Does the Distance to Normal Renal Parenchyma (DTNRP) in Nephron-Sparing Surgery for Renal Cell Carcinoma Have an Effect on Survival?

ANTICANCER RESEARCH 25: 1629-1632 (2005)

Does the Distance to Normal Renal Parenchyma (DTNRP) in Nephron-sparing Surgery for Renal Cell Carcinoma have an Effect on Survival?

Z. AKÇETIN1, V. ZUGOR1, D. ELSÄSSER1, F.S. KRAUSE1, B. LAUSEN2, K.M. SCHROTT1 and D.G. ENGEHAUSEN1

Departments of 1Urology and 2Medical Informatics, Biometry and Epidemiology, University of Erlangen-Nuremberg, Germany

Abstract. Background: The effect of the distance to normal renal solitary kidneys. Additionally, organ preservation in the parenchyma (DTNRP) on survival after nephron-sparing surgery presence of an intact contralateral kidney can be performed (NSS) for renal cell cancer (RCC) was analyzed. Additionally, for small localized tumors with nearly equivalent results for the role of T-classification, tumor diameter and tumor grading tumor-specific survival, compared to nephrectomy (1). The was considered. Patients and Methods: NSS was performed on question of whether a small safety margin in intraoperative 126 patients with RCC between 1988 and 2000. Eighty-six patients histology may be adequate for favorable outcome of the were submitted to annual follow-up. These 86 patients were sub- patient constitutes an everyday issue for the practitioner classified into statistical groups according to the distance performing nephron-sparing surgery. In this context, the to normal renal parenchyma (≤ 2mm; > 2mm – ≤ 5mm; clinical impact of defined surgical margin widths for >5 mm), T-classification, tumor diameter (≤ 20mm; > 20mm - avoiding local tumor recurrence and, therefore, improved ≤ 30 mm; >30 mm – ≤ 50mm; >50mm) and tumor grading. survival after nephron-sparing surgery has been discussed The effect of belonging to one of these groups on survival was but still remains controversial. analyzed using the Log-Rank-Test (SPSS; version 11.0) and the In this retrospective study, we investigated the data of 86 Kaplan and Meier survival data. The level of significance was set patients who underwent nephron-sparing surgery at our at p<0.05. Results: During the follow-up period, 4 patients died department. Survival of the patients was analyzed by sub- related to RCC and 15 patients died from other causes. The classifying the population into statistical groups, focusing on tumor-specific survival was 95.4%. At the end of 2002, the mean distance to normal renal parenchyma (DTNRP), as well as follow-up time was 5.5 years (range 0.1 – 14.7). None of the on tumor diameter, T-stadium and tumor grading. variables which had been analyzed in our statistical groups had an effect on the overall survival. Conclusion: The distance to Patients and Methods normal renal parenchyma does not influence survival, suggesting an additional resection to be unnecessary even in cases where the The data of 126 patients, who underwent nephron-sparing surgery DTNRP is reported by frozen section to be less than 2 mm. RCC at our department between 1988 and 2000, were retrospectively up to 5 cm in tumor diameter can be safely removed by NSS, even reviewed. Eighty-six of these patients were followed-up at our in the presence of a functional intact contralateral kidney. centre, whereas 31 patients failed because of geographical reasons. Nine patients simultaneously suffered from additional malignant tumors and were therefore excluded, too. All other patients were Nephron-sparing surgery (NSS) for renal cell carcinoma included, regardless of possible selection criteria as elective or (RCC) represents a standard procedure for synchronous imperative indication or RCC in their former history. All patients bilateral tumors as well as for functional or anatomically were sub-classified into statistical groups according to the distance to normal renal parenchyma (≤ 2mm; >2 mm – ≤5 mm; >5 mm) as well as T-classification, tumor diameter (≤20 mm; >20 mm – 30 mm; >30 mm – ≤50 mm; >50mm) and tumor grading. Margin Correspondence to: Dr. David Elsässer, University of Erlangen- width was specified by direct measurement of the distance to Nuremberg, Department of Urology, Maximiliansplatz 1, D-91054 normal renal parenchyma (DTNRP) on the frozen section or by Erlangen, Germany. Tel: ++49-9131-822178, Fax: ++49-9131- quantitation of tumor-free second resection width in case of primary 822179, e-mail: [email protected] positive margins during operation. The histological data were recorded from the original histology and the T-stage was adjusted in Key Words: Margins, nephron sparing surgery, NSS, RCC, survival. accordance to the new TNM system of 1997 (2). The mean overall

