The Changing Evolution of Renal Tumours: A Single Center Experience over atwo-decade Period

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1 European Urology European Urology 45 (2004) The Changing Evolution of Renal Tumours: A Single Center Experience over atwo-decade Period Jean-Jacques Patard a,*, Hicham Tazi a, Karim Bensalah a, Alejandro Rodriguez a, Sebastien Vincendeau a, Nathalie Rioux-Leclercq b, François Guillé a, Bernard Lobel a a Service d Urologie, CHU Pontchaillou, rue Henri Le Guilloux, Rennes, France b Department of Pathology, CHU Rennes, France Accepted 22 December 2003 Published online 24 January 2004 Abstract Objectives: To study the evolution of renal tumours treated in a single institution over a 2-decade period. Material and Methods: 729 patients surgically treated due to a renal tumour were included in this study. Age at diagnosis, gender, tumour size, TNM stage, percentage (%) of benign tumours, type of treatment, histologic subtype and mode of presentation were compared over 3 periods ( , , and ). Results: During the period of the study, the median tumour size decreased from 7.5 to 6 cm while the rate of nephron-sparing surgery (NSS) increased from 1.6 to 19.6% and from 3.1 to 46.9% in all tumours and in tumours measuring less than 4 cm respectively. In this former group, the percentage of benign tumours increased from 6.3 to 15.2% while the percentage of radical nephrectomies decreased from 100% to 54.2%. Conclusion: We are treating today a great amount of small good prognosis renal tumors as well as an increasing percentage of benign tumours. In both cases, expanding the role of NSS will significantly reduce the rate of useless radical nephrectomies. # 2004 Elsevier B.V. All rights reserved. Keywords: Carcinoma; Renal Cell; Diagnosis; Prognosis; Survival 1.Introduction Renal cell carcinoma (RCC) accounts for 3% of cancers in adults and 85% of all primary malignant kidney tumours [1]. Its incidence is being increasing [2]. While all stages are increasing together, it seems that localized, regional and metastatic disease have significantly different growth patterns [3]. Additionally, despite progress in imaging and detection modalities, mortality due to renal cancer also continues to increase [4]. Undoubtedly, the mode of presentation of renal tumours has changed with time [5]. Thus, it is now well known that incidental tumours that accounted for less than 10% in the 70s do represent today almost 60% * Corresponding author. Tel. þ ; Fax: þ address: jean-jacques.patard2@libertysurf.fr (J.-J. Patard). of all cases [6]. The rapid development of new conservative treatments going from laparoscopic nephronsparing surgery (NSS) to cryo and radiofrequency ablation of tumours is an indirect proof for such an evolution [7]. However, these changes are difficult to proof from tumour registries that do not provide an accurate description of each case or from reference centers that treat selected patterns of patients. The objective of this study was to describe in detail the changing evolution of renal cancer presentation and treatment in a single urological center with general recruitment. 2.Material and methods 2.1. Patients and tumours All patients who were operated at our institution for a renal parenchymal lesion suspicious for cancer between 1984 and /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eururo

2 J.-J. Patard et al. / European Urology 45 (2004) February 2003 were included in this study with the exception of urothelial tumours, at final pathology or incomplete dataset. Data were organized in a single database (File Maker Pro 5). Patients who were not suitable for surgery due to highly advanced disease, poor health condition or important co-morbidities were not considered for analysis. Based on symptoms at presentation the population was divided into 3 groups: incidental tumours which were defined as tumours discovered by routine examination or by US, CT or any other radiological imaging exam demanded after patient complaints not related to a renal tumour, tumours revealed by flank pain or hematuria, and tumours associated with altered health condition (weight loss, loss of appetite, loss of energy). Tumours were classified according to the 1997 TNM staging system [8] and to the Fuhrman grade [9]. Tumour size was determined on pathological specimens as the greater diameter in centimeters (cm). Among malignant tumours, histological subtypes were stratified according to the 1997 UICC classification [10]. Surgical policy regarding lymph node dissection remained consistent during all the period of the