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Laparoscopic Lymph Node Dissection in Clinically Node-Negative Patients Undergoing Laparoscopic Nephrectomy for Renal Carcinoma
Oncology Laparoscopic Lymph Node Dissection in Clinically Node-Negative Patients Undergoing Laparoscopic Nephrectomy for Renal Carcinoma Terence N. Chapman, Satish Sharma, Shaozeng Zhang, Michael K. Wong, and Hyung L. Kim OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
Accurate staging of renal cell carcinoma (RCC) is important when risk-stratifying patients for clinical trials and identifying patients most likely to benefit from adjuvant therapy. We investigated the feasibility and potential role of laparoscopic lymph node dissection (LND) in patients undergoing radical nephrectomy with clinically node-negative RCC. We retrospectively compared 50 consecutive patients undergoing laparoscopic nephrectomy without LND (Nx group) with 50 consecutive patients undergoing combined laparoscopic nephrectomy and retroperitoneal LND (LND group). The two groups had similar clinical and pathological characteristics; the only difference was a higher proportion of non– clear cell histology in the LND group. In the Nx group, no patient was identified as having node-positive RCC; 5 of 50 patients (10%) in the LND group had nodal disease (P ⫽ 0.0155). Among a subgroup of patients with clinically localized RCC, 3 of 46 (6.5%) patients had node-positive disease identified by LND. All patients with positive nodes had primary tumors that were at least 7 cm in diameter, pT3 or pT4, and high grade. With increased surgeon experience, extent of the LND was incrementally increased. The mean number of nodes recovered was 7.8; however, a mean of 12.1 nodes were recovered using an extended LND. The mean numbers of nodes recovered from the paraaortic, interaortocaval, paracaval, and retrocaval regions were 9.8, 4.2, 2.4, and 5.0, respectively. The overall risk of intraoperative and postoperative complications was similar between groups. Laparoscopic LND in patients undergoing nephrectomy for RCC is safe and feasible, and may improve staging accuracy. UROLOGY 71: 287–291, 2008. © 2008 Elsevier Inc.
R
enal tumors represent approximately 3% of all malignancies.1 Increased use of ultrasounds and computed tomography (CT) scans and incidental detection of early renal cell carcinoma (RCC) have at least in part accounted for an increase in incidence each year since the 1970s.2 The standard of care for both localized and metastatic renal cell carcinoma includes a nephrectomy. The role of lymph node dissection (LND) for RCC has been debated for over half a century.3–5 The goal of surgical resection for localized renal cancer is cure, and potential benefits of LND at the time of nephrectomy include more accurate staging, decreased risk of local recurrence, and improved survival. The goal of surgical resection for patients with metastatic disease is cytoreduction, and patients undergoing cytoreductive neFrom the Departments of Urologic Oncology, Department of Pathology, and Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York Reprint requests: Dr. Hyung Kim, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: [email protected] Submitted: March 4, 2007; accepted (with revisions): August 28, 2007
© 2008 Elsevier Inc. All Rights Reserved
phrectomy with LND for bulky lymphadenopathy may gain a survival advantage.6 The practice patterns of academic urologists in the United States illustrate a lack of consensus on the role of LND for RCC.7 A survey of members of the Society of Urologic Oncology and urologic oncologists in the American Association of Genitourinary Surgeons was conducted in 2003. When performing open radical nephrectomy for localized renal cell carcinoma, 26% reported that they do not perform a formal lymph node dissection, whereas 41% perform a limited node dissection and 33% perform a full retroperitoneal lymph node dissection that extends from the crus of the diaphragm to the bifurcation of the aorta or vena cava. For metastatic renal cell carcinoma, 21% do not perform a formal node dissection, 43% perform a limited LND, and 36% perform a full retroperitoneal LND. Several multicenter phase III clinical trials are under way evaluating adjuvant therapies for patients with RCC who remain at high risk for recurrence after nephrec0090-4295/08/$34.00 doi:10.1016/j.urology.2007.08.057
287
tomy.8 If these adjuvant therapies prove effective, accurate staging will be critical for identifying patients most likely to benefit from systemic treatments. Furthermore, it may be useful to incorporate accurate staging of the lymph nodes in future clinical trials of adjuvant therapies. Laparoscopic approaches for performing both radical and partial nephrectomies are well-established standards for treating renal tumors.9,10 However, the feasibility and potential benefits of performing an LND at the time of a laparoscopic radical nephrectomy remain undefined. We retrospectively compared our experience with 50 consecutive patients who underwent laparoscopic radical nephrectomy and retroperitoneal lymph node dissection, and 50 consecutive patients who underwent standard laparoscopic radical nephrectomy. To our knowledge, this is the first study to evaluate the safety and feasibility, and potential staging role, of laparoscopic lymph node dissection in patients undergoing nephrectomy for RCC.