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Table I. ∂ighty-six patients were analyzed in 4 statistical groups (DTNRP, T-classification, tumor diameter, tumor grading), respectively. The first vertical column shows absolute count of patients as well as percent distribution into the sub-groups. In the second column, all cases of death are given. The p- value was calculated by analyzing the statistical sub-groups for survival using the Log-Rank-Test. The next columns show tumor-related and non-tumor- related cases of death. A separate calculation of significance for these groups was not performed due to the small absolute counts of events.

Patients Deaths p-value Tumor- Non-tumor- related deaths related deaths n% n %

DTNRP <2 mm 38 44.10 7 18.4 0.808 2 5 >2 mm<5 mm 27 31.40 7 25.9 1 6 >5 mm 21 24.40 5 23.8 1 4

T-stage T1 74 86.00 14 18.9 0.260 3 11 T2 2 2.30 1 50.0 0 1 T3 10 11.60 4 40.0 1 3

Tumor diameter <20 mm 28 32.55 7 25.0 1 6 >20 mm<30 mm 28 32.55 6 21.4 0.105 0 6 >30 mm<50 mm 21 24.41 1 4.7 1 0 >50 mm 9 10.40 5 55.5 2 3

Tumor grading G1 33 38.37 8 24.2 0.626 1 7 G2 53 61.63 11 20.7 3 8

follow-up time was 5.5 (range 0.1 - 14.7) years. The mean overall not performed since the absolute number of patients was too survival was 5.99 years with a SD of 3.4 years. Four patients died small. The first row describes the three groups of distance to from progression of their RCC with only one local recurrence after normal parenchyma (<2mm, >2<5mm, >5mm). The a primary tumor of 6.5 cm. The indication of NSS in this single case majority of patients (38) was classified into the first group, was emergerd by renal agenesis of the contralateral side. The other 3 patients developed systemic disease, and all 3 patients had however fewer patients died compared with the total imperative indications for NSS. No patients with elective indication population and only two tumor-related deaths were found. for organ preservation have been lost due to progression of RCC. The following row shows the distribution of T-stage with 74 The overall tumor-specific survival was 96.5% in our study. patients belonging to the T1 group. These data are a result The follow-up data were provided by the tumor centrum of our of allocating all tumors up to 7 cm to T1 according to the University. The follow-up procedure basically included interval revised TNM-System of 1997 and therefore fail to provide history, physical examination, serum chemistry and ultrasonography. suitable information for survival after NSS. In contrast, after Additionally, chest X-ray and/or renal and chest CT were performed depending on surveillance intervals or clinical status. All classifying the population for tumor diameter (<20 mm, data were recorded to a SPSS database (version 11.0). Follow-up >20<30 mm, >30<50 mm and >50 mm), comparable was measured from the time of surgery to the current date or until groups could be generated, as displayed. Interestingly, no death, if appropriate. significant differences in outcome were found when analyzing The statistical groups were analyzed for survival using the Log- the first three groups and best survival was found for tumors Rank-Test and the Kaplan and Meier survival data. The level of >30<50 mm. In contrast, with tumor diameters >50 mm, significance was set at p<0.05. survival was worsened. These findings are emphasized by the Results data of tumor-related survival with 2 deaths among 9 cases, as displayed. However, no statistical significance could been All variables are displayed in Table I. The median follow-up derived from this observation. The last row demonstrates a was 5.5 years (range 0.1 – 14.7). The last two columns present typical distribition of tumors after NSS, with a majority of whether death was related to RCC or caused by other grade 2 RCC. However, G2 tumors had survival rates reasons. A separate calculation of p-value for this groups was comparable to G1 tumors.

