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Zero Ischemia Laparoscopic Radio Frequency Ablation Assisted Enucleation of Renal Cell Carcinoma: Experience with 42 Patients
Zero Ischemia Laparoscopic Radio Frequency Ablation Assisted Enucleation of Renal Cell Carcinoma: Experience with 42 Patients Xiaozhi Zhao,* Shiwei Zhang,* Guangxiang Liu, Changwei Ji, Wei Wang, Xiaofeng Chang, Jun Chen, Xiaogong Li, Weidong Gan, Gutian Zhang, Andrea Minervini and Hongqian Guo† From the Urology (XZ, SZ, GL, CJ, WW, XC, XL, WG, GZ, HG) and Pathology (JC) Departments, The Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical School, Jiangsu, People’s Republic of China, and Department of Urology, University of Florence, Careggi Hospital (AM), Florence, Italy
Purpose: We evaluated the safety and efficacy of zero ischemia, radio frequency ablation assisted tumor enucleation for renal cell carcinoma. We report the incidence of complications, positive surgical margins, local recurrence, and progression-free and disease specific survival rates. Materials and Methods: We retrospectively reviewed data on 42 patients with renal cell carcinoma treated with zero ischemia laparoscopic radio frequency ablation assisted tumor enucleation between March 2006 and November 2009. Median age was 60 years (range 37 to 82) and 31 patients (73.8%) were male. The median greatest tumor dimension was 3.4 cm (range 1.8 to 6.1). The MannWhitney U, chi-square and Fisher exact tests were used to compare bleeding and complications. The paired t and Mann-Whitney U tests were used to compare glomerular filtration rates. The Kaplan-Meier method was used to calculate survival. Results: We found 32 tumors with a greatest dimension of 4 cm or less and 10 with a greatest dimension of 4 to 7 cm. Median blood loss was 82.5 ml (range 15 to 210). Overall 7 complications (16.6%) occurred, including postoperative fever in 4 cases (Clavien grade II) and prolonged urinary leakage in 3 (Clavien grade III). The PADUA (preoperative aspects and dimensions used for an anatomical) score was associated with prolonged urinary leakage (p ⫽ 0.03) but not with overall complications. No patient had positive surgical margins. The glomerular filtration rate did not differ before vs 12 months after surgery. Three-year cancer specific, cumulative and progression-free survival was 100%, 97.3% and 96.4%, respectively. Conclusions: Zero ischemia, laparoscopic radio frequency ablation assisted tumor enucleation of renal cell carcinoma is a safe, effective nephron sparing treatment that provides excellent oncological and functional outcomes.
Abbreviations and Acronyms CT ⫽ computerized tomography eGFR ⫽ estimated GFR GFR ⫽ glomerular filtration rate NSS ⫽ nephron sparing surgery RCC ⫽ renal cell carcinoma RFA ⫽ radio frequency ablation TE ⫽ tumor enucleation Submitted for publication February 11, 2012. Study received local ethics committee approval. * Equal study contribution. † Correspondence:, 321 Zhongshan Rd., Nanjing 210008, Jiangsu, People’s Republic of China (e-mail: [email protected]).
Key Words: kidney; carcinoma, renal cell; catheter ablation; ischemia; surgical procedures, minimally invasive NEPHRON sparing surgery has become the gold standard for small, incidental renal tumors.1 Excision of the tumor with a 1 cm margin of normal-appearing parenchyma and perinephric adipose tissue was considered the standard
surgical technique to avoid local recurrence.2 Recent publications concluded that, if the tumor is completely excised, the width of resected margins is not associated with disease progression.3,4
0022-5347/12/1884-1095/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.06.035 Vol. 188, 1095-1101, October 2012 RESEARCH, INC. Printed in U.S.A.
AND
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The TE technique of excising the tumor by blunt dissection without a visible rim of normal parenchyma recently showed excellent oncological and surgical results at long-term followup for RCC in several large retrospective studies.5–9 RFA is a minimally invasive technique that has been used to treat renal tumors for the last decade. RFA is promising for renal tumors because of its short learning curve and low complication rate.10,11 With long-term data available, RFA is increasingly being used to manage small renal tumors.12,13 However, the risk of residual tumor and local recurrence remains a major concern.14 Moreover, only a few pathological studies have confirmed complete ablation with the technique and imaging methods are limited to identify incomplete ablation and recurrence when the tumor is hypovascular. In 2003 Jacomides et al reported a technique that combines laparoscopic RFA with NSS without clamping the renal pedicle.15 This technique allows for improved hemostasis and no need for ischemia. Also, the surgical sample can be evaluated for positive margins. Series of RFA assisted clampless NSS have shown successful hemostasis during tumor excision and oncology outcomes comparable to those of conventional NSS.16 –18 However, 5 to 10 mm normal parenchyma must be sacrificed with this technique because of the ablation of healthy tissue around the tumor. In addition, this extra width of ablated tissue might translate into significant calyceal and vascular injuries. Since 2006, we have performed zero ischemia laparoscopic RFA assisted TE in patients with RCC. The aim of the current study was to specifically report oncological and functional outcomes in our 42 cases with a median followup of 37.5 months.
PATIENTS AND METHODS We retrospectively reviewed data on 42 patients who underwent zero ischemia laparoscopic RFA assisted TE between March 2006 and November 2009. We included only
patients with sporadic, unilateral, pathologically confirmed RCC 7 cm or less in greatest dimension. Median patient age was 60 years (range 37 to 82) and 31 (73.8%) were male. Median tumor greatest dimension was 3.4 cm (range 1.8 to 6.1). We included 11 patients in the study with an anatomically or functionally solitary kidney. Tumors were staged according to the 2010 UICC TNM classification system. No patient had preoperative or intraoperative suspected positive nodes (N0) and no patient showed distant metastasis before surgery (M0). Preoperatively patients underwent ultrasound and CT of the abdomen, chest x-ray and serum creatinine measurement. The eGFR of all patients was calculated preoperatively and postoperatively. All patients were informed about alternative options (RFA/NSS/active surveillance) and all provided signed informed consent to be in the study, which was approved by the local ethics committee.