MATERIAL AND METHODS Patient Selection and Study Design Between February 2006 and June 2007, 50 consecutive patients undergoing radical nephrectomy also received a retroperitoneal lymph node dissection. We compared this group 50 consecutive patients treated with nephrectomy alone between September 2004 and February 2006. We performed a retrospective reviewed after approval by the Institutional Review Board (EDR 53605). Patients with both localized and metastatic disease were included. Patients who underwent nephrectomy were excluded from the analysis if they had clinically significant enlargement of retroperitoneal lymph nodes (more than 2 cm) on preoperative CT or magnetic resonance imaging, multifocal disease, solitary kidney, or non-RCC. Patients undergoing partial nephrectomy or open nephrectomy were also excluded. All patients underwent laparoscopic radical nephrectomy, which included removal of the adrenal gland and perinephric fat contained within Gerota’s fascia. The specimen was removed intact through a midline, infraumbilical incision using an entrapment bag. With increased experience, the limits for the LND were incrementally extended. For the first 36 cases, the limits for the left-sided LND were the crus of the diaphragm, the bifurcation of the common iliac artery, Gerota’s fascia, and the medial aspect of the aorta. The limits for the right-sided LND were the adrenal vein, the bifurcation of the common iliac vein, Gerota’s fascia, and the medial aspect of the vena cava. The next 14 cases (6 left and 8 right) included dissection of the interaortocaval nodes between the renal vein and the bifurcation of the aorta or vena cava. The last four right-sided LNDs included formal dissection of the retrocaval nodes.
Study Parameter and Statistical Methods Tumor histologic type and grade were determined according to the 1997 World Health Organization classification11 and the Fuhrman criteria,12 respectively. Patients were staged according to the 2002 TNM criteria proposed by the American Joint Committee on Cancer (AJCC).13 Metastatic status was determined at initial presentation. Localized disease was defined as N0M0. Patient performance status was evaluated using the Eastern Cooperative Oncology Group performance score 288
Table 1. Patient characteristics
Characteristic
Laparoscopic Nephrectomy
Demographics Mean age 64 Male/female 30/20 Side (left/right) 29/21 ECOG-PS 0 44 Surgery time (min) 210 (122–341) EBL (mL) 140 (5–650)* Hospital stay 1.9 (1–8) (days)‡ Pathology Tumor size (cm) 6.0 (1.5–12) T1/T2/T3/T4 31/9/10/0 Metastasis (M⫹) 6 Node positive (N⫹)† 0 RCC histology Clear cell 48 Papillary 1 Chromophobe 1 Others 0 Nuclear grade 3/4 16
Laparoscopic Nephrectomy ⫹ Lymph Node Dissection 65 36/14 26/24 47 217 (108–357) 150 (10–900) 1.7 (1–5) 6.7 (1.5–14) 27/10/12/1 4 5 38 6 4 2 23
ECOG-PS ⫽ Eastern Cooperative Group-Performance Status; EBL ⫽ estimated blood loss; RCC ⫽ renal cell carcinoma. * Two patients with preoperative anemia required transfusions. † P ⫽ 0.0155. ‡ Patients with postoperative stays 5 days or more had combined procedures that included a laparoscopic nephrectomy and a concomitant open procedure performed by another surgical service.
(ECOG-PS) scale.14 Tumor size was based on pathology review. Events requiring medical attention within 30 days of the nephrectomy were considered postoperative complications. We summarized results using standard descriptive statistics. The two primary cohorts were compared using unpaired Student t-test, Fisher’s exact test, and the two-sample test of proportions. All calculations were performed using Stata 8 (College Station, Tex) and a two-sided P value of 0.05 was considered statistically significant.
RESULTS Patients undergoing nephrectomy alone and patients undergoing nephrectomy with LND had similar demographics and intraoperative parameters (Table 1). The average tumor size and distribution of T categories were similar. However, the LND group had a higher proportion of non– clear cell tumors (P ⫽ 0.027). All patients had ECOG-PS 0 or 1. Two patients in the nephrectomy-only group with an estimated blood loss of 200 and 600 mL, respectively, received intraoperative transfusions for preexisting anemia. No patients required postoperative transfusions. In the two groups, 10 patients underwent cytoreductive nephrectomy followed by systemic cytokine therapy for metastatic RCC. There were no conversions to an open surgical approach. The hospital stays were similar in the two groups, with 53% of patients discharged to home on postoperative day 1 and 29% discharged to home on postoperative day 2. UROLOGY 71 (2), 2008
Table 2. Postoperative complications Laparoscopic Nephrectomy Intraoperative* IVC tear Enterotomy Pneumothorax ⫻2 Postoperative Pneumonia Prolonged intubation (24 h) Myocardia infarction Respiratory failure Gastrointestinal bleed Wound infection
Laparoscopic Nephrectomy ⫹ Lymph Node Dissection IVC tear Pneumothorax Port site hernia Ileus Chylous ascites ⫻2 Stroke
* All intraoperative injuries were repaired laparoscopically with no need for conversion.