study: only hilar lymph nodes were removed with kidney and no extensive nodal dissection was performed. On the contrary, indications for nephrectomy in metastatic patients were subject to variations with time according to the state of the art in the different periods Variables analysed and statistical analysis The following variables were determined in each case: year of treatment, age, gender, symptoms at presentation, type of surgery (NSS vs. radical nephrectomy), benign or malignant tumour, histological subtype, tumour size, TNM stage and Fuhrman grade. w 2 -tests and Anova regression analysis were used respectively for qualitative and quantitative variables comparison. The so defined variables were compared among three distinct periods: , and SPSS 10.1 software was used for analysis. 3.Results Patients and tumour characteristics are shown in Table 1. A tendency to an older age at diagnosis was noted with a 63-year median age in the first period Table 1 Patient and tumour characteristics Gender, Male 447 (61.3%) Median age 64 (17 91) Median tumour size 7 (1 21) Benign tumours 43 (5.9%) Tumour stage T1 T2 373 (54.4%) T3 T4 313 (45.6%) Nodal invasion 86 (12.5%) Metastatic disease 104 (15.2%) Fuhrman grade GI GII 318 (46.4%) GIII GIV 358 (53.6%) Clear cell conventional RCC 635 (92.6%) Clinical symptoms Asymptomatic 268 (39.1%) Haematuria, flank pain 238 (34.7%) Altered health condition 180 (26.2%) % periods incidental tumors tumors <=4 cm NSS Fig. 1. Evolution of the rates of incidental tumours, tumours suitable for NSS and NSS procedures over a 20-year period. compared to a 66-year median age in the second period ( p ¼ 0:01). The changes which were very significant from period 1 to period 3 were: median tumour size (7.5 to 6 cm), the percentage of tumours suitable for NSS (12.2 to 26.9%), the rate of NSS (1.6 to 19.5%), the rate of NSS in tumours measuring less than 4 cm (3.1 to 46.9%), the percentage of benign tumours (4.6 to 9.8%) and the percentage of incidental tumours (24.4 to 51.1%) ( p < 0:01). The main trends that were found to be significant are depicted in Fig. 1. The percentage of radical nephrectomies which were performed for benign tumours decreased from 100% in the first period to 54.2% in the third period ( p ¼ 0:001). The percentage of benign tumours within tumours measuring less than 4 cm increased from 6.3% during the first period to 15.2% during the third period (p: ns). Additionally, changes did not occur at the same time for all the studied variables. For some variables such as age or migration within the T1 stage, the change occurred between periods 1 and 2 while a further stabilization occurred. However, for other variables such as percentage of NSS, percentage of incidental tumours the changing evolution continued within the last period. Then, the percentage of incidental tumours was 47% in 1998, 57% in 2002 and 67% in the first months of 2003 (p: ns). Four variables did not change significantly with time: sex ratio, T stage, M stage and Fuhrman grade. Thus the percentage of T3 tumours was 42% in the first period and it remained 43% in the last period. The same stability was observed for metastatic tumours which percentage was 15.6% in the first period compared to 15.4% in the last period. However, migrations occurred inside the TNM stage. By considering the 2002 revised T1 subclassification, it appeared that the percentage of T1a tumours was 31.7% in the first period compared to 52.8% in the third period ( p < 0:01). Similarly the amount of tumours with positive lymph nodes

3 492 J.-J. Patard et al. / European Urology 45 (2004) Table 2 Evolution of clinical presentation, tumour characteristics and treatment options in 729 patients over a 2-decade period p Period 1 Period 2 Period 3 Number of patients Gender, Male 162 (61.8%) 129 (58.1%) 156 (63.7%) 0.45 (ns) Median age 63 (19 85) 66 (17 89) 65 (21 91) 0.05 Median tumour size 7.5 (1 21) 7 (1 20) 6 (1.3 18) <0.01 Benign tumours 12 (4.6%) 7 (3.2%) 24 (9.8%) <0.01 Tumour stage T1 T2 135 (54%) 114 (53%) 124 (56.1%) p: 0.80 (ns) T3 T4 115 (46%) 101 (47%) 97 (43.9%) T1 substage T1a 26 (31.7%) 43 (53.1%) 47 (52.8%) <0.01 T1b 56 (68.3%) 38 (46.9%) 42 (47.2%) Nodal invasion 43 (17.2%) 25 (11.6%) 18 (8.1%) 0.01 Metastatic disease 39 (15.6%) 31 (14.4%) 34 (15.4%) 0.93 (ns) Fuhrman grade GI GII 119 (47.6%) 103 (47.9%) 96 (43.4%) 0.57 (ns) GIII GIV 131 (52.4%) 112 (52.1%) 125 (56.6%) Conventional RCC 235 (94.0%) 203 (94.4%) 197 (89.1%) 0.06 Benign tumours 12 (4.6%) 7 (3.2%) 24 (9.8%) <0.01 Radical Nx in benign tumours 12 (100%) 5 (71.4%) 13 (54.2%) <0.01 Tumour size 4 cm 32 (12.2%) 50 (22.5%) 66 (26.9%) <0.01 Benign tumours in tumours 4 cm 2 (6.3%) 4 (8%) 10 (15.2%) 0.08 (ns) NSS 4 (1.6%) 18 (8.2%) 47 (19.5%) <0.01 NSS in tumours 4 cm 1 (3.1%) 16 (32%) 30 (46.9%) <0.01 Clinical symptoms Asymptomatic 61 (24.4%) 94 (43.7%) 113 (51.1%) <0.01 Haematuria, flank pain 111 (44.4%) 68 (31.6%) 59 (26.7%) Altered health condition 78 (31.2%) 53 (24.7%) 49 (22.2%) ns: not significant, RCC: Renal cell carcinoma, NSS: Nephron-sparing surgery, Nx: Nephrectomy. decreased from 18.1% to 8.1% during the period of the study ( p < 0:01). All results are summarized in Table 2. 