Surgical Technique of Zero Ischemia Laparoscopic RFA Assisted TE Patients were placed in the lateral position. A retroperitoneal or transperitoneal 3 to 4-trocar laparoscopic approach was used depending on tumor location (fig. 1). After the renal fascia was opened, the renal artery was identified and suspended. The tumor and surrounding tissue were defatted. The tumor was localized under direct vision and laparoscopic ultrasonography. All tumors were biopsied using a 22 gauge TruCore® before RFA. The electrode was introduced through the abdominal wall or through the laparoscopic trocar to avoid an extra puncture. Intraoperative ultrasonography was used to guide electrode insertion and monitor ablation to ensure that thermal energy covered the base of the tumor. RFA was performed by the Cool-tip™ system controlled by a feedback algorithm. The radio frequency generator monitored tissue impedance and automatically adjusted the output of maximum energy delivery. Single electrodes (17 gauge) with a maximal ablation diameter of 1, 2 or 3 cm were used according to lesion size. RFA was performed for 1 to 3 cycles for 6 to 12 minutes each depending on tumor size and depth. The electrode track was ablated before it was withdrawn. The tumor was dehydrated and contracted after RFA, and laparoscopic enucleation without hilar clamping was performed in all cases. The kidney capsule was incised
Figure 1. Intraoperative images of zero ischemia laparoscopic RFA assisted renal tumor enucleation. Electrode insertion in renal tumor under ultrasound probe guidance (a). Enucleation of tumor from tumor bed after RFA (b). Ablation of tumor bed with bipolar coagulation (c).
LAPAROSCOPIC RADIO FREQUENCY ABLATION ENUCLEATION OF RENAL CELL CANCER
sharply toward the pseudocapsule, starting a few mm away from the lesion. When the tumor was reached, it was enucleated without a rim of normal parenchyma by blunt dissection and scissors on the natural cleavage plane between the pseudocapsule and normal parenchyma. Enucleation bed bleeding was controlled by bipolar coagulation or ablation with a 1 cm electrode for a few minutes. Incidental opening of the calyces was ligated by a running or single suture with 3-zero monofilament. The parenchymal defect was kept open after fibrin glue apposition and a drain was left at the end of surgery. All procedures were performed by a single surgeon (HG).
Pathological Evaluation Biopsy samples and the enucleated tumor underwent standard hematoxylin and eosin staining. Stage was assigned according to the 2010 UICC TNM classification system. The Fuhrman classification was used to assign nuclear grade.19
Followup Regimen Followup included blood chemistry studies, chest x-ray and serum creatinine measurement with CT or magnetic
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resonance imaging of the abdomen 3 and 6 months postoperatively, every 6 months until the end of year 2 and annually thereafter. The eGFR was calculated using the modified Modification of Diet in Renal Disease equation.20
Statistical Analysis Data are shown as the median and range. The KaplanMeier method was used to calculate survival. The chisquare and Mann-Whitney U tests were used to compare tumors 4 cm or less and 4 to 7 cm, as appropriate. The paired t test was used to compare eGFR preoperatively and postoperatively. The Fisher exact test was used to analyze the association of tumor size or PADUA score21 and complications. Statistical significance was considered at p ⬍0.05. Statistical analysis was done with SPSS® 17.0.
RESULTS Laparoscopic RFA assisted TE without clamping the renal hilar vessels was done in all cases (see table). The greatest dimension was 4 cm or less, and be-
Oncological and renal function outcomes of laparoscopic RFA and enucleation of RCC Tumor 4 cm or Less No. pts Median age (range) No. men/women No. side: Lt Rt Median cm tumor size (range) No. solitary kidney No. tumor location: Anterior Posterior Median Charlson comorbidity index (range) No. PADUA score: 6–7 8–9 10 or Greater Median mins operative time (range) Median ml blood loss (range) Median days hospital stay (range) No. histopathology: Clear cell Papillary Chromophobe No. tumor grade: G1 G2 G3 No. complication: Bleeding requiring transfusion Postop fever Prolonged urinary leakage No. recurrence Median ml/min/1.73 m2 eGFR modification of diet in renal disease (range):* Preop 12 mos Postop Mean mos followup (range) * Preop vs 12 months postop paired t test p ⫽ 0.09.
32 59 24/8 18 14 3.2 8 15 17 1.5 20 8 4 115 80 6
(37–82)
(1.8–3.9)
Tumor 4-7 cm 10 61 7/3 4 6 4.8 3
(0–3)
5 5 1.5
(70–160) (15–160) (5–9)
2 5 3 137.5 115 7
(45–78)
(4.1–6.1)
(0–3)
(95–185) (35–210) (5–11)
p Value 0.52 0.75 0.37
⬍0.001 0.75 0.86
0.78 0.045
0.03 0.24 0.06
Overall 42 60 31/11 22 20 3.4 11
(0–3)
22 13 7 120 82.5 6
(70–185) (15–210) (5–11)
9 1 0
37 4 1
13 17 2 5 0 3 2 1
2 7 1 2 0 1 1 0
15 24 3 7 0 4 3 1
67.5 (29.2–117.2) 65.4 (29.4–107.3) 44 (24–68)
68.6 (33.3–113.2) 65.4 (31.6–110.6) 35.5 (25–45)
1.0 1.0
0.81 0.78 0.04
(1.8–6.1)
20 22 1.5
28 3 1
1.0
(37–82)
68.6 (29.2–117.2) 65.4 (29.4–110.6) 37.5 (24–68)
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tween 4 and 7 cm for 32 and 10 tumors, respectively. Median operative time was 120 minutes (range 70 to 185). Median blood loss was 82.5 ml (range 15 to 210). Median hospital stay was 6 days (range 5 to 11). No residual tumor was found by enhanced CT (fig. 2). Operative time was significantly different between tumors 4 cm or less and those 4 to 7 cm (p ⫽ 0.03). However, no difference in blood loss and hospital stay was found between the 2 groups (p ⫽ 0.24 and 0.06, respectively). No intraoperative complications were recorded. Postoperative complications were classified according to the modified Clavien classification system.22 Overall 7 complications (16.6%) occurred, including postoperative fever in 4 cases (Clavien grade II) and prolonged urinary leakage requiring stent insertion in 3 (Clavien grade III). No patient underwent blood transfusion. No grade IV or V complications were recorded. Tumor size was not associated with overall complications or the incidence of urinary leakage. We found 22, 13 and 7 tumors with a PADUA score of 6 –7, 8 –9 and 10 or greater, respectively. PADUA score was associated with urinary leakage (p ⫽ 0.03) but not with overall complications.