The overall complication rates for the two groups were similar (Table 2). In the nephrectomy-only group, 1 patient with preexisting emphysema remained intubated overnight after surgery, 1 patient was rehospitalized for gastrointestinal hemorrhage, and another patient was rehospitalized for respiratory distress and required intubation. In the group undergoing nephrectomy and LND, one patient required surgical exploration for complete small bowel obstruction resulting from a port-site hernia. In the LND group, two patients were diagnosed with chylous ascites; one patient presented to the clinic with abdominal distention resulting from chylous ascites, which resolved with percutaneous drainage and total parental nutrition. A second patient required drainage of chylous ascites, which was diagnosed 3 months after nephrectomy while the patient was receiving chemotherapy for a second malignancy. Figure 1 shows the average number of nodes retrieved from four anatomic zones we included in the LND. When all dissection templates used throughout the study are considered collectively, a mean of 10.5 (range, 0 to 25) nodes were recovered from a left-sided LND. A mean of 4.8 (range, 0 to 18) nodes were recovered from a rightsided LND. When only the most extensive LND templates are considered, a mean of 14.3 (range, 5 to 20; n ⫽ 6) and 8.8 (range, 4 to 14; n ⫽ 4) were recovered from left- and right-sided LNDs, respectively. The retroaortic nodes were dissected en bloc with the paraaortic nodes and are not reported separately. Patients undergoing LND were more likely to be staged with node-positive disease (Table 1). Positive nodes were identified from a paraaortic LND in 3 patients, from a paracaval LND in 1 patient, and from a retrocaval LND in 1 patient. Of the patients undergoing LND, 10% had node-positive disease, which included 3 patients who were N1 and 2 who were N2. Of patients with clinically localized RCC undergoing LND, 6.5% had node-positive disease. All patients (n ⫽ 5) with node-positive disease had high-risk features. All tumors were greater than 7 cm (range, 7 to 11 cm) in diameter, nuclear grade 3 to 4, and T3 or T4. In this group, 4 of 5 patients had tumor UROLOGY 71 (2), 2008
Figure 1. Average number of nodes retrieved from laparoscopic dissection of retroperitoneal lymph nodes. The boundaries for the paracaval, interaortocaval, and paraaortic lymph nodes (left to right) are outlined. The filled diamond indicates the number of nodes retrieved from a formal retrocaval node dissection.
extending beyond the capsule of the kidney, 2 patients had tumor with renal vein involvement, and 2 patients were clinically M⫹. The positive nodes were identified during a right nephrectomy in 2 patients and during a left nephrectomy in 3 patients. In 1 patient undergoing a right nephrectomy, positive nodes were identified only in the retrocaval packet.
COMMENT There is no consensus regarding the need to perform retroperitoneal LND for patients undergoing nephrectomy.7 LND has been reported to improve staging accuracy when performed using an open approach,15 and many urologists routinely include LND as part of an open nephrectomy. Some have proposed that future clinical trials of adjuvant therapies should include a standard LND. However, the safety and feasibility of performing a retroperitoneal LND as part of a laparoscopic nephrec289
tomy have not been established. Furthermore, it remains uncertain whether a LND performed laparoscopically will contribute to staging accuracy. In the current study, patients undergoing laparoscopic retroperitoneal LND at the time of radical nephrectomy were more likely to be staged with node-positive disease than patients undergoing standard laparoscopic nephrectomy, which suggests that laparoscopic LND improves staging accuracy. To assess the number of nodes retrieved surgically, 50 consecutive patients undergoing LND were evaluated and patients with hematogenous metastasis were included as long as their retroperitoneal nodes were clinically negative. All patients found to have nodepositive disease had high-grade, pT3/pT4 tumors; therefore, the incidence of node-positive RCC is likely higher when only high-risk patients are considered. Based on the current body of medical literature, the most compelling argument for performing LND is to improve staging accuracy. Our study suggests that the false-negative rate for preoperative imaging is approximately 10%. In a recent report, 14.2% of patients undergoing nephrectomy with LND had lymph node involvement.16 The false-positive rate for preoperative imaging has been reported to be as high as 58% to 75%.17,18 In patients undergoing open radical nephrectomy, Terrone et al. reported that LND resulted in more accurate staging and that number of lymph nodes removed during radical nephrectomy correlated with the percentage of patients with pathologically positive lymph nodes.15 This relationship persisted after controlling for local extent of disease, tumor grade, and metastasis status. Patients with node-positive disease have high risk for recurrence and may benefit from adjuvant therapy. In a multicenter, phase III clinical trial, autologous renal carcinoma cell vaccine was shown to delay the risk of tumor progression after radical nephrectomy.19 Although this treatment is not available commercially, patients with node-positive disease can be considered for several clinical trials of adjuvant therapies that allow patient registration after nephrectomy and surgical staging.8 If these studies are not available at the institution performing surgery, eligibility criteria allow qualified patients to be referred to sites participating in the trials. In our study, more nodes were retrieved during left than right nephrectomy, which likely reflects asymmetric nodal anatomy. There is currently no consensus on the extent of the node dissection that should be performed for RCC. The primary reason for the lack of consensus is the wide variability in lymphatic drainage of the kidney.20 Although the primary drainage sites of the kidney are predictable, the secondary drainage sites can cross the midline or pass through the diaphragm into the chest. The current AJCC recommends that at least eight nodes be examined to determine nodal staging. To obtain eight nodes consistently on the right side requires dissection of the interaortocaval and retrocaval nodes. In our series, 290