1630 Akçetin et al: Distance to Normal Renal Parenchyma in Nephron-sparing Surgery

Discussion local or systemic relapse after NSS with margins >1 mm, whereas 1 local recurrence was found in 11 patients with Nephron-sparing surgery is a highly attractive alternative to margins <1 mm at a mean follow-up of 60 months. nephrectomy and provides long-term local control and cure The major argument against NSS comes from the of renal cell carcinoma (1). Besides imperative indications incidence of multifocal RCC, which has been reported to like solitary kidneys or bilateral renal tumors, studies with occur at an overall frequency of about 15% in a meta-analysis more than 10 years of follow-up have elucidated the safety of 1180 patients (9). Even for tumors smaller than 5 cm, of elective NSS in selected patients with normal multifocality has been described at a frequency of 15.6% (10). contralateral kidneys (3). A common problem for the Satellite tumors are often located close to the primary tumor, surgeon performing NSS is whether additional resections suggesting the incidence of multifocality to be found at a of peritumoral tissue have to be conducted if the distance similar level compared with potential tumor recurrence after to normal parenchyma is found to be very small in the NSS. In contrast to this hypothesis, a meta-analysis of NSS frozen section, as identified by intraoperative histological for tumors <4 cm, without defined margins of healthy tissue, results. In everyday practice, extensive reconstruction of revealed a local recurrence rate of only 0-3% (9). In a intrarenal structures and/or fibrin cleaving of parenchyma recently published study, NSS was performed electively in 53 already will have been performed, when the pathological patients with a safety margin of 10 mm, addressing the result of margin width may arrive. Therefore, not only the incidence of peritumoral satellite lesions (11). Three lesions operation times are affected by further resection were detected, including 2 which were histologically benign, procedures, but increasing the total ischemia time by and one of papillary RCC. This corresponds well with the additional clamping of the hilus may worsen the finding of about 70% adenoma origin of satellite lesions postoperative renal performance. Since tumor enucleation outlined previously (12). The cancer-specific survival in this has failed to provide acceptable local tumor control (4), a study was 96.3% at a mean follow-up of 61 months, which definite safety margin of healthy tissue has to be achieved. was nearly at an equal level (96.5%) in our analysis. Several recommendations for distance to normal renal Following radical tumor nephrectomy, histologically- parenchyma (DTNRP) between 5 and 10 mm or more have confirmed multifocality in the removed kidney had no been mentioned by different authors (1, 3). Our results significant impact for outcome of disease (7). As multifocality demonstrate that tumor freedom at the margin per se in the remaining kidney after NSS can not be excluded and, defines the outcome of patients with renal tumors <5 cm. therefore, its prognostic value can not be defined, risk factors These findings are in accordance with recently published for the presence of multifocality, like vascular invasion (10) studies focusing on the prognostic impact of margin width: or the presence of papillary components in the histology (13), Sutherland et al. investigated 44 cases of NSS with a have to be evaluated carefully in further studies for median size for DTNRP of 2 mm and found only one local correlation with survival after NSS. recurrance distant from the primary lesion at a follow-up In conclusion, nephron-sparing surgery for renal cancer of 49 months (5). Castilla et al. reviewed 69 patients with a can be performed safely even with minimal margins of remarkable follow-up of 8.5 years and stated no association healthy peritumoral tissue. For a selected patient population between margin width and disease progression (6). In with tumors <5 cm, tumor freedom at the resection site per contrast to our data, in this study TNM-stage and Fuhrman se presently defines the outcome of the disease. However, nuclear grade correlated positively with the outcome of further efforts are necessary to identify risk factors for patients. A possible explanation for this difference may be treatment failure other than T-stage, grading and tumor found in the heterogenity of their patient population with diameter, suggesting extended surveillance after NSS for a 50% bilateral tumors, suggesting a high percentage of defined group of patients. advanced or systemic disease. In a recently published prediction model for outcome of RCC, TNM-stage, tumor Acknowledgements size >5 cm, nuclear grade and histological tumor necrosis were found multivariately associated with patient survival The authors would like to thank Dipl.-Inf. S. Schick from the (7). However, the risk score derived from these data Tumorzentrum Erlangen, Germany, for providing surveillance data of the patients evaluated in this study. merges most cases of NSS into only two groups, therefore explaining the lack of significance for predicting survival by References each single tumor-related variable in our patient population. Confirming our results, a study reported by 1 Lerner SE, Hawkins CA, Blute ML, Grabner A, Wollan PC, Piper et al. with 67 patients revealed no correlation of Eickholt JT and Zincke H: Disease outcome in patients with tumor stage and grade with outcome of disease after NSS low stage renal cell carcinoma treated with nephron sparing or (8). Additionally, 49 patients in this study were without radical surgery. J Urol 155: 1868-1873, 1996.

