- Email: [email protected]
Prognostic and Biological Significance of Lymph Node Spreading in Renal Cell Carcinoma
european urology 49 (2006) 220–222
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Editorial
Prognostic and Biological Significance of Lymph Node Spreading in Renal Cell Carcinoma Jean-Jacques Patard * Department of Urology and UMR 6061-CNRS, Rennes 1 University, France
Why it is still worthwhile to reassess the TNM classification The TNM classification is currently the most widely recognized prognostic system for renal cell carcinoma (RCC). However, this classification has many limitations because in many situations it is unable to predict the great outcome variability of RCC. Undoubtedly, the great strength of the TNM classification is that it is a universally accepted system due to its simplicity. However, its weakness is also due to its rudimentary character: obviously the TNM staging system does not take into account a variety of variables that reflect the biological complexity of the tumour. For this reason some prognostic systems have been recently developed that combine independent clinical and biological variables. However, all those systems are based on the TNM classification, which explains why reassessing this imperfect tool is still worthwhile. Most recent TNM revisions have been based on readjustments of tumour size cut-offs. Those controversies will likely continue because tumour size is a continuous variable that is unable by itself to be a unique valuable prognostic factor. However, other recent debates have focused on the relationship between T stage and peri-nephric fat, adrenal gland, IVC, and urinary collecting system invasion [1]. Although it has been specified since the 6th edition of the TNM classification that histological examina-
tion of a regional lymphadenectomy specimens should routinely include eight or more lymph nodes (LNs), to our knowledge no article has challenged the N1-N2 sub-classification that is recommended since the two latest TNM classifications. Previous studies mainly focused on the number of LNs that were required for an accurate staging as well as on the utility and extent of lymph node dissection (LND) [2]. The paper of Terrone et al. in this issue of European Urology reassesses the TNM classification based on the number of LNs involved and analyzes whether one or more than one positive LN is a relevant prognostic cut-off [3]. In his series, which included 618 patients who underwent a lymphadenectomy, he found a 14.2% positive LN rate, which is comparable to what is usually found in most RCC surgical series. The great majority of patients (84.4%) underwent an extensive standardized LND that provides a median number of 13 LNs for analysis. Interestingly, a significantly high percentage (48.8%) of distant metastases was associated with nodal invasion. However, the most informative result brought by Terrone’s paper is that no survival difference in locally advanced and in metastatic disease was found between N1 (n = 29) and N2 (n = 59) tumours. Among patients with positive LNs, the two relevant prognostic cut-offs were four involved nodes and a 60% LN density cut-off. Additionally, LN density was retained as an independent prognostic variable. Finally, in the case of a
* Department of Urology, Rennes University Hospital, CHU Pontchaillou, Rue Henri le Guillou, 35 033 Rennes, France. Tel. +33 2 99 28 42 70; Fax: +33 2 99 28 41 13. E-mail address: [email protected]. 0302-2838/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.12.025
european urology 49 (2006) 220–222
LN node invasion, the median survival time was 14.4 months, although an extensive LND was performed in most cases. This is consistent with the literature results independently from the extent of LND. Should a lymph node dissection be performed in RCC cases: Is it a debate from the past? The more we perform renal surgery for RCC, the less we observe the initial rules defined by Robson. The natural history of RCC is changing, and we are discovering an increasing number of renal tumours at an early stage. Additionally, with the development of conservative options in the management of RCC, it is becoming obvious for all urologists that an LND is no longer mandatory in all cases. A significant proportion of T1T2 renal tumours are now treated by laparoscopic radical nephrectomy and achieved good long-term results, even though eight LNs are likely not removed in all cases. For small tumours, laparoscopic partial nephrectomy as well as cryo- or radiofrequency ablation techniques now challenge the standard option, which is open partial nephrectomy. In all these conservative approaches, an LND is almost never discussed. Why is that? Although many old retrospective studies promoted the value of LND, more recent studies failed to show any benefit [4]. A selection of less advanced cases in the contemporary era could explain this difference, but survival data from randomized studies are still missing. The only randomized study that compares radical nephrectomy with and