one patient had nodal disease detected only in the retrocaval nodes. The variability in lymphatic drainage of the kidney also suggests that complete and curative resection of node-positive disease may not be possible, especially in the context of extensive nodal metastasis. To assess the potential survival benefits associated with LND, the European Organization for Research and Treatment of Cancer is conducting a prospective, randomized study to assess the role of LND for localized renal cell carcinoma.21 A total of 772 patients were randomized to undergo open radical nephrectomy alone or open radical nephrectomy and complete lymph node dissection. In a preliminary report, 3.3% of patients had unsuspected lymph-node metastasis. Maturation of survival data is required to assess for improved survival associated with LND. The current study documents the safety and feasibility of performing laparoscopic LND in patients undergoing laparoscopic nephrectomy. LND did not increase operative time, blood loss, or length of hospital stay. The 50 consecutive patients undergoing nephrectomy only were treated before the 50 patients undergoing both nephrectomy and LND. Therefore, the second group benefited from greater hospital and surgeon experience, which may in part account for the comparable operative times in the two groups. The LND did not increase the overall complication rate; however, two patients who underwent LND developed symptomatic chylous ascites that resolved with conservative, nonoperative management. After these two complications our surgical technique has been modified to minimize blunt dissection further and ligate all visible lymphatic structures with clips or ultrasonic coagulation.
CONCLUSIONS Laparoscopic lymphadenectomy can be performed safely and adds additional staging information, which may prove useful as new paradigms for the treatment of advanced renal carcinoma are developed. References 1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56: 106 –130, 2006. 2. Kidney cancer. J Urol 177: 2006 –2018; discussion 2018 –2009, 2007. 3. Flocks RH, and Kadesky MC: Malignant neoplasms of the kidney: an analysis of 353 patients followed five years or more. J Urol 79: 196 –201, 1958. 4. Foot NC, Humphreys GA, and Whitmore WF: Renal tumors: pathology and prognosis in 295 cases. J Urol 66: 190 –200, 1951. 5. Mintz ER, and Gaul EA: Kidney tumors: some causes of poor end results. N Y State J Med 39: 1405–1410, 1939. 6. Pantuck AJ, Zisman A, Dorey F, et al: Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 169: 2076 –2083, 2003. 7. Kim HL, Lam J, and Belldegrun A: Surgical management of renal cell carcinoma: role of lymphadenectomy in renal cell carinoma surgery, role of lymph node dissection in renal cell carcinoma, in Vogelzang N, Scardino P, Shipley W, et al. (Eds): Comprehensive Textbook of Genitourinary Oncology. Philadelphia, Lippincott Williams and Wilkins, 2006, pp 739 –743.
UROLOGY 71 (2), 2008
8. Lam JS, Belldegrun AS, and Figlin RA: Adjuvant treatment for renal cell carcinoma. Expert Opin Pharmacother 7: 705–720, 2006. 9. Lane BR, and Gill IS: 5-Year outcomes of laparoscopic partial nephrectomy. J Urol 177: 70 –74; discussion 74, 2007. 10. Portis AJ, Yan Y, Landman J, et al: Long-term followup after laparoscopic radical nephrectomy. J Urol 167: 1257–1262, 2002. 11. Storkel S, Eble JN, Adlakha K, et al: Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80: 987–989, 1997. 12. Fuhrman SA, Lasky LC, and Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6: 655– 663, 1982. 13. Green FL, Page DL, Fleming ID, et al: AJCC Cancer Staging Manual. New York, Springer-Verlag, 2002. 14. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5: 649 – 655, 1982. 15. Terrone C, Guercio S, De Luca S, et al: The number of lymph nodes examined and staging accuracy in renal cell carcinoma. BJU Int 91: 37– 40, 2003.
UROLOGY 71 (2), 2008
16. Terrone C, Cracco C, Porpiglia F, et al: Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 49: 324–331, 2006. 17. Studer UE, Scherz S, Scheidegger J, et al: Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases. J Urol 144: 243–245, 1990. 18. Minervini A, Lilas L, Morelli G, et al: Regional lymph node dissection in the treatment of renal cell carcinoma: is it useful in patients with no suspected adenopathy before or during surgery? BJU Int 88: 169 –172, 2001. 19. Jocham D, Richter A, Hoffmann L, et al: Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 363: 594 –599, 2004. 20. Parker AE: Studies on the main posterior lymph channels of the abdomen and their connections with the lymphatics of the genitourinary system. Am J Anat 56: 409 – 413, 1935. 21. Blom JH, van Poppel H, Marechal JM, et al: Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group. Eur Urol 36: 570 –575, 1999.