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2 Sobin L and Wittekind C: UICC - TNM Classification of 10 Gohji K, Hara I, Gotoh A, Eto H, Miyake H, Sugiyama T, Malignant Tumours. 5th edition. Wiley-Liss New York, 1997. Okada H, Arakawa S and Kamidono S: Multifocal renal cell 3 Herr HW: Partial nephrectomy for unilateral renal carcinoma carcinoma in Japanese patients with tumors with maximal and a normal contralateral kidney: 10-year followup. J Urol diameters of 50 mm or less. J Urol 159: 1144-1147, 1998. 161: 33-34, 1999. 11 Zucchi A, Mearini L, Mearini E, Costantini E, Vivacqua C and 4 Rosenthal CL, Kraft R and Zingg EJ: Organ-preserving surgery Porena M: Renal cell carcinoma: histological findings on in renal cell carcinoma: tumor enucleation versus partial kidney surgical margins after nephron sparing surgery. J Urol 169: 905- resection. Eur Urol 10: 222-228, 1984. 908, 2003. 5 Sutherland SE, Resnick MI, Maclennan GT and Goldman HB: 12 Steinbach F, Stockle M, Griesinger A, Storkel S, Stein R, Miller Does the size of the surgical margin in partial nephrectomy for DP and Hohenfellner R: Multifocal renal cell tumors: a renal cell cancer really matter? J Urol 167: 61-64, 2002. retrospective analysis of 56 patients treated with radical 6 Castilla EA, Liou LS, Abrahams NA, Fergany A, Rybicki LA, nephrectomy. J Urol 152: 1393-1396, 1994. Myles J and Novick AC: Prognostic importance of resection 13 Kletscher BA, Qian J, Bostwick DG, Andrews PE and Zincke margin width after nephron-sparing surgery for renal cell H: Prospective analysis of multifocality in renal cell carcinoma: carcinoma. Urology 60: 993-997, 2002. influence of histological pattern, grade, number, size, volume 7 Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL and and deoxyribonucleic acid ploidy. J Urol 153: 904-906, 1995. Zincke H: An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 168: 2395-2400, 2002. 8 Piper NY, Bishoff JT, Magee C, Haffron JM, Flanigan RC, Mintiens A, Van Poppel HP, Thompson IM and Harmon WJ: Is a 1-CM margin necessary during nephron-sparing surgery for renal cell carcinoma? Urology 58: 849-852, 2001. 9 Uzzo RG and Novick AC: Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol 166: 6- Received August 2, 2004 18, 2001. Accepted February 4, 2005

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