Figure 2. Enhanced CT of patients with renal tumors, including 60-year-old female with 5.1 cm RCC (PADUA score 7) preoperatively (a) and postoperatively (b), 52-year-old male with 3.4 cm RCC (PADUA score 9) preoperatively (c) and postoperatively (d), and 34-year-old male with 5.1 cm RCC (PADUA score 11) preoperatively (e) and postoperatively (f).
Figure 3. Laparoscopic RFA assisted enucleation in 51-year-old male with 4.8 cm RCC. Pseudocapsule was intact and fat attached to tumor was retained after procedure (a). Necrosis was evident on pseudocapsule surface. After tumor was dissected, necrosis and hemorrhage were extensively found in tumor (b). Necrosis was more evident on parenchymal than on external side.
Histopathology revealed clear cell RCC in 37 cases (88.1%), papillary RCC in 4 (9.5%) and chromophobe RCC in 1 (2.4%). Overall 15 tumors (35.7%) were Fuhrman grade 1, 24 (57.1%) were grade 2 and 3 (7.1%) were grade 3. No patient showed positive surgical margins (figs. 3 and 4). Microscopy revealed that the pseudocapsule was intact in all cases and no viable tumor cells were identified on the parenchymal side of the tumor. Tumor cells were found on the fat side in some tumors that were large. Median followup was 37.5 months (range 24 to 68). Median GFR before surgery was 68.6 ml/minute/1.73 m2 (range 29.2 to 117.2) and 47.6% of patients (20 of 42) had a GFR of 60 ml/minute/1.73 m2
Figure 4. Laparoscopic RFA assisted enucleation in 61-year-old male with 2.8 cm RCC. Pathological evaluation showed intact pseudocapsule free of tumor cell invasion. Hemorrhage and microscopic hemorrhage were extensive. Tumor cell nuclei lost normal appearance. Few inflammatory cells infiltrated pseudocapsule. Reduced from ⫻40.
LAPAROSCOPIC RADIO FREQUENCY ABLATION ENUCLEATION OF RENAL CELL CANCER
or less. Median GFR was 65.4 ml/minute/1.73 m2 (range 29.4 to 110.6) 1 year postoperatively (vs preoperatively p ⫽ 0.09). Three-year cancer specific, cumulative and progression-free survival was 100%, 97.3% and 96.4%, respectively. One patient died of another cause 28 months after surgery. One patient with grade 3 clear cell RCC 3.8 cm in greatest dimension had recurrence in the nonablated zone, which was detected 35 months after surgery (kidney recurrence rate 2.4%). He underwent ultrasound guided percutaneous RFA and was free from any relapse 13 months after the procedure.
DISCUSSION Besides standard NSS, various techniques have been reported to treat renal tumors with promising outcomes, including TE, RFA and cryotherapy alone, and RFA assisted NSS. In the current study we retrospectively reviewed our series of patients with RCC treated with zero ischemia laparoscopic RFA assisted TE to determine whether this technique is effective and oncologically safe. With cumulative evidence, European Association of Urology guidelines concluded that a minimal tumor-free surgical margin appears appropriate to avoid local recurrence after conservative treatment.1 TE preserves more parenchyma and avoids major bleeding and opening of the collecting system. Longterm outcomes have resulted in a growing number of supporters.5–9 Carini et al reviewed data on 232 patients with T1a RCC who underwent TE, noting disease progression in 6.4% and no local recurrence at the enucleation bed.5 Minervini et al retrospectively analyzed data on 982 patients who underwent standard NSS and 537 who underwent TE for localized RCC, and noted equivalent oncological outcomes.6 However, oncological safety, particularly the incidence of positive surgical margins and local recurrence, remains a concern. In some studies TE involved ablation of the tumor base to eliminate potential residual tumor,8,9 although others reported excellent results of pure TE without ablation of the tumor bed. Minervini et al prospectively analyzed data on 90 consecutive patients who underwent TE for RCC.23 The surgical margin was negative in all cases and the investigators concluded that a thin layer of tissue can result in a negative surgical margin.23 Moreover, they prospectively evaluated data on 164 consecutive patients who underwent pure TE and noted a negligible local recurrence rate and negative surgical margins in all.24 Our technique has several advantages. It can minimize the damage caused by RFA energy to normal renal parenchyma, be easily performed with no hilar clamping and simplify the technical difficulty
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inherent to laparoscopic partial nephrectomy, decreasing the need for suturing. Unlike RFA as a single procedure, RFA assisted TE enables the surgeon to remove the tumor, which allows for precise pathological results with the possibility of identifying positive surgical margins as well as easier followup. The primary consideration with laparoscopic partial nephrectomy is minimizing renal ischemia, which is associated with a higher incidence of renal complications.25,26 Eliminating warm ischemia and preserving the maximal parenchyma may potentially prevent or delay a renal function decrease. Besides RFA assisted TE and RFA assisted NSS, there is another zero ischemia partial nephrectomy technique using renal arterial branch microdissection, which was reported by Gill et al.27 They reported longer operative time (mean 4.4 hours) and more blood loss (mean 206 ml) than for laparoscopic RFA assisted TE. The overall complication rate in our series was 16.6%. This was lower than for zero ischemia anatomical partial nephrectomy (22.8%) and the incidence reported in 2 recent NSS studies by Ficarra21 and Hew28 et al, which showed an overall complication rate of 22.6% and 23%, respectively. The complication spectrum differs among laparoscopic RFA assisted TE, TE alone and zero ischemia anatomical partial nephrectomy. Minervini et al found a surgical complication rate of 13.5% after pure TE (27 of 200 cases).29 Postoperatively blood loss occurred in 21 patients (10.5%) and urine leakage developed in 6 (3%). The postoperative complications of zero ischemia anatomical partial nephrectomy in 22.8% of cases reported by Gill et al were low grade (Clavien grades I and II) in 19.3% and high grade (Clavien grades III to V) in 3.5%.27 Overall 21% of patients received blood transfusion perioperatively. Urine leakage occurred in 3 patients (5.3%), which resolved spontaneously in all. We found a higher incidence of urine leakage and a lower incidence of postoperative blood loss. In the current study median blood loss was 82.5 ml, which is negligible and comparable to that in some robotic and open partial nephrectomy series. Although this technique did not achieve better intraoperative bleeding control, it decreased the incidence of blood transfusion after surgery. The clampless technique that we used may have advantages for hemostasis and allow for identification of the vessel at the tumor base. The incidence of urine leakage (7.1%) was higher than that of conventional laparoscopic NSS (range 1.7% to 3.6%) and TE (3%) according to published data. The reason for the higher incidence of urine leakage was probably a thermal lesion of the renal excretory system, which could have happened when the renal tumor was close to the calyces.