291
METHODS
RESULTS
CONCLUSIONS
Accurate staging of renal cell carcinoma (RCC) is important when risk-stratifying patients for clinical trials and identifying patients most likely to benefit from adjuvant therapy. We investigated the feasibility and potential role of laparoscopic lymph node dissection (LND) in patients undergoing radical nephrectomy with clinically node-negative RCC. We retrospectively compared 50 consecutive patients undergoing laparoscopic nephrectomy without LND (Nx group) with 50 consecutive patients undergoing combined laparoscopic nephrectomy and retroperitoneal LND (LND group). The two groups had similar clinical and pathological characteristics; the only difference was a higher proportion of non– clear cell histology in the LND group. In the Nx group, no patient was identified as having node-positive RCC; 5 of 50 patients (10%) in the LND group had nodal disease (P ⫽ 0.0155). Among a subgroup of patients with clinically localized RCC, 3 of 46 (6.5%) patients had node-positive disease identified by LND. All patients with positive nodes had primary tumors that were at least 7 cm in diameter, pT3 or pT4, and high grade. With increased surgeon experience, extent of the LND was incrementally increased. The mean number of nodes recovered was 7.8; however, a mean of 12.1 nodes were recovered using an extended LND. The mean numbers of nodes recovered from the paraaortic, interaortocaval, paracaval, and retrocaval regions were 9.8, 4.2, 2.4, and 5.0, respectively. The overall risk of intraoperative and postoperative complications was similar between groups. Laparoscopic LND in patients undergoing nephrectomy for RCC is safe and feasible, and may improve staging accuracy. UROLOGY 71: 287–291, 2008. © 2008 Elsevier Inc.
R
enal tumors represent approximately 3% of all malignancies.1 Increased use of ultrasounds and computed tomography (CT) scans and incidental detection of early renal cell carcinoma (RCC) have at least in part accounted for an increase in incidence each year since the 1970s.2 The standard of care for both localized and metastatic renal cell carcinoma includes a nephrectomy. The role of lymph node dissection (LND) for RCC has been debated for over half a century.3–5 The goal of surgical resection for localized renal cancer is cure, and potential benefits of LND at the time of nephrectomy include more accurate staging, decreased risk of local recurrence, and improved survival. The goal of surgical resection for patients with metastatic disease is cytoreduction, and patients undergoing cytoreductive neFrom the Departments of Urologic Oncology, Department of Pathology, and Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York Reprint requests: Dr. Hyung Kim, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: [email protected] Submitted: March 4, 2007; accepted (with revisions): August 28, 2007
© 2008 Elsevier Inc. All Rights Reserved
phrectomy with LND for bulky lymphadenopathy may gain a survival advantage.6 The practice patterns of academic urologists in the United States illustrate a lack of consensus on the role of LND for RCC.7 A survey of members of the Society of Urologic Oncology and urologic oncologists in the American Association of Genitourinary Surgeons was conducted in 2003. When performing open radical nephrectomy for localized renal cell carcinoma, 26% reported that they do not perform a formal lymph node dissection, whereas 41% perform a limited node dissection and 33% perform a full retroperitoneal lymph node dissection that extends from the crus of the diaphragm to the bifurcation of the aorta or vena cava. For metastatic renal cell carcinoma, 21% do not perform a formal node dissection, 43% perform a limited LND, and 36% perform a full retroperitoneal LND. Several multicenter phase III clinical trials are under way evaluating adjuvant therapies for patients with RCC who remain at high risk for recurrence after nephrec0090-4295/08/$34.00 doi:10.1016/j.urology.2007.08.057
287
tomy.8 If these adjuvant therapies prove effective, accurate staging will be critical for identifying patients most likely to benefit from systemic treatments. Furthermore, it may be useful to incorporate accurate staging of the lymph nodes in future clinical trials of adjuvant therapies. Laparoscopic approaches for performing both radical and partial nephrectomies are well-established standards for treating renal tumors.9,10 However, the feasibility and potential benefits of performing an LND at the time of a laparoscopic radical nephrectomy remain undefined. We retrospectively compared our experience with 50 consecutive patients who underwent laparoscopic radical nephrectomy and retroperitoneal lymph node dissection, and 50 consecutive patients who underwent standard laparoscopic radical nephrectomy. To our knowledge, this is the first study to evaluate the safety and feasibility, and potential staging role, of laparoscopic lymph node dissection in patients undergoing nephrectomy for RCC.