without LND has not yet provided survival data. However, it provides the important notion that when a proper preoperative imaging analysis is performed, the incidence of unsuspected node metastases is only 3.3% [5]. That means, as suggested by Pantuck et al., that LND can be safely omitted both for staging and curative purposes if preoperative CT imaging is negative, as is the case in most organ-confined tumours [4]. Thus, the only remaining question is the value of LND in locally advanced and metastatic tumours. Unfortunately, only data from retrospective studies are available. The group from the University of California–Los Angeles in a series of 129 RCC patients with LN invasion found that survival was better in patients who underwent LND compared with patients who not. The retrospective character of the study makes it difficult to ensure there was no unrecognized favourable selection bias within the operated group, although the two groups were not different for tumour stage or ECOG performance status [4]. Finally, in the context of metastatic disease, positive LN seems to be an unfavourable
221
predictor for systemic treatment response. Vasselli et al. divided patients with retroperitoneal lymphadenopathy and metastatic disease who were suitable for IL-2 cytokine therapy in different groups regarding positivity of LN and complete resection, and found no survival difference between patients with completely resected positive LNs and patients with negative LNs, whereas patients with incompletely resected masses had poorer survival [6]. Then in advanced disease, it seems reasonable to perform an LND when technically feasible. However, when considering the important proportion of patients with regional positive LN who have at the same time distant occult metastases as reported from autopsy studies [7], it is obvious that aggressive LND in case of metastatic disease makes sense only if patients are suitable for systemic treatment. This is confirmed by Pantuck at al., who reported a 4.5month median survival time in N + M1 patients who did not receive immunotherapy compared to 10.8 in patients who did [8]. Clearly, surgery alone is not able to cure patients with advanced disease. Understanding molecular pathways for lymphatic spreading: future therapeutic implications? Clinical data indicate that pathways for lymphatic and hematogenous tumour spreading are not similar. Among 900 patients with available data for N and M stage, Pantuck et al. reported 43 patients (4.8%) with isolated nodal invasion, 236 patients (26%) with distant metastases only, and 86 patients (9.6%) with nodal and distant metastases. When comparing survival in patients with limited nodal extension to patients with isolated distant metastases, and finally to patients with both nodal and systemic disease, it appeared that survival of patients with nodal disease only was equivalent to survival of patients with distant metastases; survival of patients with both nodal and distant metastases was worse [4]. However, when patients died from another cause nodal spreading appeared to be almost always associated with distant metastases, probably because of a longer natural history [7]. Recently, substantial progress has been made in the understanding of molecular pathways that lead to nodal or hematogenous spreading, respectively. RCC is a highly vascularized tumour and the VHL/ VEGF (vascular endothelial growth factor) pathway is believed to play an important role in tumour development and spreading. VEGF-A and related molecules such as VEGF-C and VEGF-D are potent pro-angiogenic factors involved in tumour growth and metastasis. Their intra-cellular signalling pathway, through specific receptors (VEGFRs) with
222
european urology 49 (2006) 220–222
tyrosine kinase activity provides interesting targets for anti-angiogenic designed drugs. Preliminary results in metastatic settings with these new antiangiogenic molecules are very promising. VEGFs-C and D bind with VEGFR-3, whereas VEGF A does not. VEGFR-2 is mainly expressed at the surface of the endothelial cells of blood vessels and appears to be essential for differentiation, proliferation, and vascular permeability; VEGFR-3 is expressed predominantly on lymphatic vessels and on tumour blood vessels. Robust experimental data suggest that VEGF-D promotes metastatic spreading through lymphatics and that lymphatic spread could be blocked with specific antibodies [9]. Finally, it has also been shown in animal models that blocking VEGF-C/VEGFR-3 pathway effectively prevents nodal spreading [10]. Although preliminary, this information and these experiments could form a rationale for proposing, based on VEGF/VEGFR tumour profile, specific targeted therapies for preventing or stopping lymphatic and hematogenous spreading, respectively. Those approaches could be valuable in an adjuvant and in a metastatic setting. Undoubtedly, in the future, improvements in tumour molecular profiling will be as important as an accurate preoperative imaging for determining optimal treatment strategy.