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RFA assisted NSS is defined as using an RFA electrode, which is inserted in the tumor and the normal parenchyma around the tumor to create an avascular plane 5 to 10 mm wide around the tumor. NSS is then performed without clamping the renal hilum and 5 mm of normal parenchyma are dissected with the tumor. Our technique differs from RFA assisted NSS. 1) RFA is performed to the tumor and thermal damage to normal parenchyma is limited by controlling the energy output and time. 2) The placement of electrodes in RFA assisted NSS could be complicated if the tumor is large, endophytic or close to vital structures, such as the renal pedicle or collecting system, and the complication rate may increase. 3) After ablating normal renal parenchyma in RFA assisted NSS, the incision starts within the ablated area and the tumor burden is difficult to identify, which may result in an increased risk of positive surgical margins.16 The same concern of positive surgical margins may exist with the current technique since the tumor was dehydrated and solidified, and tended to contract toward the electrode. However, the renal parenchyma around the tumor, relatively far from the electrode, was only slightly contracted. The cleavage plane between the pseudocapsule and normal parenchyma was easy to identify. The tumor was easy to
isolate from the base because it was solidified and the pseudocapsule became firm after ablation. In our study no positive margins were recorded and the pseudocapsule was intact at pathological evaluation in all cases. At a median followup of 37.5 months we recorded a true local recurrence and kidney recurrence rate of 0% and 2.4%, respectively. Only 1 patient had local recurrence but it was elsewhere in the kidney. Moreover, the cancer specific, cumulative and progression-free survival rates were 100%, 97.3% and 96.4%, respectively. These data indicate that the procedure is oncologically safe. However, we acknowledge that the current study can be criticized for the small sample size and the medium term followup reported, which is not long enough to clearly draw conclusions on the risk of systemic recurrence and the cancer specific survival rate. Moreover, this is a retrospective series and, therefore, it is associated with all the shortcomings of retrospective studies. We also lacked a control group to compare the results of pure TE during the same period. In conclusion, zero ischemia laparoscopic RFA assisted TE of RCC is a safe, acceptable nephron sparing treatment with promising oncological and functional outcomes, and a low complication rate.
REFERENCES 1. Ljungberg B, Hanbury DC, Kuczyk MA et al: Renal cell carcinoma guideline. Eur Urol 2007; 51: 1502. 2. Uzzo RG and Novick AC: Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol 2001; 166: 6. 3. Sutherland SE, Resnick MI, Maclennan GT et al: Does the size of the surgical margin in partial nephrectomy for renal cell cancer really matter? J Urol 2002; 167: 61. 4. Puppo P, Introini C, Calvi P et al: Long term results of excision of small renal cancer surrounded by a minimal layer of grossly normal parenchyma: review of 94 cases. Eur Urol 2004; 46: 477. 5. Carini M, Minervini A, Masieri L et al: Simple enucleation for the treatment of PT1a renal cell carcinoma: our 20-year experience. Eur Urol 2006; 50: 1263. 6. Minervini A, Ficarra V, Rocco F et al: Simple enucleation is equivalent to traditional partial nephrectomy for renal cell carcinoma: results of a nonrandomized, retrospective, comparative study. J Urol 2011; 185: 1604. 7. Minervini A, Serni S, Tuccio A et al: Simple enucleation versus radical nephrectomy in the treatment of pT1a and pT1b renal cell carcinoma. Ann Surg Oncol 2012; 19: 694.
8. Kutikov A, Vanarsdalen KN, Gershman B et al: Enucleation of renal cell carcinoma with ablation of the tumour base. BJU Int 2008; 102: 688. 9. Lapini A, Serni S, Minervini A et al: Progression and long-term survival after simple enucleation for the elective treatment of renal cell carcinoma: experience in 107 patients. J Urol 2005; 174: 57. 10. Ji C, Li X, Zhang S et al: Laparoscopic radiofrequency ablation of renal tumors: 32-month mean follow-up results of 106 patients. Urology 2011; 77: 798. 11. Gupta A, Raman JD, Leveillee RJ et al: General anesthesia and contrast-enhanced computed tomography to optimize renal percutaneous radiofrequency ablation: multi-institutional intermediate-term results. J Endourol 2009; 23: 1099.
15. Jacomides L, Ogan K, Watumull L et al: Laparoscopic application of radio frequency energy enables in situ renal tumor ablation and partial nephrectomy. J Urol 2003; 169: 49. 16. Zeltser IS, Moonat S, Park S et al: Intermediateterm prospective results of radiofrequency-assisted laparoscopic partial nephrectomy: a nonischaemic coagulative technique. BJU Int 2008; 101: 36. 17. Coleman J, Singh A, Pinto P et al: Radiofrequency-assisted laparoscopic partial nephrectomy: clinical and histologic results. J Endourol 2007; 21: 600. 18. White WM, Klein FA and Waters WB: Nephron sparing surgery using a bipolar radio frequency resection device. J Urol 2008; 180: 2343.
