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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 816926, 5 pages doi:10.1155/2011/816926 Review Article The Current Role of Lymph Node Dissection in the Management of Renal Cell Carcinoma Joseph Edmund Jamal and Thomas William Jarrett Department of Urology, The George Washington University Medical Faculty Associates, 2150 Pennsylvania Avenue, NW, Washington, DC 20037, USA Correspondence should be addressed to Joseph Edmund Jamal, email@example.com Received 1 February 2011; Accepted 3 April 2011 Academic Editor: Timothy M. Pawlik Copyright © 2011 J. E. Jamal and T. W. Jarrett. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The role of lymph node dissection remains controversial in the surgical management of renal cell carcinoma. Incidental renal masses are being diagnosed at increasing rates due to the routine useofCTscans. Despite theincreasein incidental diagnosis of renal masses, 20% to 30% of patients present with metastatic disease. Currently, surgeons do not routinely perform lymph node dissection unless there is gross evidence of lymphadenopathy, as patients without clinical evidence of lymphadenopathy rarely have positive nodes at the time of surgery. Patients with metastatic disease to the regional lymph nodes have a poor overall prognosis. However, some evidence supports a therapeutic beneﬁt of lymphadenectomy in these patients. Further, the staging information gained from diagnosing lymph node involvement may allow for the use of new agents to treat metastatic disease and eﬀect outcomes. 1. Introduction management of RCC, but nor did it increase the morbidity of surgical management. This has spurred signiﬁcant debate The role of lymph node dissection (LND) remains contro- in the urologic oncology community [3, 11, 12]. Indeed, versial in the surgical management of renal cell carcinoma this study was aimed at determining the long-term outcomes (RCC) [1–3]. To date, there is no deﬁnitive data which in patients with clinically localized disease, and found that indicates an overall survival advantage imparted by perform- 70% of patients had pT1 or pT2 disease. The majority of ing LND in patients with RCC. Additionally, a complete these patients were therefore unlikely to beneﬁt from LND LND during radical nephrectomy (RN) adds signiﬁcant time, in the ﬁrst place. Therefore, it is important to emphasize potential morbidity, and requires dissection of and around that although being a landmark study, it does not negate the great vessels. What is clear is that in patients with renal the role for LND in RCC. With the recent availability of cell carcinoma without evidence of distant metastases, the new adjuvant agents, prospective adjuvant protocol studies presence of lymph node-only metastases is associated with a nearing completion, and neoadjuvant protocols currently poor prognosis [4–10]. For this reason, identifying patients under study, the importance of LND may change, either as a at risk for positive lymph nodes at the time of surgical therapeutic or staging procedure. The topic of LND therefore treatment of their renal mass remains essential. requires further discourse. Recently, the ﬁrst prospective, randomized trial was In clinical practice, the role of LND in the management conducted by the European Organization for Research and of RCC remains controversial due to variability of lymphatic Treatment of Cancer (EORTC) to compare the long-term drainage of the kidney, the absence of lymphatic involvement results of radical nephrectomy alone (n = 389) versus in many patients with disseminated disease, and the lack radical nephrectomy with complete lymphadenectomy (n = of deﬁnitive evidence of any survival beneﬁt imparted by 383) for patients with clinically N0, M0 disease . They LND . We address the current controversies regarding concluded that LND is not therapeutic in the routine the role of lymphadenectomy in the surgical management 2 International Journal of Surgical Oncology of renal tumors in this review. Ultimately, the therapeutic removedwithLND. For right-sidedtumors, the primary beneﬁt of LND in RCC, whether it be beneﬁcial by itself or lymphatic drainage was the paracaval, precaval, retrocaval, in that it may be diagnostic of metastatic disease resulting in and interaortocaval lymph nodes. For left-sided tumors, the initiation of adjuvant chemotherapy, may only be realized in primary lymphatic drainage