MATERIAL AND METHODS Patient Selection and Study Design Between February 2006 and June 2007, 50 consecutive patients undergoing radical nephrectomy also received a retroperitoneal lymph node dissection. We compared this group 50 consecutive patients treated with nephrectomy alone between September 2004 and February 2006. We performed a retrospective reviewed after approval by the Institutional Review Board (EDR 53605). Patients with both localized and metastatic disease were included. Patients who underwent nephrectomy were excluded from the analysis if they had clinically significant enlargement of retroperitoneal lymph nodes (more than 2 cm) on preoperative CT or magnetic resonance imaging, multifocal disease, solitary kidney, or non-RCC. Patients undergoing partial nephrectomy or open nephrectomy were also excluded. All patients underwent laparoscopic radical nephrectomy, which included removal of the adrenal gland and perinephric fat contained within Gerota’s fascia. The specimen was removed intact through a midline, infraumbilical incision using an entrapment bag. With increased experience, the limits for the LND were incrementally extended. For the first 36 cases, the limits for the left-sided LND were the crus of the diaphragm, the bifurcation of the common iliac artery, Gerota’s fascia, and the medial aspect of the aorta. The limits for the right-sided LND were the adrenal vein, the bifurcation of the common iliac vein, Gerota’s fascia, and the medial aspect of the vena cava. The next 14 cases (6 left and 8 right) included dissection of the interaortocaval nodes between the renal vein and the bifurcation of the aorta or vena cava. The last four right-sided LNDs included formal dissection of the retrocaval nodes.
Study Parameter and Statistical Methods Tumor histologic type and grade were determined according to the 1997 World Health Organization classification11 and the Fuhrman criteria,12 respectively. Patients were staged according to the 2002 TNM criteria proposed by the American Joint Committee on Cancer (AJCC).13 Metastatic status was determined at initial presentation. Localized disease was defined as N0M0. Patient performance status was evaluated using the Eastern Cooperative Oncology Group performance score 288
Table 1. Patient characteristics
Characteristic
Laparoscopic Nephrectomy
Demographics Mean age 64 Male/female 30/20 Side (left/right) 29/21 ECOG-PS 0 44 Surgery time (min) 210 (122–341) EBL (mL) 140 (5–650)* Hospital stay 1.9 (1–8) (days)‡ Pathology Tumor size (cm) 6.0 (1.5–12) T1/T2/T3/T4 31/9/10/0 Metastasis (M⫹) 6 Node positive (N⫹)† 0 RCC histology Clear cell 48 Papillary 1 Chromophobe 1 Others 0 Nuclear grade 3/4 16
Laparoscopic Nephrectomy ⫹ Lymph Node Dissection 65 36/14 26/24 47 217 (108–357) 150 (10–900) 1.7 (1–5) 6.7 (1.5–14) 27/10/12/1 4 5 38 6 4 2 23
ECOG-PS ⫽ Eastern Cooperative Group-Performance Status; EBL ⫽ estimated blood loss; RCC ⫽ renal cell carcinoma. * Two patients with preoperative anemia required transfusions. † P ⫽ 0.0155. ‡ Patients with postoperative stays 5 days or more had combined procedures that included a laparoscopic nephrectomy and a concomitant open procedure performed by another surgical service.
(ECOG-PS) scale.14 Tumor size was based on pathology review. Events requiring medical attention within 30 days of the nephrectomy were considered postoperative complications. We summarized results using standard descriptive statistics. The two primary cohorts were compared using unpaired Student t-test, Fisher’s exact test, and the two-sample test of proportions. All calculations were performed using Stata 8 (College Station, Tex) and a two-sided P value of 0.05 was considered statistically significant.
RESULTS Patients undergoing nephrectomy alone and patients undergoing nephrectomy with LND had similar demographics and intraoperative parameters (Table 1). The average tumor size and distribution of T categories were similar. However, the LND group had a higher proportion of non– clear cell tumors (P ⫽ 0.027). All patients had ECOG-PS 0 or 1. Two patients in the nephrectomy-only group with an estimated blood loss of 200 and 600 mL, respectively, received intraoperative transfusions for preexisting anemia. No patients required postoperative transfusions. In the two groups, 10 patients underwent cytoreductive nephrectomy followed by systemic cytokine therapy for metastatic RCC. There were no conversions to an open surgical approach. The hospital stays were similar in the two groups, with 53% of patients discharged to home on postoperative day 1 and 29% discharged to home on postoperative day 2. UROLOGY 71 (2), 2008
Table 2. Postoperative complications Laparoscopic Nephrectomy Intraoperative* IVC tear Enterotomy Pneumothorax ⫻2 Postoperative Pneumonia Prolonged intubation (24 h) Myocardia infarction Respiratory failure Gastrointestinal bleed Wound infection
Laparoscopic Nephrectomy ⫹ Lymph Node Dissection IVC tear Pneumothorax Port site hernia Ileus Chylous ascites ⫻2 Stroke
* All intraoperative injuries were repaired laparoscopically with no need for conversion.