4.Discussion Increasing evidence exists that we do no longer treat the same renal tumours today than 20 years ago [11]. The dramatic development of new conservative approaches specially designed for the treatment of small tumours is an indirect proof for such an evolution [12,13]. Although convincing data exist that all stages of renal tumours [2] as well as the rate of incidental tumours increases with time [6], no comprehensive report has been made of the evolution within TNM stage, grade, tumour size, clinical presentation and treatment modalities in a single institution. In this study, we, as well as many authors [14], observed a dramatic increase in the amount of incidental renal tumours that progressed from 24.4% to 51.1% during a 20-year period. The most amazing fact is that this trend continues within the actual period and that today incidental tumours do represent the great majority of the tumours that we treat. It is consistent with the fact that treatment has evolved in the same time: during a 2-decade period, our rate of NSS has increased from 1.6 to 19.5%, while tumours suitable for NSS (4 cm) increased from 12.2 to 26.9%. In the same time the gap between theoretical indications for NSS and the rate of NSS procedures that were really done in tumours measuring less than 4 cm tended to reduce. This evolution had already been noticed by Herr, who reported a NSS increment at his institution, raising from 8% to 30% in less than 10 years [15]. Unfortunately the indication for nephron-sparing surgery was not recorded for the purpose of our study. Obviously it would have been interesting to study the evolution of the respective part of mandatory and elective NSS with time. Additionally, it is clear that the proportion of benign tumours that we have now to treat has increased with time. It has doubled during the period of this study (4.6% to 9.8%) and in the third period as much as 15.2% of tumours measuring less than 4 cm were benign tumours. An encouraging result is the evolution

4 J.-J. Patard et al. / European Urology 45 (2004) of the rate of radical surgery in benign tumours that decreased from 100% to 54.2%. It suggests that performing nephron-sparing surgery as often as technically possible in small renal tumours results in a decreased rate of useless radical nephrectomies. However, since imaging is not accurate enough for the diagnosis of benign tumours a more systematically use of NSS is required for definitively improving these results. It also reactivates the discussion on the usefulness of tumour biopsies in tumours measuring less than 4 cm. In our study no significant change was observed within the T stage of the TNM classification, based on the 1997 version. However, when considering the 2002 T1 sub classification, it appeared that T1a tumours increased from 31.7% to 52.8% during the period of the study. Similarly, tumour size lowered from a median size of 7.5 to 6 cm. Since 7 cm is a high size cut off, it explains why changes that occur for small tumours did not appear when the whole population of localized tumours was considered. Conversely we did not find a significant shift toward lower grades as it could have been expected from an increased number of small incidental tumours. 5.Conclusion The evolution of RCC presentation, TNM characteristics and changes in treatment options is visible and measurable in a single institution over a 2-decade period. Indeed, major changes have occurred within the low stage tumours. These facts conduct toward a predominant role of NSS in the near future. References [1] Dhote R, Pellicer-Coeuret M, Thiounn N, Debre B, Vidal-Trecan G. Risk factors for adult renal cell carcinoma: a systematic review and implications for prevention. BJU Int 2000;86:20 7. [2] Chow WH, Devesa SS, Warren JL, Fraumeni JF. Rising incidence of renal cell cancer in the United States. JAMA 1999;281: [3] Hock LM, Lynch J, Balaji KC. Increasing incidence of all stages of kidney cancer in the last 2 decades in the United States: an analysis of surveillance, epidemiology and end results program data. J Urol 2002;167: [4] Parsons JK, Schoenberg MS, Carter HB. Incidental renal tumors: casting doubt on the efficacy of early intervention. Urology 2001;57: [5] Pantuck AJ, Zisman A, Rauch MK, Belldegrun A. Incidental renal tumors. Urology 2000;56: [6] Jayson M, Sanders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology 1998;51: [7] Gill IS. Editorial review: Minimally invasive nephron-sparing surgery. Curr Opin Urol 2003;13:179. [8] Guinan P, Sobin LH, Algaba F, Badellino F, Kameyama S, MacLennan G, et al. TNM staging of renal cell carcinoma: Workgroup No. 3. Union International Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997;80: [9] Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6: [10] Storkel S, Eble JN, Adlakha K, Amin M, Blute ML, Bostwick DG, et al. Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997;80: [11] Pantuck AJ, Zisman A, Belldegrun A. The changing natural history of renal cell carcinoma. J Urol 2001;166: [12] Kaouk JH, Gill IS. Laparoscopic partial nephrectomy: a new horizon. Curr Opin Urol 2003;13: [13] Lowry PS, Nakada SY. Renal cryotherapy: 2003 clinical status. Curr Opin Urol 2003;13: [14] Luciani LG, Cestari R, Tallarigo C. Incidental renal cell carcinomaage and stage characterization and clinical implications: study of 1092 patients ( ). Urology 2000;56: [15] Herr HW. Partial nephrectomy for incidental renal cell carcinoma. Br J Urol 1994;74: Editorial Comment A. Zisman, Tel-Aviv, Israel Time trends in the biology of RCC, avoiding selection bias, are traceable using data originating from nationwide cancer databases. Alternatively, long term time trends originating from one institution as offered in this paper by Patard et al. also shed light on RCC biology and on therapeutic policy. Patard et al. report on smaller tumor size, an order of magnitude increase in the incidence of nephron-sparing surgery (NSS) performed in patients with normal contralateral kidney, fewer radical nephrectomies and a rise in the rate of benign tumors diagnosed in up to 15% of T1a tumours. An increase in the detection of incidental and smaller renal masses are attributed to the availability of slice imaging. Questions regarding their clinical significance, tumor characteristics, and optimal treatment are raised frequently and many of these issues are still controversial. It becomes evident that incidental RCC are of lower stage and grade and are associated with significantly improved survival. Therefore patients with low stage disease are thought to have now more therapeutic options other than radical nephrectomy. A variety of approaches to nephron-sparing surgery exist including open and laparoscopic partial nephrectomy, as well as cryosurgery, radiofrequency ablation and perhaps, in the future other non-invasive modalities

5 494 J.-J. Patard et al. / European Urology 45 (2004) such as photodynamic therapy or extracorporeal ablation, i.e. high frequency focused ultrasound ablation. The rise in the incidence of small T1 renal masses that turn to be of benign nature bring back the discussion on pre-operative renal mass biopsy. According to Patard s results in this issue, every seventh patient with a T1a lesion will not have cancer. Pertinent questions concerning renal mass biopsy are, is it safe? Is it accurate and conclusive? and does a conclusive benign pathology it exclude malignancy. Running through the literature, it becomes evident that the procedure is safe and percutaneous tract seeding is not a major concern. At the Mayo clinic, the overall accuracy of renal mass biopsy is 72%, the non-diagnostic rate is 21%, sensitivity is 83%, and specificity is poor (33%) [1]. Using the UCLA kidney cancer database, Chao et al. demonstrated 8% of RCC within benign oncocytomas [2], demonstrating that benign pathologic diagnosis does not completely exclude malignancy. Intuitively, it seems worthwhile to perform six T1a renal mass biopsies in order to spare one unnecessary nephrectomy, however there is still a major technological barrier to go across in order to be able to include renal mass biopsy in management flow chart of T1a renal mass. References [1] Dechet CB, Zincke H, Sebo TJ, King BF, LeRoy AJ, Farrow GM, et al. Prospective analysis of computerized tomography and needle biopsy with permanent sectioning to determine the nature of solid renal masses in adults. J Urol 2003;169(1):71 4. [2] Chao DH, Zisman A, Pantuck AJ, Freedland SJ, Figlin RA, dekernion JB, et al. Renal oncocytoma: clinical and pathological correlates (Submitted for publication).