Solid renal masses: histopathologic and clinical prediction based on preoperative evaluation through the R.E.N.A.L. Nephrometry Scoring System

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1 Rev Mex Urol 2015;75(1):8-13 ÓRGANO OFICIAL DE DIFUSIÓN DE LA SOCIEDAD MEXICANA DE UROLOGÍA, COLEGIO DE PROFESIONISTAS, A.C. Original article Solid renal masses: histopathologic and clinical prediction based on preoperative evaluation through the R.E.N.A.L. Nephrometry Scoring System I.A. Ramírez-Galindo*, A. Alias-Melgar, F. Carreño-de la Rosa, M. Pelayo-Nieto, E. Linden-Castro, A. González-Serrano and R. Cortez-Betancourt Department of Urology Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de lostrabajadores del Estado (ISSSTE), Mexico City, Mexico Received 29 September 2014; accepted 20 November 2014 Available online 22 January 2015 KEYWORDS Nephrometry; Renal tumor; R.E.N.A.L; Renal mass; Kidney cancer; Mexico Abstract Background: The R.E.N.A.L. Nephrometry Scoring System was developed as an imaging tool in the therapeutic approach to solid renal masses that enables a reproducible and quantitative evaluation of their anatomic characteristics. Methods: The surgical implications, complications, and histopathologic results were retrospectively analyzed in 38 patients that underwent nephron-sparing surgery for solid renal masses at the CMN 20 de Noviembre. The grade of complexity of the renal masses was calculated according to the R.E.N.A.L. Nephrometry Scoring System, subdividing the sample into 3 tumor complexity subgroups: low (4 to 6), moderate (7 to 9), and high (10 to 12) Results: There was a positive correlation between radiologic tumor complexity and the Fuhrman histologic grade (0.8283, 95%CI ), intraoperative blood loss (0.7073, 95%CI ), required intraoperative ischemia time (0.6627, 95%CI ), and overall surgical complication rate (0.5944, 95%CI ). Conclusions: Our results showed a correlation between surgical implication and radiologic complexity grade in renal masses. The reproducibility of and access to this tool make it useful in the prediction of surgical results, along with its having an impact on renal mass oncologic management Sociedad Mexicana de Urología. Published by Masson Doyma México S.A. All rights reserved. * Corresponding author at: Aristides 640 Col. Cumbres 3.er Sector Monterrey Nl. CP Telephone: +(52) drantoniozapata@icloud.com (J.A. Zapata-González) / 2015 Sociedad Mexicana de Urología. Publicado por Masson Doyma México S.A. Todos los derechos reservados.

2 Solid renal masses: histopathologic and clinical prediction based on preoperative evaluation through the R.E.N.A.L. Nephrometry Scoring System 9 PALABRAS CLAVES Seguridad clínica; Diálisis; Encuesta; Promoción de la salud Masas renales sólidas: predicción histopatológica y clínica en función de la evaluación preoperatoria con el uso del sistema de nefrometría R.E.N.A.L. Resumen Introducción: El sistema de nefrometría R.E.N.A.L., desarrollado como herramienta imagenológica de abordaje terapéutico para masas renales sólidas permite la evaluación reproducible y cuantitativa de sus características anatómicas. Metodología: Se analizaron retrospectivamente los resultados histopatológicos, así como las implicaciones quirúrgicas y complicaciones en 38 pacientes del CMN 20 de Noviembre, sometidos a cirugía preservadora de nefronas por masas renales sólidas. Se calculó el grado de complejidad de las masas renales de acuerdo al sistema de nefrometría R.E.N.A.L. subdividiendo la muestra en 3 subgrupos, baja (4-6), moderada (7-9) y alta complejidad (10-12) Resultados: Se estableció una correlación positiva entre la complejidad radiológica de la masa tumoral con el grado histológico de Fuhrman (0.8283, IC 95% ), con la cantidad de hemorragia transoperatoria (0.7073, IC 95% ), el tiempo requerido de isquemia transoperatoria (0.6627, IC 95% ) y la tasa global de complicaciones derivadas del procedimiento quirúrgico. (0.5944, IC 95% ). Conclusiones: De acuerdo a los resultados obtenidos, se evidencia la correlación de implicaciones quirúrgicas con el grado de complejidad radiológica en masas renales. Su reproductibilidad y accesibilidad la convierten en una herramienta útil para predicción de resultados quirúrgicos e incluso de impacto a nivel oncológico en el manejo de masas renales 2014 Sociedad Mexicana de Urología. Publicado por Masson Doyma México S.A. Todos los derechos reservados. Introduction The finding of a renal mass through an imaging study results in the need to characterize it by means of paraclinical studies in relation to its topography, dimensions, and anatomic relations in order to plan the definitive management. It is estimated that 20-30% of the solid renal masses that are incidentally diagnosed have a benign histology in the definitive analysis. Likewise, only 10-30% may have a potentially aggressive clinical behavior. 