The overall complication rates for the two groups were similar (Table 2). In the nephrectomy-only group, 1 patient with preexisting emphysema remained intubated overnight after surgery, 1 patient was rehospitalized for gastrointestinal hemorrhage, and another patient was rehospitalized for respiratory distress and required intubation. In the group undergoing nephrectomy and LND, one patient required surgical exploration for complete small bowel obstruction resulting from a port-site hernia. In the LND group, two patients were diagnosed with chylous ascites; one patient presented to the clinic with abdominal distention resulting from chylous ascites, which resolved with percutaneous drainage and total parental nutrition. A second patient required drainage of chylous ascites, which was diagnosed 3 months after nephrectomy while the patient was receiving chemotherapy for a second malignancy. Figure 1 shows the average number of nodes retrieved from four anatomic zones we included in the LND. When all dissection templates used throughout the study are considered collectively, a mean of 10.5 (range, 0 to 25) nodes were recovered from a left-sided LND. A mean of 4.8 (range, 0 to 18) nodes were recovered from a rightsided LND. When only the most extensive LND templates are considered, a mean of 14.3 (range, 5 to 20; n ⫽ 6) and 8.8 (range, 4 to 14; n ⫽ 4) were recovered from left- and right-sided LNDs, respectively. The retroaortic nodes were dissected en bloc with the paraaortic nodes and are not reported separately. Patients undergoing LND were more likely to be staged with node-positive disease (Table 1). Positive nodes were identified from a paraaortic LND in 3 patients, from a paracaval LND in 1 patient, and from a retrocaval LND in 1 patient. Of the patients undergoing LND, 10% had node-positive disease, which included 3 patients who were N1 and 2 who were N2. Of patients with clinically localized RCC undergoing LND, 6.5% had node-positive disease. All patients (n ⫽ 5) with node-positive disease had high-risk features. All tumors were greater than 7 cm (range, 7 to 11 cm) in diameter, nuclear grade 3 to 4, and T3 or T4. In this group, 4 of 5 patients had tumor UROLOGY 71 (2), 2008
Figure 1. Average number of nodes retrieved from laparoscopic dissection of retroperitoneal lymph nodes. The boundaries for the paracaval, interaortocaval, and paraaortic lymph nodes (left to right) are outlined. The filled diamond indicates the number of nodes retrieved from a formal retrocaval node dissection.
extending beyond the capsule of the kidney, 2 patients had tumor with renal vein involvement, and 2 patients were clinically M⫹. The positive nodes were identified during a right nephrectomy in 2 patients and during a left nephrectomy in 3 patients. In 1 patient undergoing a right nephrectomy, positive nodes were identified only in the retrocaval packet.
COMMENT There is no consensus regarding the need to perform retroperitoneal LND for patients undergoing nephrectomy.7 LND has been reported to improve staging accuracy when performed using an open approach,15 and many urologists routinely include LND as part of an open nephrectomy. Some have proposed that future clinical trials of adjuvant therapies should include a standard LND. However, the safety and feasibility of performing a retroperitoneal LND as part of a laparoscopic nephrec289
tomy have not been established. Furthermore, it remains uncertain whether a LND performed laparoscopically will contribute to staging accuracy. In the current study, patients undergoing laparoscopic retroperitoneal LND at the time of radical nephrectomy were more likely to be staged with node-positive disease than patients undergoing standard laparoscopic nephrectomy, which suggests that laparoscopic LND improves staging accuracy. To assess the number of nodes retrieved surgically, 50 consecutive patients undergoing LND were evaluated and patients with hematogenous metastasis were included as long as their retroperitoneal nodes were clinically negative. All patients found to have nodepositive disease had high-grade, pT3/pT4 tumors; therefore, the incidence of node-positive RCC is likely higher when only high-risk patients are considered. Based on the current body of medical literature, the most compelling argument for performing LND is to improve staging accuracy. Our study suggests that the false-negative rate for preoperative imaging is approximately 10%. In a recent report, 14.2% of patients undergoing nephrectomy with LND had lymph node involvement.16 The false-positive rate for preoperative imaging has been reported to be as high as 58% to 75%.17,18 In patients undergoing open radical nephrectomy, Terrone et al. reported that LND resulted in more accurate staging and that number of lymph nodes removed during radical nephrectomy correlated with the percentage of patients with pathologically positive lymph nodes.15 This relationship persisted after controlling for local extent of disease, tumor grade, and metastasis status. Patients with node-positive disease have high risk for recurrence and may benefit from adjuvant therapy. In a multicenter, phase III clinical trial, autologous renal carcinoma cell vaccine was shown to delay the risk of tumor progression after radical nephrectomy.19 Although this treatment is not available commercially, patients with node-positive disease can be considered for several clinical trials of adjuvant therapies that allow patient registration after nephrectomy and surgical staging.8 If these studies are not available at the institution performing surgery, eligibility criteria allow qualified patients to be referred to sites participating in the trials. In our study, more nodes were retrieved during left than right nephrectomy, which likely reflects asymmetric nodal anatomy. There is currently no consensus on the extent of the node dissection that should be performed for RCC. The primary reason for the lack of consensus is the wide variability in lymphatic drainage of the kidney.20 Although the primary drainage sites of the kidney are predictable, the secondary drainage sites can cross the midline or pass through the diaphragm into the chest. The current AJCC recommends that at least eight nodes be examined to determine nodal staging. To obtain eight nodes consistently on the right side requires dissection of the interaortocaval and retrocaval nodes. In our series, 290