12. Zagoria RJ, Pettus JA, Rogers M et al: Long-term outcomes after percutaneous radiofrequency ablation for renal cell carcinoma. Urology 2011; 77: 1393.
19. Fuhrman SA, Lasky LC and Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6: 655.
13. Ferakis N, Bouropoulos C, Granitsas T et al: Long-term results after computed-tomographyguided percutaneous radiofrequency ablation for small renal tumors. J Endourol 2010; 24: 1909.
20. Lucas SM, Stern JM, Adibi M et al: Renal function outcomes in patients treated for renal masses smaller than 4 cm by ablative and extirpative techniques. J Urol 2008; 179: 75.
14. Kunkle DA, Egleston BL and Uzzo RG: Excise, ablate or observe: the small renal mass dilemma—a metaanalysis and review. J Urol 2008; 179: 1227.
21. Ficarra V, Novara G, Secco S et al: Preoperative aspects and dimensions used for an anatomical (PADUA) classification of renal tumours in patients
LAPAROSCOPIC RADIO FREQUENCY ABLATION ENUCLEATION OF RENAL CELL CANCER
who are candidates for nephron-sparing surgery. Eur Urol 2009; 56: 786. 22. Clavien PA, Sanabria JR and Strasberg SM: Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992; 111: 518. 23. Minervini A, di Cristofano C, Lapini A et al: Histopathologic analysis of peritumoral pseudocapsule and surgical margin status after tumor enucleation for renal cell carcinoma. Eur Urol 2009; 55: 1410.
24. Minervini A, Serni S, Tuccio A et al: Local recurrence after tumour enucleation for renal cell carcinoma with no ablation of the tumour bed: results of a prospective single-centre study. BJU Int 2011; 107: 1394. 25. Desai MM, Gill IS, Ramani AP et al: The impact of warm ischaemia on renal function after laparoscopic partial nephrectomy. BJU Int 2005; 95: 377. 26. Thompson RH, Frank I, Lohse CM et al: The impact of ischemia time during open nephron sparing surgery on solitary kidneys: a multi-institutional study. J Urol 2007; 177: 471.
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27. Gill IS, Patil MB, Abreu AL et al: Zero ischemia anatomical partial nephrectomy: a novel approach. J Urol 2012; 187: 807. 28. Hew MN, Baseskioglu B, Barwari K et al: Critical appraisal of the PADUA classification and assessment of the R.E.N.A.L. nephrometry score in patients undergoing partial nephrectomy. J Urol 2011; 186: 42. 29. Minervini A, Vittori G, Lapini A et al: Morbidity of tumour enucleation for renal cell carcinoma (RCC): results of a single-centre prospective study. BJU Int 2012; 109: 372.
Purpose: We evaluated the safety and efficacy of zero ischemia, radio frequency ablation assisted tumor enucleation for renal cell carcinoma. We report the incidence of complications, positive surgical margins, local recurrence, and progression-free and disease specific survival rates. Materials and Methods: We retrospectively reviewed data on 42 patients with renal cell carcinoma treated with zero ischemia laparoscopic radio frequency ablation assisted tumor enucleation between March 2006 and November 2009. Median age was 60 years (range 37 to 82) and 31 patients (73.8%) were male. The median greatest tumor dimension was 3.4 cm (range 1.8 to 6.1). The MannWhitney U, chi-square and Fisher exact tests were used to compare bleeding and complications. The paired t and Mann-Whitney U tests were used to compare glomerular filtration rates. The Kaplan-Meier method was used to calculate survival. Results: We found 32 tumors with a greatest dimension of 4 cm or less and 10 with a greatest dimension of 4 to 7 cm. Median blood loss was 82.5 ml (range 15 to 210). Overall 7 complications (16.6%) occurred, including postoperative fever in 4 cases (Clavien grade II) and prolonged urinary leakage in 3 (Clavien grade III). The PADUA (preoperative aspects and dimensions used for an anatomical) score was associated with prolonged urinary leakage (p ⫽ 0.03) but not with overall complications. No patient had positive surgical margins. The glomerular filtration rate did not differ before vs 12 months after surgery. Three-year cancer specific, cumulative and progression-free survival was 100%, 97.3% and 96.4%, respectively. Conclusions: Zero ischemia, laparoscopic radio frequency ablation assisted tumor enucleation of renal cell carcinoma is a safe, effective nephron sparing treatment that provides excellent oncological and functional outcomes.
Abbreviations and Acronyms CT ⫽ computerized tomography eGFR ⫽ estimated GFR GFR ⫽ glomerular filtration rate NSS ⫽ nephron sparing surgery RCC ⫽ renal cell carcinoma RFA ⫽ radio frequency ablation TE ⫽ tumor enucleation Submitted for publication February 11, 2012. Study received local ethics committee approval. * Equal study contribution. † Correspondence:, 321 Zhongshan Rd., Nanjing 210008, Jiangsu, People’s Republic of China (e-mail: [email protected]).
Key Words: kidney; carcinoma, renal cell; catheter ablation; ischemia; surgical procedures, minimally invasive NEPHRON sparing surgery has become the gold standard for small, incidental renal tumors.1 Excision of the tumor with a 1 cm margin of normal-appearing parenchyma and perinephric adipose tissue was considered the standard
surgical technique to avoid local recurrence.2 Recent publications concluded that, if the tumor is completely excised, the width of resected margins is not associated with disease progression.3,4
0022-5347/12/1884-1095/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.06.035 Vol. 188, 1095-1101, October 2012 RESEARCH, INC. Printed in U.S.A.