was the paraaortic, preaortic, a select subset of patients. retroaortic, and interaortocaval lymph nodes. They advocate for a standard removal of all the lymphatic tissue in these primary lymphatic landing zones. When examining 2. Epidemiology and Relevance their data of patients with positive nodal disease, left-sided Renal cell carcinoma comprises 2% to 3% of malignant tumors corresponded with 76% of left hilar and 62% of neoplasms in adults. In the United States, 31,000 new cases paraaortic positive lymph nodes (of patients with positive of RCC are diagnosed annually, and 11,900 patients die nodal disease). On the right side, patients with positive of disease [13, 14]. There is a male-to-female ratio of lymph node involvement were found to occur in 57% of 3: 2 , and a 10% to 20% higher incidence in African paracaval and 43% of right hilar nodes. On both sides, Americans . The majority of cases of RCC are believed lymph nodes from the renal hilum were not always involved to be sporadic, with only 4% familial according to National in patients with nodal disease, supporting the argument Cancer Institute estimates. Approximately 20% to 30% of against merely sampling the renal hilar lymph nodes as patients with RCC present with metastatic disease , but being suﬃcient. Based on these ﬁndings, they recommend ranges from 3% in surgical series to 63.6% in autopsy series that when lymphadenectomy is performed in patients with- . Of these patients with metastatic disease, historically, out palpable disease, that left-sided disease LND includes 40% have distant metastases only without evidence of paraaortic and interaortocaval lymph nodes, and right-sided lymph node involvement, 50% have both distant metastases disease LND includes paracaval and interaortocaval lymph and lymph node involvement, and approximately 3–10% nodes. present with lymph node involvement only [1, 17–19]. Morbidity of LND has largely been found to be minimal Additionally, one-third of patients with localized RCC will when compared to nephrectomy alone. Retrospective review eventually develop recurrence or progression. There has been has shown little diﬀerence in morbidity of LND . downward stage migration, as well as increasing incidence Additionally, the recent prospective EORTC 30881 trial also of RCC due to extensive utilization of cross-sectional showed no appreciable diﬀerence in morbidity between their imaging. two randomized groups. They did not comment on the In combination, the clinical stage and pathologic grade additional length of time the LND added, nor the total of the tumor is highly predictive of positive lymph node number of lymph nodes removed. They included morbidities metastases. When LND is performed, a number of studies such as bleeding >1 liter, pleural injury, infection, bowel have shown that positive lymph nodes have an independent injury, embolism, and lymph ﬂuid drainage, and found adverse eﬀect on outcome, irrespective of other variables no signiﬁcant diﬀerences between patients who had LND [20–22]. Patients with node-positive disease have 5-year and those who did not. Siminovitch and colleagues  survival rates ranging from 5% to 35% . performed a direct comparison of extended, hilar, and regional LND templates. They found no diﬀerences in morbidity or survival rates between the three diﬀerent LND 3. Templates for Lymph Node Dissection templates. Regardless, LND remains a complex procedure, and carries risk for serious intraoperative complications. Renal lymphatic drainage is variable, adding to the con- troversy of performing LND at the time of RN. There is Great care must be taken when performing the procedure to currently no consensus on the anatomic extent of LND. ensure minimal morbidity. This makes it exceedingly diﬃcult to compare studies as there is a clear lack of standardization. Further, many studies 4. Indications and Assessment do not delineate the template used for LND. A “standard” LND for RCC on the left side includes the paraaortic and Indications for LND at the time of RN are not generally clear. preaortic nodes from the crus of the diaphragm to the Signs of lymphadenopathy or evidence of locally advanced inferior mesenteric artery (IMA). On the right, a “standard” disease on cross-sectional imaging, warrants LND. Palpable LND includes the paracaval and precaval nodes from the lymphadenopathy, or evidence of bulky lymph nodes with adrenal vein along the vena cava, also