1-4 Despite the recent increase in the employment of other tools for predicting the clinical behavior of renal masses that includes percutaneous renal biopsy, its systematic use is not likely due to the need for supplies and trained personnel to perform it and interpret the results. 5-7 The R.E.N.A.L. Nephrometry Scoring System was developed in 2009 at the Fox Chase Cancer Center of Philadelphia by Kutikov and Uzzo 8 as a tool for the therapeutic approach to solid renal masses. It enables reproducible and quantitative evaluation of the anatomic characteristics of solid renal masses. There is increasing evidence of the correlation between renal mass anatomy and their histology and clinical behavior, as well as the risk for complications derived from definitive management Aims The aim of this study was to determine the usefulness and predictive value of the score obtained through the R.E.N.A.L. Nephrometry Scoring System, quantitatively establishing the anatomic complexity of solid renal masses, with the definitive histopathologic result and with surgical implications that included intraoperative blood loss, ischemia time, and complications arising from the procedure in patients that underwent open and laparoscopic partial nephrectomy at the CMN 20 de Noviembre. Methods A retrospective analysis of the histopathologic results, as well as the surgical implications and complications was carried out on 38 patients that underwent nephron-sparing surgery for solid renal masses at the CMN 20 de Noviembre within a 36-month time frame (July 2012 to July 2014). To be included in the study, the patients had to have available radiologic studies for calculating the R.E.N.A.L. score, as well as providing axial views and sagittal and coronal plane reconstructions for evaluation. Only patients with renal masses with significantly enhanced densities (+20 HU) in the computed tomography nephrographic phase or after administration of contrast medium in magnetic resonance imaging were included. Tables 1 and 2 show the demographic characteristics, the R.E.N.A.L. system scores, and the values taken into account for statistical correlation. Once selected, the score was calculated according to the R.E.N.A.L. Nephrometry Scoring System with the review of the corresponding imaging studies (35 contrast computed tomography scans and 3 contrast magnetic

3 10I i.a. Ramírez-Galindo et al Table 1 Demographic characteristics of the study population and the histopathologic and surgical results analyzed Demographic characteristics Women (n=20) Men (n=18) Mean age: years (29 76) Women: years (29-75) Men: 57.2 years (40-76) Type of Surgery Open partial nephrectomy (n=23) Laparoscopic partial nephrectomy (n=15) T stage T1a (n=23) T1b (n=15) Nephrometry (R.E.N.A.L.) score 4 to 6 (n=21) 7 to 9 (n=14) 10 or higher (n=3) Masses with anterior location (A) : 18 Masses with posterior location (P) : 13 Masses with undefined location (X) : 7 4 hilar masses (H), all in the group with the score of 7 to 9 Histology Benign (n=17) Oncocytoma (n=8) Angiomyolipoma (n=4) Leiomyoma (n=2) Focal pyelonephritis (n=3) Metanephric adenoma (n=1) Fuhrman I and II (n=14) Fuhrman III and IV (n= 8) Mean intraoperative blood loss Open partial nephrectomy: 496 ml Laparoscopic partial nephrectomy: 190 ml Mean warm ischemia time Open partial nephrectomy: min Laparoscopic partial nephrectomy: 5 min a Complications Need for transfusion (n=13) Urinary leakage (n=1) a Ischemia was carried out in only 4 patients in the laparoscopic PN group. Figure 1 Schematic illustration of the parameters evaluated by the R.E.N.A.L. system and related to the content of table 1. Taken from the original article by Kutikov et al. 5 resonance images). It is advisable to recall the imaging parameters evaluated by the R.E.N.A.L. Nephrometry Scoring System and the score calculated for each variable (fig. 1). Three subgroups were formed in accordance with the R.E.N.A.L. scores: low complexity (score of 4-6; n = 21); moderate complexity (score of 7-9; n = 14), and high complexity (score of 10-12; n = 3). The sample was made up of 20 women and 18 men, with a mean age of 53 years. Fifteen patients underwent laparoscopic partial nephrectomy and 23 with the open approach. Figure 2 shows the tomographic analysis taken into consideration for establishing the complexity of the evaluated tumors. Through the analysis of these data, the correlation was established between the grade of complexity of the renal masses and the Fuhrman nuclear