AND
www.jurology.com
1095
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LAPAROSCOPIC RADIO FREQUENCY ABLATION ENUCLEATION OF RENAL CELL CANCER
The TE technique of excising the tumor by blunt dissection without a visible rim of normal parenchyma recently showed excellent oncological and surgical results at long-term followup for RCC in several large retrospective studies.5–9 RFA is a minimally invasive technique that has been used to treat renal tumors for the last decade. RFA is promising for renal tumors because of its short learning curve and low complication rate.10,11 With long-term data available, RFA is increasingly being used to manage small renal tumors.12,13 However, the risk of residual tumor and local recurrence remains a major concern.14 Moreover, only a few pathological studies have confirmed complete ablation with the technique and imaging methods are limited to identify incomplete ablation and recurrence when the tumor is hypovascular. In 2003 Jacomides et al reported a technique that combines laparoscopic RFA with NSS without clamping the renal pedicle.15 This technique allows for improved hemostasis and no need for ischemia. Also, the surgical sample can be evaluated for positive margins. Series of RFA assisted clampless NSS have shown successful hemostasis during tumor excision and oncology outcomes comparable to those of conventional NSS.16 –18 However, 5 to 10 mm normal parenchyma must be sacrificed with this technique because of the ablation of healthy tissue around the tumor. In addition, this extra width of ablated tissue might translate into significant calyceal and vascular injuries. Since 2006, we have performed zero ischemia laparoscopic RFA assisted TE in patients with RCC. The aim of the current study was to specifically report oncological and functional outcomes in our 42 cases with a median followup of 37.5 months.
PATIENTS AND METHODS We retrospectively reviewed data on 42 patients who underwent zero ischemia laparoscopic RFA assisted TE between March 2006 and November 2009. We included only
patients with sporadic, unilateral, pathologically confirmed RCC 7 cm or less in greatest dimension. Median patient age was 60 years (range 37 to 82) and 31 (73.8%) were male. Median tumor greatest dimension was 3.4 cm (range 1.8 to 6.1). We included 11 patients in the study with an anatomically or functionally solitary kidney. Tumors were staged according to the 2010 UICC TNM classification system. No patient had preoperative or intraoperative suspected positive nodes (N0) and no patient showed distant metastasis before surgery (M0). Preoperatively patients underwent ultrasound and CT of the abdomen, chest x-ray and serum creatinine measurement. The eGFR of all patients was calculated preoperatively and postoperatively. All patients were informed about alternative options (RFA/NSS/active surveillance) and all provided signed informed consent to be in the study, which was approved by the local ethics committee.
Surgical Technique of Zero Ischemia Laparoscopic RFA Assisted TE Patients were placed in the lateral position. A retroperitoneal or transperitoneal 3 to 4-trocar laparoscopic approach was used depending on tumor location (fig. 1). After the renal fascia was opened, the renal artery was identified and suspended. The tumor and surrounding tissue were defatted. The tumor was localized under direct vision and laparoscopic ultrasonography. All tumors were biopsied using a 22 gauge TruCore® before RFA. The electrode was introduced through the abdominal wall or through the laparoscopic trocar to avoid an extra puncture. Intraoperative ultrasonography was used to guide electrode insertion and monitor ablation to ensure that thermal energy covered the base of the tumor. RFA was performed by the Cool-tip™ system controlled by a feedback algorithm. The radio frequency generator monitored tissue impedance and automatically adjusted the output of maximum energy delivery. Single electrodes (17 gauge) with a maximal ablation diameter of 1, 2 or 3 cm were used according to lesion size. RFA was performed for 1 to 3 cycles for 6 to 12 minutes each depending on tumor size and depth. The electrode track was ablated before it was withdrawn. The tumor was dehydrated and contracted after RFA, and laparoscopic enucleation without hilar clamping was performed in all cases. The kidney capsule was incised
Figure 1. Intraoperative images of zero ischemia laparoscopic RFA assisted renal tumor enucleation. Electrode insertion in renal tumor under ultrasound probe guidance (a). Enucleation of tumor from tumor bed after RFA (b). Ablation of tumor bed with bipolar coagulation (c).
LAPAROSCOPIC RADIO FREQUENCY ABLATION ENUCLEATION OF RENAL CELL CANCER
sharply toward the pseudocapsule, starting a few mm away from the lesion. When the tumor was reached, it was enucleated without a rim of normal parenchyma by blunt dissection and scissors on the natural cleavage plane between the pseudocapsule and normal parenchyma. Enucleation bed bleeding was controlled by bipolar coagulation or ablation with a 1 cm electrode for a few minutes. Incidental opening of the calyces was ligated by a running or single suture with 3-zero monofilament. The parenchymal defect was kept open after fibrin glue apposition and a drain was left at the end of surgery. All procedures were performed by a single surgeon (HG).
Pathological Evaluation Biopsy samples and the enucleated tumor underwent standard hematoxylin and eosin staining. Stage was assigned according to the 2010 UICC TNM classification system. The Fuhrman classification was used to assign nuclear grade.19
Followup Regimen Followup included blood chemistry studies, chest x-ray and serum creatinine measurement with CT or magnetic
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resonance imaging of the abdomen 3 and 6 months postoperatively, every 6 months until the end of year 2 and annually thereafter. The eGFR was calculated using the modified Modification of Diet in Renal Disease equation.20
Statistical Analysis Data are shown as the median and range. The KaplanMeier method was used to calculate survival. The chisquare and Mann-Whitney U tests were used to compare tumors 4 cm or less and 4 to 7 cm, as appropriate. The paired t test was used to compare eGFR preoperatively and postoperatively. The Fisher exact test was used to analyze the association of tumor size or PADUA score21 and complications. Statistical significance was considered at p ⬍0.05. Statistical analysis was done with SPSS® 17.0.
