have been subjected to double-blind drug testing. This study is unique since it is a placebo controlled, randomized, double-blind study and has renewed interest in the management of PD. However, there are a few points that need to be clarified. The method used for randomization is unclear, as there seems to be a discrepancy in the number of subjects in the collagenase Clostridium histolyticum (CCh) group vs the placebo group. Treatment related adverse effects were higher in the CCh group compared to controls. As both groups underwent penile plaque remodeling, the increased adverse events in the CCh group should be due to the intralesional injection of collagenase per se, which, if true, is a matter of serious concern. It could also be due to the discrepant number of patients in each group, and should be further evaluated. The ecchymotic lesions when healed may also form new plaques. The long-term effect of this ecchymosis needs to be observed. Although this study showed a statistically significant improvement in penile curvature, with mean SD 17.0 14.8 degrees change per subject in the CCh group, this improvement would not have been sufficient to avoid surgery. For example a 17-degree improvement in a subject with a 60 to 70 degrees curvature would have resulted in a final curvature of 43 to 53 degrees, which could preclude normal intercourse. The basis of the interval between the 2 injection sessions is unclear in the article.
561