References [1] Han KR, Bui MH, Pantuck AJ, Freitas DG, Leibovich BC, Dorey FJ, et al. TNM T3a renal cell carcinoma: adrenal
[2]
[3]
[4]
[5]
[6]
[7] [8]
[9]
[10]
gland involvement is not the same as renal fat invasion. J Urol 2003;169:899–903, discussion 903-894. Joslyn SA, Sirintrapun SJ, Konety BR. Impact of lymphadenectomy and nodal burden in renal cell carcinoma: retrospective analysis of the National Surveillance, Epidemiology, and End Results database. Urology 2005;65: 675–80. Terrone C, Cracco F, Porpiglia F, Bollito E, Scoffone C, Poggio M, et al. Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 2006;49:324–31. Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 2003;169: 2076–83. Blom JH, van Poppel H, Marechal JM, Jacqmin D, Sylvester R, Schroder FH, et al. Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group. Eur Urol 1999;36:570–5. Vasselli JR, Yang JC, Linehan WM, White DE, Rosenberg SA, Walther MM. Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma. J Urol 2001;166:68–72. Johnsen JA, Hellsten S. Lymphatogenous spread of renal cell carcinoma: an autopsy study. J Urol 1997;157:450–3. Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer 2003;97:2995–3002. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;7:186–91. Lin J, Lalani AS, Harding TC, Gonzalez M, Wu WW, Luan B, et al. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res 2005;65:6901–9.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Editorial
Prognostic and Biological Significance of Lymph Node Spreading in Renal Cell Carcinoma Jean-Jacques Patard * Department of Urology and UMR 6061-CNRS, Rennes 1 University, France
Why it is still worthwhile to reassess the TNM classification The TNM classification is currently the most widely recognized prognostic system for renal cell carcinoma (RCC). However, this classification has many limitations because in many situations it is unable to predict the great outcome variability of RCC. Undoubtedly, the great strength of the TNM classification is that it is a universally accepted system due to its simplicity. However, its weakness is also due to its rudimentary character: obviously the TNM staging system does not take into account a variety of variables that reflect the biological complexity of the tumour. For this reason some prognostic systems have been recently developed that combine independent clinical and biological variables. However, all those systems are based on the TNM classification, which explains why reassessing this imperfect tool is still worthwhile. Most recent TNM revisions have been based on readjustments of tumour size cut-offs. Those controversies will likely continue because tumour size is a continuous variable that is unable by itself to be a unique valuable prognostic factor. However, other recent debates have focused on the relationship between T stage and peri-nephric fat, adrenal gland, IVC, and urinary collecting system invasion [1]. Although it has been specified since the 6th edition of the TNM classification that histological examina-
tion of a regional lymphadenectomy specimens should routinely include eight or more lymph nodes (LNs), to our knowledge no article has challenged the N1-N2 sub-classification that is recommended since the two latest TNM classifications. Previous studies mainly focused on the number of LNs that were required for an accurate staging as well as on the utility and extent of lymph node dissection (LND) [2]. The paper of Terrone et al. in this issue of European Urology reassesses the TNM classification based on the number of LNs involved and analyzes whether one or more than one positive LN is a relevant prognostic cut-off [3]. In his series, which included 618 patients who underwent a lymphadenectomy, he found a 14.2% positive LN rate, which is comparable to what is usually found in most RCC surgical series. The great majority of patients (84.4%) underwent an extensive standardized LND that provides a median number of 13 LNs for analysis. Interestingly, a significantly high percentage (48.8%) of distant metastases was associated with nodal invasion. However, the most informative result brought by Terrone’s paper is that no survival difference in locally advanced and in metastatic disease was found between N1 (n = 29) and N2 (n = 59) tumours. Among patients with positive LNs, the two relevant prognostic cut-offs were four involved nodes and a 60% LN density cut-off. Additionally, LN density was retained as an independent prognostic variable. Finally, in the case of a
* Department of Urology, Rennes University Hospital, CHU Pontchaillou, Rue Henri le Guillou, 35 033 Rennes, France. Tel. +33 2 99 28 42 70; Fax: +33 2 99 28 41 13. E-mail address: [email protected]. 0302-2838/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.12.025
european urology 49 (2006) 220–222
LN node invasion, the median survival time was 14.4 months, although an extensive LND was performed in most cases. This is consistent with the literature results independently from the extent of LND. Should a lymph node dissection be performed in RCC cases: Is it a debate from the past? The more we perform renal surgery for RCC, the less we observe the initial rules defined by Robson. The natural history of RCC is changing, and we are discovering an increasing number of renal tumours at an early stage. Additionally, with the development of conservative options in the management of RCC, it is becoming obvious for all urologists that an LND is no longer mandatory in all cases. A significant proportion of T1T2 renal tumours are now treated by laparoscopic radical nephrectomy and achieved good long-term results, even though eight LNs are likely not removed in all cases. For small tumours, laparoscopic partial nephrectomy as well as cryo- or radiofrequency ablation techniques now challenge the standard option, which is open partial nephrectomy. In all these conservative approaches, an LND is almost never discussed. Why is that? Although many old retrospective studies promoted the value of LND, more recent studies failed to show any benefit [4]. A selection of less advanced cases in the contemporary era could explain this difference, but survival data from randomized studies are still missing. The only randomized study that compares radical nephrectomy with and without LND has not yet provided survival data. However, it provides the