RESULTS Laparoscopic RFA assisted TE without clamping the renal hilar vessels was done in all cases (see table). The greatest dimension was 4 cm or less, and be-
Oncological and renal function outcomes of laparoscopic RFA and enucleation of RCC Tumor 4 cm or Less No. pts Median age (range) No. men/women No. side: Lt Rt Median cm tumor size (range) No. solitary kidney No. tumor location: Anterior Posterior Median Charlson comorbidity index (range) No. PADUA score: 6–7 8–9 10 or Greater Median mins operative time (range) Median ml blood loss (range) Median days hospital stay (range) No. histopathology: Clear cell Papillary Chromophobe No. tumor grade: G1 G2 G3 No. complication: Bleeding requiring transfusion Postop fever Prolonged urinary leakage No. recurrence Median ml/min/1.73 m2 eGFR modification of diet in renal disease (range):* Preop 12 mos Postop Mean mos followup (range) * Preop vs 12 months postop paired t test p ⫽ 0.09.
32 59 24/8 18 14 3.2 8 15 17 1.5 20 8 4 115 80 6
(37–82)
(1.8–3.9)
Tumor 4-7 cm 10 61 7/3 4 6 4.8 3
(0–3)
5 5 1.5
(70–160) (15–160) (5–9)
2 5 3 137.5 115 7
(45–78)
(4.1–6.1)
(0–3)
(95–185) (35–210) (5–11)
p Value 0.52 0.75 0.37
⬍0.001 0.75 0.86
0.78 0.045
0.03 0.24 0.06
Overall 42 60 31/11 22 20 3.4 11
(0–3)
22 13 7 120 82.5 6
(70–185) (15–210) (5–11)
9 1 0
37 4 1
13 17 2 5 0 3 2 1
2 7 1 2 0 1 1 0
15 24 3 7 0 4 3 1
67.5 (29.2–117.2) 65.4 (29.4–107.3) 44 (24–68)
68.6 (33.3–113.2) 65.4 (31.6–110.6) 35.5 (25–45)
1.0 1.0
0.81 0.78 0.04
(1.8–6.1)
20 22 1.5
28 3 1
1.0
(37–82)
68.6 (29.2–117.2) 65.4 (29.4–110.6) 37.5 (24–68)
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LAPAROSCOPIC RADIO FREQUENCY ABLATION ENUCLEATION OF RENAL CELL CANCER
tween 4 and 7 cm for 32 and 10 tumors, respectively. Median operative time was 120 minutes (range 70 to 185). Median blood loss was 82.5 ml (range 15 to 210). Median hospital stay was 6 days (range 5 to 11). No residual tumor was found by enhanced CT (fig. 2). Operative time was significantly different between tumors 4 cm or less and those 4 to 7 cm (p ⫽ 0.03). However, no difference in blood loss and hospital stay was found between the 2 groups (p ⫽ 0.24 and 0.06, respectively). No intraoperative complications were recorded. Postoperative complications were classified according to the modified Clavien classification system.22 Overall 7 complications (16.6%) occurred, including postoperative fever in 4 cases (Clavien grade II) and prolonged urinary leakage requiring stent insertion in 3 (Clavien grade III). No patient underwent blood transfusion. No grade IV or V complications were recorded. Tumor size was not associated with overall complications or the incidence of urinary leakage. We found 22, 13 and 7 tumors with a PADUA score of 6 –7, 8 –9 and 10 or greater, respectively. PADUA score was associated with urinary leakage (p ⫽ 0.03) but not with overall complications.
Figure 2. Enhanced CT of patients with renal tumors, including 60-year-old female with 5.1 cm RCC (PADUA score 7) preoperatively (a) and postoperatively (b), 52-year-old male with 3.4 cm RCC (PADUA score 9) preoperatively (c) and postoperatively (d), and 34-year-old male with 5.1 cm RCC (PADUA score 11) preoperatively (e) and postoperatively (f).
Figure 3. Laparoscopic RFA assisted enucleation in 51-year-old male with 4.8 cm RCC. Pseudocapsule was intact and fat attached to tumor was retained after procedure (a). Necrosis was evident on pseudocapsule surface. After tumor was dissected, necrosis and hemorrhage were extensively found in tumor (b). Necrosis was more evident on parenchymal than on external side.
Histopathology revealed clear cell RCC in 37 cases (88.1%), papillary RCC in 4 (9.5%) and chromophobe RCC in 1 (2.4%). Overall 15 tumors (35.7%) were Fuhrman grade 1, 24 (57.1%) were grade 2 and 3 (7.1%) were grade 3. No patient showed positive surgical margins (figs. 3 and 4). Microscopy revealed that the pseudocapsule was intact in all cases and no viable tumor cells were identified on the parenchymal side of the tumor. Tumor cells were found on the fat side in some tumors that were large. Median followup was 37.5 months (range 24 to 68). Median GFR before surgery was 68.6 ml/minute/1.73 m2 (range 29.2 to 117.2) and 47.6% of patients (20 of 42) had a GFR of 60 ml/minute/1.73 m2
Figure 4. Laparoscopic RFA assisted enucleation in 61-year-old male with 2.8 cm RCC. Pathological evaluation showed intact pseudocapsule free of tumor cell invasion. Hemorrhage and microscopic hemorrhage were extensive. Tumor cell nuclei lost normal appearance. Few inflammatory cells infiltrated pseudocapsule. Reduced from ⫻40.
LAPAROSCOPIC RADIO FREQUENCY ABLATION ENUCLEATION OF RENAL CELL CANCER
or less. Median GFR was 65.4 ml/minute/1.73 m2 (range 29.4 to 110.6) 1 year postoperatively (vs preoperatively p ⫽ 0.09). Three-year cancer specific, cumulative and progression-free survival was 100%, 97.3% and 96.4%, respectively. One patient died of another cause 28 months after surgery. One patient with grade 3 clear cell RCC 3.8 cm in greatest dimension had recurrence in the nonablated zone, which was detected 35 months after surgery (kidney recurrence rate 2.4%). He underwent ultrasound guided percutaneous RFA and was free from any relapse 13 months after the procedure.