one patient had nodal disease detected only in the retrocaval nodes. The variability in lymphatic drainage of the kidney also suggests that complete and curative resection of node-positive disease may not be possible, especially in the context of extensive nodal metastasis. To assess the potential survival benefits associated with LND, the European Organization for Research and Treatment of Cancer is conducting a prospective, randomized study to assess the role of LND for localized renal cell carcinoma.21 A total of 772 patients were randomized to undergo open radical nephrectomy alone or open radical nephrectomy and complete lymph node dissection. In a preliminary report, 3.3% of patients had unsuspected lymph-node metastasis. Maturation of survival data is required to assess for improved survival associated with LND. The current study documents the safety and feasibility of performing laparoscopic LND in patients undergoing laparoscopic nephrectomy. LND did not increase operative time, blood loss, or length of hospital stay. The 50 consecutive patients undergoing nephrectomy only were treated before the 50 patients undergoing both nephrectomy and LND. Therefore, the second group benefited from greater hospital and surgeon experience, which may in part account for the comparable operative times in the two groups. The LND did not increase the overall complication rate; however, two patients who underwent LND developed symptomatic chylous ascites that resolved with conservative, nonoperative management. After these two complications our surgical technique has been modified to minimize blunt dissection further and ligate all visible lymphatic structures with clips or ultrasonic coagulation.
CONCLUSIONS Laparoscopic lymphadenectomy can be performed safely and adds additional staging information, which may prove useful as new paradigms for the treatment of advanced renal carcinoma are developed. References 1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56: 106 –130, 2006. 2. Kidney cancer. J Urol 177: 2006 –2018; discussion 2018 –2009, 2007. 3. Flocks RH, and Kadesky MC: Malignant neoplasms of the kidney: an analysis of 353 patients followed five years or more. J Urol 79: 196 –201, 1958. 4. Foot NC, Humphreys GA, and Whitmore WF: Renal tumors: pathology and prognosis in 295 cases. J Urol 66: 190 –200, 1951. 5. Mintz ER, and Gaul EA: Kidney tumors: some causes of poor end results. N Y State J Med 39: 1405–1410, 1939. 6. Pantuck AJ, Zisman A, Dorey F, et al: Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 169: 2076 –2083, 2003. 7. Kim HL, Lam J, and Belldegrun A: Surgical management of renal cell carcinoma: role of lymphadenectomy in renal cell carinoma surgery, role of lymph node dissection in renal cell carcinoma, in Vogelzang N, Scardino P, Shipley W, et al. (Eds): Comprehensive Textbook of Genitourinary Oncology. Philadelphia, Lippincott Williams and Wilkins, 2006, pp 739 –743.
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8. Lam JS, Belldegrun AS, and Figlin RA: Adjuvant treatment for renal cell carcinoma. Expert Opin Pharmacother 7: 705–720, 2006. 9. Lane BR, and Gill IS: 5-Year outcomes of laparoscopic partial nephrectomy. J Urol 177: 70 –74; discussion 74, 2007. 10. Portis AJ, Yan Y, Landman J, et al: Long-term followup after laparoscopic radical nephrectomy. J Urol 167: 1257–1262, 2002. 11. Storkel S, Eble JN, Adlakha K, et al: Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80: 987–989, 1997. 12. Fuhrman SA, Lasky LC, and Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6: 655– 663, 1982. 13. Green FL, Page DL, Fleming ID, et al: AJCC Cancer Staging Manual. New York, Springer-Verlag, 2002. 14. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5: 649 – 655, 1982. 15. Terrone C, Guercio S, De Luca S, et al: The number of lymph nodes examined and staging accuracy in renal cell carcinoma. BJU Int 91: 37– 40, 2003.
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16. Terrone C, Cracco C, Porpiglia F, et al: Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 49: 324–331, 2006. 17. Studer UE, Scherz S, Scheidegger J, et al: Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases. J Urol 144: 243–245, 1990. 18. Minervini A, Lilas L, Morelli G, et al: Regional lymph node dissection in the treatment of renal cell carcinoma: is it useful in patients with no suspected adenopathy before or during surgery? BJU Int 88: 169 –172, 2001. 19. Jocham D, Richter A, Hoffmann L, et al: Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 363: 594 –599, 2004. 20. Parker AE: Studies on the main posterior lymph channels of the abdomen and their connections with the lymphatics of the genitourinary system. Am J Anat 56: 409 – 413, 1935. 21. Blom JH, van Poppel H, Marechal JM, et al: Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group. Eur Urol 36: 570 –575, 1999.
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