down to the level laparoscopy, at the time of RN can be indications for of the IMA. An “extended” LND adds the interaortocaval LND. Unfortunately, radiographic lymphadenopathy only nodesdownto the bifurcationofthe great vessels on both modestly correlates with metastatic involvement, with 32%– sides, with the inclusion of retrocaval nodes for right-sided 43% of nodes >1 cm harboring cancer [27, 28]. Other studies primary tumors. have shown that 16%–42% of lymph nodes suspicious Crispen and colleagues recently examined their series of on are falsely positive [1, 18, 29]. Many of these nodes patients with LND and evaluated the lymphatic drainage are inﬂammatory in nature, and therefore no beneﬁt is patterns for recommendations for surgical templates . imparted by their removal. The diﬃculties lie in determining Of 169 patients who ﬁt the criteria for LND, 64 (38%) the lymphatic drainage patterns of each kidney, which were found to have metastatic disease to their retroperi- lymph nodes are potentially positive, and to what extent a toneal lymph nodes, with the median of 6 lymph nodes lymphadenectomy should be performed. International Journal of Surgical Oncology 3 Nomograms have been developed to aid in risk stratiﬁ- 5. Outcomes of LND cation. One nomogram had 78% accuracy by incorporating Patients with clinically localized RCC have not been shown patient age, radiographic tumor size, and symptoms . to beneﬁt from routine LND . The EORTC 30881 trial Another preoperative nomogram, which included 4844 conﬁrmed that after appropriate clinical staging, in patients patients, found a concordance index of 0.76 when including with clinical N0M0 disease, the incidence of unsuspected symptoms at presentation, radiographic lymphadenopathy, lymph-node metastases was only 4.0%. When compared tumor size, and hematuria . Neither of these nomograms with nephrectomy alone, they showed no advantage to have gained widespread acceptance. performing LND on patients with clinically localized disease Crispen and colleagues evaluated the performance of with regards to overall survival, local regional progression, LND in high-risk clear cell RCC patients between 2002 and or distant progression. Of the 346 patients in whom LND 2006 . They had previously identiﬁed ﬁve intraoperative was performed, 51 had palpably enlarged lymph nodes at the pathological features which were considered high-risk for time of surgery. Of these, only 10 patients (20%) had lymph nodal metastases, and performed LND if at least two of these node metastases. Remarkably, of the 311 remaining patients risk factors were present intraoperatively. These were nuclear without palpable nodes, only 4 patients (1%) were shown grade 3 or 4, sarcomatoid component, tumor size ≥10 cm, to have metastatic disease to their lymph nodes (P< .001). tumor stage pT3 or pT4, and coagulative tumor necrosis. Of The potential beneﬁts of staging for these patients are also 169 RNs that had 2 high-risk intraoperative factors, 63 (38%) minimal. These statements are especially true for more low- had nodal metastases. risk disease (T1-2, N0, M0). Others have novel approaches to expanding indications Themorediﬃcult patient population to address is those for LND. Bex and colleagues evaluated the role of sentinel with clinically localized, high-risk disease (T3-4, N0, M0). node detection in patients with RCC . Previous series The root of this diﬃculty stems from the fact that there is indicate that 58–95% of patients with lymph node disease substantial risk of hematogenous dissemination of disease, have associated hematogenous spread [32, 33], prompting and relatively low risk of node-only involvement. The ther- Bex and colleagues to assess the feasibility of identifying a apeutic beneﬁt of LND in these patients is questionable at sentinel node to aid in staging. Eight patients with cT1 cN0 best. As previously discussed, Blute and colleagues identiﬁed cM0 RCC had their tumors injected (percutaneously under 99m 5 risk factors (including clinical stage T3-4) for lymph ultrasound guidance) with a radionuclide tracer, Tc- node metastases. The presence of at least 2 risk factors nanocolloid. Both lymphoscintigraphy and SPECT/CT were was associated with a 15-fold higher incidence of regional performed to determine the anatomic location of the sentinel lymph node involvement. Although diﬃcult to implement, node, as there is variable lymphatic drainage of the kidney. this