DISCUSSION Besides standard NSS, various techniques have been reported to treat renal tumors with promising outcomes, including TE, RFA and cryotherapy alone, and RFA assisted NSS. In the current study we retrospectively reviewed our series of patients with RCC treated with zero ischemia laparoscopic RFA assisted TE to determine whether this technique is effective and oncologically safe. With cumulative evidence, European Association of Urology guidelines concluded that a minimal tumor-free surgical margin appears appropriate to avoid local recurrence after conservative treatment.1 TE preserves more parenchyma and avoids major bleeding and opening of the collecting system. Longterm outcomes have resulted in a growing number of supporters.5–9 Carini et al reviewed data on 232 patients with T1a RCC who underwent TE, noting disease progression in 6.4% and no local recurrence at the enucleation bed.5 Minervini et al retrospectively analyzed data on 982 patients who underwent standard NSS and 537 who underwent TE for localized RCC, and noted equivalent oncological outcomes.6 However, oncological safety, particularly the incidence of positive surgical margins and local recurrence, remains a concern. In some studies TE involved ablation of the tumor base to eliminate potential residual tumor,8,9 although others reported excellent results of pure TE without ablation of the tumor bed. Minervini et al prospectively analyzed data on 90 consecutive patients who underwent TE for RCC.23 The surgical margin was negative in all cases and the investigators concluded that a thin layer of tissue can result in a negative surgical margin.23 Moreover, they prospectively evaluated data on 164 consecutive patients who underwent pure TE and noted a negligible local recurrence rate and negative surgical margins in all.24 Our technique has several advantages. It can minimize the damage caused by RFA energy to normal renal parenchyma, be easily performed with no hilar clamping and simplify the technical difficulty
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inherent to laparoscopic partial nephrectomy, decreasing the need for suturing. Unlike RFA as a single procedure, RFA assisted TE enables the surgeon to remove the tumor, which allows for precise pathological results with the possibility of identifying positive surgical margins as well as easier followup. The primary consideration with laparoscopic partial nephrectomy is minimizing renal ischemia, which is associated with a higher incidence of renal complications.25,26 Eliminating warm ischemia and preserving the maximal parenchyma may potentially prevent or delay a renal function decrease. Besides RFA assisted TE and RFA assisted NSS, there is another zero ischemia partial nephrectomy technique using renal arterial branch microdissection, which was reported by Gill et al.27 They reported longer operative time (mean 4.4 hours) and more blood loss (mean 206 ml) than for laparoscopic RFA assisted TE. The overall complication rate in our series was 16.6%. This was lower than for zero ischemia anatomical partial nephrectomy (22.8%) and the incidence reported in 2 recent NSS studies by Ficarra21 and Hew28 et al, which showed an overall complication rate of 22.6% and 23%, respectively. The complication spectrum differs among laparoscopic RFA assisted TE, TE alone and zero ischemia anatomical partial nephrectomy. Minervini et al found a surgical complication rate of 13.5% after pure TE (27 of 200 cases).29 Postoperatively blood loss occurred in 21 patients (10.5%) and urine leakage developed in 6 (3%). The postoperative complications of zero ischemia anatomical partial nephrectomy in 22.8% of cases reported by Gill et al were low grade (Clavien grades I and II) in 19.3% and high grade (Clavien grades III to V) in 3.5%.27 Overall 21% of patients received blood transfusion perioperatively. Urine leakage occurred in 3 patients (5.3%), which resolved spontaneously in all. We found a higher incidence of urine leakage and a lower incidence of postoperative blood loss. In the current study median blood loss was 82.5 ml, which is negligible and comparable to that in some robotic and open partial nephrectomy series. Although this technique did not achieve better intraoperative bleeding control, it decreased the incidence of blood transfusion after surgery. The clampless technique that we used may have advantages for hemostasis and allow for identification of the vessel at the tumor base. The incidence of urine leakage (7.1%) was higher than that of conventional laparoscopic NSS (range 1.7% to 3.6%) and TE (3%) according to published data. The reason for the higher incidence of urine leakage was probably a thermal lesion of the renal excretory system, which could have happened when the renal tumor was close to the calyces.
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LAPAROSCOPIC RADIO FREQUENCY ABLATION ENUCLEATION OF RENAL CELL CANCER
RFA assisted NSS is defined as using an RFA electrode, which is inserted in the tumor and the normal parenchyma around the tumor to create an avascular plane 5 to 10 mm wide around the tumor. NSS is then performed without clamping the renal hilum and 5 mm of normal parenchyma are dissected with the tumor. Our technique differs from RFA assisted NSS. 1) RFA is performed to the tumor and thermal damage to normal parenchyma is limited by controlling the energy output and time. 2) The placement of electrodes in RFA assisted NSS could be complicated if the tumor is large, endophytic or close to vital structures, such as the renal pedicle or collecting system, and the complication rate may increase. 3) After ablating normal renal parenchyma in RFA assisted NSS, the incision starts within the ablated area and the tumor burden is difficult to identify, which may result in an increased risk of positive surgical margins.16 The same concern of positive surgical margins may exist with the current technique since the tumor was dehydrated and solidified, and tended to contract toward the electrode. However, the renal parenchyma around the tumor, relatively far from the electrode, was only slightly contracted. The cleavage plane between the pseudocapsule and normal parenchyma was easy to identify. The tumor was easy to
isolate from the base because it was solidified and the pseudocapsule became firm after ablation. In our study no positive margins were recorded and the pseudocapsule was intact at pathological evaluation in all cases. At a median followup of 37.5 months we recorded a true local recurrence and kidney recurrence rate of 0% and 2.4%, respectively. Only 1 patient had local recurrence but it was elsewhere in the kidney. Moreover, the cancer specific, cumulative and progression-free survival rates were 100%, 97.3% and 96.4%, respectively. These data indicate that the procedure is oncologically safe. However, we acknowledge that the current study can be criticized for the small sample size and the medium term followup reported, which is not long enough to clearly draw conclusions on the risk of systemic recurrence and the cancer specific survival rate. Moreover, this is a retrospective series and, therefore, it is associated with all the shortcomings of retrospective studies. We also lacked a control group to compare the results of pure TE during the same period. In conclusion, zero ischemia laparoscopic RFA assisted TE of RCC is a safe, acceptable nephron sparing treatment with promising oncological and functional outcomes, and a low complication rate.
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