histologic grade, the risk for bleeding and requirement of intraoperative ischemia, as well as complications related to the surgery. The sample was analyzed using the Pearson correlation coefficient with a 95% confidence interval and GraphPad Prism 6.0 software was employed. Results Forty-two percent (n = 16) of the patients resulted with benign histology of the resected mass, corresponding to angiomyolipoma (n = 4), oncocytoma (n = 8), focal pyelonephritis (n = 3), and leiomyoma (n = 1). Table 2 The imaging parameters evaluated by the R.E.N.A.L. system and the score calculated for each variable 1 point 2 points 3 points (R) Radius (maximum diameter in cm) 4 > 4 but < 7 7 (E) Exophytic or endophytic 50% < 50% Completely endophytic (N) Nearness to the collecting system or renal sinus (mm) (A) Anterior or posterior 7 No score allotted; the suffix A, P, or X is added >4 but <7 No score allotted; the suffix A, P, or X is added 4 No score allotted; the suffix A, P, or X is added The boldface letters correspond to the percentage of the diameter of the tumor mass that is exophytic or endophytic in the CAT, or if the mass is completely endophytic. A: anterior; P: posterior; X: not identified or unknown.

4 Solid renal masses: histopathologic and clinical prediction based on preoperative evaluation through the R.E.N.A.L. Nephrometry Scoring System 11 Figure 2 Renal mass with 87 HU enhancement in the nephrographic phase in a patient with solitary kidney. The R.E.N.A.L. score is 7 (R = 2; E = 1; N = 1, L = 3), classifying the mass as one of moderate complexity. Laparoscopic partial nephrectomy was performed. The histopathologic report in 36.8% of the patients (n = 14) was consistent with low histologic grade (Fuhrman I-II) clear cell renal cell carcinoma, and 21% (n = 8) had a high histologic grade (Fuhrman III and IV). The mean nephrometry system score was 5.25 for the benign lesions, 6.5 for the low histologic grade RCC patients, and 7.62 for those with high histologic grade disease. There was a direct correlation between radiologic complexity of the mass and histologic grade (r = , 95% CI ). Mean intraoperative blood loss for the low complexity masses was ml, 522 ml for the moderate complexity lesions, and 850 ml for the high complexity masses. There was a positive correlation between tumor complexity and the risk for intraoperative blood loss (r = , 95% CI ). Upon sub-classifying the patient sample according to the procedure employed (open or laparoscopic partial nephrectomy), the Pearson correlation coefficient established a significant association between the two variables (r = ; 95% CI for open partial nephrectomy and r = ; 95% CI for the laparoscopic procedure). The mean warm ischemia time required for the low complexity lesions was 3.09 min (only 3 patients needed ischemia); 14.6 min for those of moderate complexity (needed by 9 patients), and 26.6 min for the complex lesions (all those patients underwent ischemia). Cold ischemia was not employed in any of the patients. The correlation between the R.E.N.A.L. score and the intraoperative ischemia time required (r = , 95% CI ) showed overall predominance. There was a consistently positive correlation in both subgroups of the nephrometry score with the type of surgical procedure performed (open or laparoscopic) (r = ; 95% CI for laparoscopic partial nephrectomy; r = , 95% CI for open partial nephrectomy) and there was a greater association with the ischemia time employed in open surgery. One patient in the high complexity group presented with urine leakage, transfusions were needed in 5 patients in the low complexity group, 6 in the moderate complexity group, and 2 in the high complexity group. No other complications attributable to the surgical event were observed in any other patients. The overall complication rate showed a weaker correlation in relation to the other variables analyzed (0.5944; 95% CI ). Discussion Solid renal masses, particularly those with enhanced tomographic density, make up a heterogeneous entity with important variability in relation to biologic behavior. In the review conducted by Kutikov et al. 12 that included a sample of 525 patients treated through nephronsparing surgery, there was a positive correlation between anatomic complexity determined by the R.E.N.A.L. Nephrometry Scoring System and the histopathologic aspects of the renal masses, demonstrating an area under the curve of 0.76 upon comparing the histopathologic reports of malignancy with those that were benign. There are other nephrometry systems besides R.E.N.A.L., such as the Preoperative Aspects and Dimensions Used for an Anatomical Classification (PADUA) 13 and C-Index systems, 14 that take into account anatomic aspects similar to the R.E.N.A.L. system; the C-Index considers tumor concentricity to be a determining and definitive aspect of complexity. The role of kidney biopsy as a preoperative evaluation tool is undeniable in the patient undergoing surgical treatment for a solid renal mass. Percutaneous kidney biopsy currently has an increasing diagnostic role in relation to solid masses due to its improved diagnostic accuracy rate and lower complication rate When a percutaneous biopsy reveals malignancy, its positive