is reasonable approach for these patients in whom occult Surgery was then performed the following day utilizing disease may be cured. intraoperative gamma probes to identify the radioactive Patients who present with clinical nodal disease should nodes. Of the eight patient tumors injected, six patients were have LND performed. It is relatively infrequent for patients found to have identiﬁable sentinel nodes on scintigraphy. In to present with isolated positive nodes, without distant two patients, no identiﬁable drainage of the radiotracer was metastases, but is estimated to occur in 3% to 10% of found. In this small study, an identiﬁable sentinel node could cases [1, 17–19]. It is essential, therefore, to accurately rule be found in 75% of tumors. The authors suggest that this may out distant metastatic disease if one suspects lymph node be helpful in patients in which biopsy of the sentinel node involvement only. Survival of these patients improves when could clarify the extent of lymphatic involvement, which LND is performed compared to nephrectomy alone . could have diagnostic and therapeutic implications . Further, the overall survival of these patients who undergo Ming and colleagues evaluated the utility in performing LND with radical nephrectomy is far superior to patients frozen section analysis of enlarged lymph nodes during who present with distant metastases, and in fact more closely RN for RCC . They performed frozen section analysis approximates the survival of patients with T3, N0, M0 on lymph nodes >1 cm, before undertaking an extended disease [35, 36]. Giuliani and colleagues showed that 5-year lymphadenectomy. Of 702 consecutive patients, 114 had survival in patients with lymph node only disease was 47.9%, evidence of enlarged lymph nodes or palpably enlarged compared with 7% for patients with distant metastases. An nodes and underwent frozen section analysis. On ﬁnal extended lymph node dissection, as described previously, is pathology, they found that 78 patients (68.4%) with enlarged recommended in these patients. lymph nodes did not harbor cancer while 36 (31.6%) did have nodal metastases. Of these 36 patients with nodal Patients with metastatic disease may beneﬁt only slightly, disease on ﬁnal pathology, 32 had positive ﬁndings on if at all, from LND at the time of nephrectomy. Nodal metas- frozen section, resulting in positive predictive value of 100% tases are poorly responsive to immunotherapy, so removal of grossly positive nodes is reasonable. Although extended and negative predictive value of 95%. The study concludes that it would be reasonable to avoid LND in patients with lymphadenectomy may theoretically be beneﬁcial, there is clinically localized RCC in whom frozen section analysis no evidence to support this, and lymphadenectomy must be of enlarged lymph nodes reveals no evidence of malignant balanced with the patient’s comorbidities and performance disease. However, this does not indicate any therapeutic status. A useful, evidence-based algorithm was oﬀered by advantage to the procedure in patients with lymph node Godoy and colleagues  that can be utilized in the decision disease. to perform LND at the time of radical nephrectomy. With 4 International Journal of Surgical Oncology the advent of new tyrosine kinase inhibitors and cytokines, CT, or if bulky lymphadenopathy is found at the time of the value of LND in patients with metastatic disease may surgery. Although lymphadenectomy undoubtedly improves increase in the near future, either as adjuvant or neoadjuvant the accuracy of staging and provides better prognostic therapy. information, there is little impact on progression-free or overall survival in patients with clinically localized disease. Risk factors may increase the likelihood of lymph node 6. Current State of Targeted Therapies metastases, and may be a way to better determine patients Previously, systemic treatment of patients with metastatic at risk for nodal involvement. Future studies with novel RCC was limited to cytokine therapy with interleukin- targeted therapies may increase the indications for LND (IL-) 2 or interferon- (IFN-) α, because of mRCC’s gen- further. eral resistance to chemotherapy. High-dose IL-2 remains the only treatment to produce durable remissions, and References it should be considered in healthy, appropriately chosen  J.H.M.Blom, H. vanPoppel, J. M. 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