important notion that when a proper preoperative imaging analysis is performed, the incidence of unsuspected node metastases is only 3.3% [5]. That means, as suggested by Pantuck et al., that LND can be safely omitted both for staging and curative purposes if preoperative CT imaging is negative, as is the case in most organ-confined tumours [4]. Thus, the only remaining question is the value of LND in locally advanced and metastatic tumours. Unfortunately, only data from retrospective studies are available. The group from the University of California–Los Angeles in a series of 129 RCC patients with LN invasion found that survival was better in patients who underwent LND compared with patients who not. The retrospective character of the study makes it difficult to ensure there was no unrecognized favourable selection bias within the operated group, although the two groups were not different for tumour stage or ECOG performance status [4]. Finally, in the context of metastatic disease, positive LN seems to be an unfavourable
221
predictor for systemic treatment response. Vasselli et al. divided patients with retroperitoneal lymphadenopathy and metastatic disease who were suitable for IL-2 cytokine therapy in different groups regarding positivity of LN and complete resection, and found no survival difference between patients with completely resected positive LNs and patients with negative LNs, whereas patients with incompletely resected masses had poorer survival [6]. Then in advanced disease, it seems reasonable to perform an LND when technically feasible. However, when considering the important proportion of patients with regional positive LN who have at the same time distant occult metastases as reported from autopsy studies [7], it is obvious that aggressive LND in case of metastatic disease makes sense only if patients are suitable for systemic treatment. This is confirmed by Pantuck at al., who reported a 4.5month median survival time in N + M1 patients who did not receive immunotherapy compared to 10.8 in patients who did [8]. Clearly, surgery alone is not able to cure patients with advanced disease. Understanding molecular pathways for lymphatic spreading: future therapeutic implications? Clinical data indicate that pathways for lymphatic and hematogenous tumour spreading are not similar. Among 900 patients with available data for N and M stage, Pantuck et al. reported 43 patients (4.8%) with isolated nodal invasion, 236 patients (26%) with distant metastases only, and 86 patients (9.6%) with nodal and distant metastases. When comparing survival in patients with limited nodal extension to patients with isolated distant metastases, and finally to patients with both nodal and systemic disease, it appeared that survival of patients with nodal disease only was equivalent to survival of patients with distant metastases; survival of patients with both nodal and distant metastases was worse [4]. However, when patients died from another cause nodal spreading appeared to be almost always associated with distant metastases, probably because of a longer natural history [7]. Recently, substantial progress has been made in the understanding of molecular pathways that lead to nodal or hematogenous spreading, respectively. RCC is a highly vascularized tumour and the VHL/ VEGF (vascular endothelial growth factor) pathway is believed to play an important role in tumour development and spreading. VEGF-A and related molecules such as VEGF-C and VEGF-D are potent pro-angiogenic factors involved in tumour growth and metastasis. Their intra-cellular signalling pathway, through specific receptors (VEGFRs) with
222
european urology 49 (2006) 220–222
tyrosine kinase activity provides interesting targets for anti-angiogenic designed drugs. Preliminary results in metastatic settings with these new antiangiogenic molecules are very promising. VEGFs-C and D bind with VEGFR-3, whereas VEGF A does not. VEGFR-2 is mainly expressed at the surface of the endothelial cells of blood vessels and appears to be essential for differentiation, proliferation, and vascular permeability; VEGFR-3 is expressed predominantly on lymphatic vessels and on tumour blood vessels. Robust experimental data suggest that VEGF-D promotes metastatic spreading through lymphatics and that lymphatic spread could be blocked with specific antibodies [9]. Finally, it has also been shown in animal models that blocking VEGF-C/VEGFR-3 pathway effectively prevents nodal spreading [10]. Although preliminary, this information and these experiments could form a rationale for proposing, based on VEGF/VEGFR tumour profile, specific targeted therapies for preventing or stopping lymphatic and hematogenous spreading, respectively. Those approaches could be valuable in an adjuvant and in a metastatic setting. Undoubtedly, in the future, improvements in tumour molecular profiling will be as important as an accurate preoperative imaging for determining optimal treatment strategy.
References [1] Han KR, Bui MH, Pantuck AJ, Freitas DG, Leibovich BC, Dorey FJ, et al. TNM T3a renal cell carcinoma: adrenal
[2]
[3]
[4]
[5]
[6]
[7] [8]
[9]
[10]
gland involvement is not the same as renal fat invasion. J Urol 2003;169:899–903, discussion 903-894. Joslyn SA, Sirintrapun SJ, Konety BR. Impact of lymphadenectomy and nodal burden in renal cell carcinoma: retrospective analysis of the National Surveillance, Epidemiology, and End Results database. Urology 2005;65: 675–80. Terrone C, Cracco F, Porpiglia F, Bollito E, Scoffone C, Poggio M, et al. Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 2006;49:324–31. Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 2003;169: 2076–83. Blom JH, van Poppel H, Marechal JM, Jacqmin D, Sylvester R, Schroder FH, et al. Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group. Eur Urol 1999;36:570–5. Vasselli JR, Yang JC, Linehan WM, White DE, Rosenberg SA, Walther MM. Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma. J Urol 2001;166:68–72. Johnsen JA, Hellsten S. Lymphatogenous spread of renal cell carcinoma: an autopsy study. J Urol 1997;157:450–3. Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer 2003;97:2995–3002. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;7:186–91. Lin J, Lalani AS, Harding TC, Gonzalez M, Wu WW, Luan B, et al. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res 2005;65:6901–9.