5 12I predictive value is greater than 95%. The negative predictive value in current case series is a bit higher than 80%, with a false positive result rate < 5%. Nevertheless, tumor histologic grade, one of the most difficult parameters to evaluate in percutaneous kidney biopsy, is not evaluated in the majority of kidney biopsy case series. However, it continues to be established as an independent outcome factor of cancer-specific survival Some current case series have shown a histologic grade determination rate as low as 62.7% in kidney biopsy series, and grade underestimation has been as high as 55% in patients that underwent percutaneous biopsy prior to surgical resection In the case series analyzed by Kutikov et al., the use of the nephrometry system resulted in a predictive capacity of 70%, 12 similar to that of percutaneous kidney biopsy. They concluded the possibility of incorporating the R.E.N.A.L. system as a potentially reproducible and predictive tool with respect to oncologic results. This would be particularly useful in advanced-age or high cardiovascular risk patients, whose morbidity derived from specific surgical treatment could be higher than that determined by the biologic properties of the tumor. One of the limitations of our analysis was the sample size. However, the correlation index facilitated a positive association in the grade of complexity established through radiologic methods with different relative aspects of cancer-specific survival and morbidity derived from surgical management. The degree of correlation with anatomic complexity prevailed, when individually taking into account the group of patients treated with open partial nephrectomy and those treated with the laparoscopic approach. Nevertheless, these results should be interpreted with the sample size kept in mind; a larger sample is needed in order to increase the possibility of the study s external validity. Conclusions According to our results, there is an obvious correlation between the clinical behavior and certain surgical implications in the management of solid renal masses in regard to their complexity determined through the R.E.N.A.L. Nephrometry Scoring System. There is increasing evidence in the medical literature with respect to the usefulness of nephrometry systems for planning the surgical treatment of solid renal masses, as well as the implications of their anatomic complexity with the surgical results and the degree of oncologic control, especially when planning nephron-sparing treatment. Its reproducibility and accessibility make it a useful tool for predicting surgical results and for having an impact at the oncologic level on the management of solid renal masses. Its systematization in relation to surgical planning, particularly in patients undergoing nephron-sparing surgery, would enable the establishment of more diverse management strategies guaranteeing satisfactory results in the area of oncologic control, as well as modulating the impact on the surgical morbidity resulting from the specific treatment, especially when there is a high cardiovascular risk. References i.a. Ramírez-Galindo et al 1. Parsons JK, Schoenberg MS, Carter HB. Incidental renal tumors: Casting doubt on the efficacy of early intervention. Urology. 2001;57: Russo P, Jang TL, Pettus JA, et al. Survival rates after resection for localized kidney cancer: 1989 to Cancer. 2008;113: Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol. 2009;182: Frank I, Blute ML, Cheville JC, et al. Solid renal tumors: An analysis of pathological features related to tumor size. J Urol. 2003;170: Lane BR, Samplaski MK, Herts BR, et al. 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6 Solid renal masses: histopathologic and clinical prediction based on preoperative evaluation through the R.E.N.A.L. Nephrometry Scoring System Leveridge M, Shiff D, Chung H, et al. Small renal mass needle core biopsy: Outcomes of non-diagnostic percutaneous biopsy and role of repeat biopsy [abstract 821]. J Urol. 2010;183: e Blumenfeld AJ, Guru K, Fuchs GJ, et al. Percutaneous biopsy of renal cell carcinoma underestimates nuclear grade. Urology. 2010;76.