CARINI M.

DI CRISTOFANO, CLAUDIO

MINERVINI A

SERNI S

English

Archivio della ricerca- Università di Roma La Sapienza

e u r o p e a n u r o l o g y 5 5 ( 2 0 0 9 ) 1 3 1 5 – 1 3 2 0 1319Rebuttal from Authors re: Vincenzo Ficarra,Antonio Galfano and Stefano Cavalleri. Is SimpleEnucleation a Minimal Partial Nephrectomy Re-sponding to the EAU Guidelines’ Recommenda-tions? Eur Urol 2009;55:1315–8Andrea Minervini a,*, Sergio Serni a,Claudio Di Cristofano b, Marco Carini aaDepartment of Urology, University of Florence, Careggi Hospital,Florence, ItalybDepartment of Experimental Medicine, Sapienza University ofRome, Polo Pontino, I.C.O.T, Latina, ItalyIn recent years current opinion in urology haschanged from widespread skepticism against tumorenucleation (TE) for the treatment of renal cellcarcinoma (RCC) to widespread acceptance based onpublished studies of larger surgical series withlonger follow-up periods [1–4]. Indeed, we ourselvesand others recently showed that TE providesoncologic results similar to those of standardnephron-sparing surgery (NSS) [1–6].We adopted the TE technique in the early 1980sbecause, along with its favorable oncologic results, ithas the advantages of preserving more kidneyparenchyma and of avoiding major bleeding andopening of the collecting system [7]. Between 1986and April 2007, 803 patients had kidney surgery forpathologically confirmed, single, sporadic renaltumors. Of these, 502 patients (62.5%) had TEs and301 patients (37.5%) had radical nephrectomies.Moreover, the number of TEs in our departmenthas increased over time due to increasing surgicalexperience and better understanding of the techni-que.Nevertheless, the retrospective nature of pub-lished series on TE, along with the reported risk ofpseudocapsule invasion on the parenchymal side(based on data obtained by studies after an ex vivoTE or tumor sections of radical nephrectomy speci-mens) led many urologists to consider TE to be anunsafe technique with a high risk of incompletetumor excision [8,9]. The excellent clinical resultsreported using the TE technique were considered tobe related to the theoretically very slow localprogression of RCC remaining in the surgical bed,which was not detectable in short-term and med-ium-term follow-ups. The host immune responseDOIs of original articles: 10.1016/j.eururo.2008.07.038, 10.1016/j.eururo.2008.08.067* Corresponding author. Clinica Urologica I, Azienda OspedalieraCareggi, Università di Firenze, Villa Monna Tessa, Viale Pieraccini18, 50139, Firenze, Italy. Tel. +39 055 417645; Fax: +39 055 4377755.E-mail address: andreamine@libero.it (A. Minervini).was proposed as a possible explanation for thepersistent good results, similar to those of partialnephrectomy reported in long-term studies; othershypothesized that the key role of laser or diathermyablation of the tumor bed was to theoretically freethe kidney parenchyma from any tumor cells thatextended beyond the pseudocapsule [1,4].The wide acceptance and approval of a surgicaltechnique that aims to cure patients with RCCdepends on its technical feasibility and oncologicsafety as reported in retrospective series, along withprospective confirmation, on pathological examina-tion, that the technique is able to obtain negativesurgical margins (SMs).Our study confirmed that the tumor pseudocap-sule can be penetrated regardless of tumor size,with a reported infiltration rate of 26.6% on theparenchymal side and 6.6% on the perinephricadipose tissue side. The presence of a thin layer ofparenchymal tissue, however, invariably allows fornegative SMs, which also occur if no efforts aremade to leave a rim of healthy kidney tissue aroundthe neoplasm.All of these data explain the excellent results of TEfor treating not only intracapsular small masses<4 cm in diameter (pT1a) but also larger lesions [10].All pT1b–pT2 RCCs enucleated in our series (18.9%)published in this issue had negative SMs on patho-logical examination [10]. Indeed, all RCCs weresurrounded by a continuous (not fenestrated) fibrouspseudocapsule, regardless of tumor size, with amean pseudocapsule thickness of 0.39 mm (range:0.048–0.798 mm) that does not correlate with tumordimension. Moreover, although the risk of aninfiltrated pseudocapsule correlates with pathologi-cal tumor size, the risk is already significant withinthe pT1a group, which explains why the 4-cmthreshold cannot define two groups of tumors witha statistically significant difference in pseudocapsuleinfiltration rate (see Table 2 and 3 in Minervini et al[10]).One possible conclusion to be drawn from ourstudy is that if the surgeon follows the naturalcleavage plane between the tumor pseudocapsuleand the kidney parenchyma by blunt dissection,there is no risk of positive SMs, even with largermasses [10]. This surgical maneuver perfectly reflectsthe strategy, ‘‘Keep your friends close but your enemycloser.’’ Always ‘‘keeping an eye’’ on the tumormargin surrounded by its pseudocapsule allows thesurgeon to avoid entry into the tumor, and if thepseudocapsule is microscopically penetrated, aminimal layer of kidney tissue with a mean thicknessof 1.05 mm (range: 0.38–1.60 mm) invariably ensuresnegative SMs. We noted that this thin rim of normaldoi:10.1016/j.eururo.2008.09.002e u r o p e a n u r o l o g y 5 5 ( 2 0 0 9 ) 1 3 1 5 – 1 3 2 01320parenchymal tissue with signs of lymphoplasmocy-tic inflammation is present as ‘‘leopard spots’’ on theintact pseudocapsule and that it is always presentin the case of neoplastic penetration of the pseudo-capsule into the kidney tissue.We concur with Ficarra et al [11], who in theireditorial published in this issue of European Urologyconcluded, in agreement with the European Associa-tion of Urology (EAU) guidelines, that TE should beconsidered to be a minimal partial nephrectomy inwhich a very small rim of peritumoral tissue isremoved. But we also think that, for the future, theEAU guidelines should focus attention on the SMstatus without considering the width of the resectionmargins. Either a ‘‘minimal’’ or a ‘‘maximal’’ tumor-free SM is irrelevant and does not correlate with therisk of either local or distant disease progression.How can we explain the presence of a microscopicmargin of normal parenchyma scattered around thepseudocapsule and invariably present in case ofpseudocapsule penetration with tumor cells beyondit? Taking into consideration the hypotheses andsuggestions for future studies by Ficarra et al [11], wecan add that the presence of a pseudocapsule withsigns of infiltration within its layers or that iscompletely penetrated (as in a third of patientsundergoing NSS) could represent the first pathologicevidence of the capacity of tumor cells to infiltrateand invade surrounding normal tissue. Cancer cellinvasion into surrounding tissue is an early andcrucial step in carcinogenesis, and several recentstudies identified the genes and the expressions oftheir corresponding products that are thought to beinvolved in local and metastatic progression. Thesefactors include matrix metalloproteinases andadhesion molecules of the integrin family, and theiroverexpression or downregulation could allowcancer cells to infiltrate surrounding tissues. Whenstarted, however, cell–cell adhesion could be moreeffective between cancer cells and parenchymalcells than within the normal parenchyma, thusexplaining negative SMs if the enucleation is carriedout bluntly [12–13]. To further investigate thisaspect, it could be useful to explore the correlationsbetween these protein levels and both pseudocap-sule status and the extension of the pseudocapsularinfiltration.In conclusion, ‘‘keeping the enemy closer’’ bystaying close to the tumor would minimize the risk ofpositive SMs. Our study clearly represents a rationalefor adopting the TE technique as the standardprocedure for the excision of pT1a and pT1b RCCtumors, in conformity with the EAU guidelines [10].For the future, we think that the EAU guidelinesshould focus attention on the SM status withoutconsideration of the width of the resection margins.Conflicts of interest: The authors have nothing to disclose.References[1] Carini M, Minervini A, Masieri L, Lapini A, Serni S. Simpleenucleation for the treatment of pT1a renal cell carcinoma:our 20-year experience. Eur Urol 2006;50:1263–71.[2] Carini M, Minervini A, Lapini A, Masieri L, Serni S. Simpleenucleation for the treatment of renal cell carcinomabetween 4 cm and 7 cm in greatest dimension: progressionand long-term survival. J Urol 2006;175:2022–6.[3] Pertia A, Managadze L. Long-term results of simple enu-cleation for the treatment of small renal cell carcinoma. IntBraz J Urol 2006;32:640–7.[4] Kutikov A, VanArsdalen KN, Gershman B, et al. Enucleationof renal cell carcinoma with ablation of the tumour base.BJU Int 2008;102:688–91.[5] Ficarra V. Open radical nephrectomy versus open partialnephrectomy: is it still an issue? Eur Urol 2007;51:593–5.[6] Cambio AJ, Evans CP. Management approaches to smallrenal tumors. BJU Int 2006;97:456–60.[7] Carini M, Selli C, Muraro GB, Trippitelli A, Masini G, TuriniD. Conservative surgery for renal cell carcinoma. Eur Urol1981;7:19–24.[8] Vermooten V. Indications for conservative surgery in cer-tain renal tumors: a study based on the growth pattern ofthe clear cell carcinoma. J Urol 1950;64:200–8.[9] Blackley SK, Ladaga L, Woolfitt RA, Schellhammer PF. Exsitu study of the effectiveness of enucleation in patientswith renal cell carcinoma. J Urol 1988;140:6–10.[10] Minervini A, di Cristofano C, Lapini A, et al. Histopatho-logic analysis of peritumoral pseudocapsule and surgicalmargin status after tumor enucleation for renal cell car-cinoma. Eur Urol 2009;55:1410–8.[11] Ficarra V, Galfano A, Cavalleri S. Is simple enucleation aminimal partial nephrectomy responding to the EAUguidelines’ recommendations? Eur Urol 2009;55:1315–8.[12] Miyata Y, Iwata T, Ohba K, Kanda S, Nishikido M, KanetakeH. Expression of matrix metalloproteinase-7 on cancercells and tissue endothelial cells in renal cell carcinoma:prognostic implications and clinical significance for inva-sion and metastases. Clin Cancer Res 2006;12:6998–7003.[13] Jones J, Berkhoff S, Weich E, et al. Transient down-regula-tion of beta 1 integrin subtypes on kidney carcinoma cellsis induced by mechanical contact with endothelial cellmembranes. J Cell Mol Med 2007;11:826–38.

Rebuttal from Authors re: Vincenzo Ficarra, Antonio Galfano and Stefano Cavalleri. Is Simple Enucleation a Minimal Partial Nephrectomy Responding to the EAU Guidelines' Recommendations? Eur Urol 2009;55:1315-8

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Rebuttal from Authors re: Vincenzo Ficarra, Antonio Galfano and Stefano Cavalleri. Is Simple Enucleation a Minimal Partial Nephrectomy Responding to the EAU Guidelines' Recommendations? Eur Urol 2009;55:1315-8

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