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Lessons learned in the surgical management of renal cell carcinoma
LESSONS LEARNED IN THE SURGICAL MANAGEMENT OF RENAL CELL CARCINOMA SHOMIK SENGUPTA
AND
HORST ZINCKE
ABSTRACT Surgical excision, the mainstay of management of renal cell carcinoma (RCC), has evolved significantly over the last 4 decades. Radiological imaging is crucial to the diagnosis and staging of RCC, and technological advances have facilitated more precise preoperative assessment. Additionally, wider use of cross-sectional imaging modalities has led to increasing incidental diagnosis of small, early-stage RCC. Nephron-sparing surgery (NSS), originally developed to treat RCC arising in a solitary functioning kidney, has been demonstrated to be a safe and effective alternative to radical nephrectomy. NSS is now also applicable to tumors of suitable size and anatomy in patients with a normal contralateral kidney, thus facilitating preservation of renal function and management of metachronous contralateral pathology. Laparoscopic and percutaneous approaches have developed over the last decade, thus providing minimally invasive modalities, with shortened convalescence and improved cosmesis. Advanced RCC, involving venous extension or nodal spread, is increasingly amenable to surgical management, although appropriate patient selection is crucial. Furthermore, surgical excision of the primary lesion appears to be an integral part of systemic therapy for metastatic RCC. UROLOGY 66 (Suppl 5A): 36–42, 2005. © 2005 Elsevier Inc.
R
enal cell carcinoma (RCC), the most common adult neoplasm in the kidney, is relatively resistant to nonsurgical modalities and therefore is primarily managed by surgery. The modern surgical management of RCC can be said to have originated from Robson et al.’s1 description of radical nephrectomy (RN) in the 1960s. In the subsequent 4 decades, the surgical armamentarium for treatment of RCC has expanded with the development of nephronsparing and minimally invasive approaches, which complement traditional open RN. Additionally, the spectrum of disease being considered for surgical management has become much broader than in the past, from small incidentally detected tumors to large lesions with associated local or distant spread. Herein we review the lessons learned in the surgical management of RCC and discuss currently available surgical options. PREOPERATIVE ASSESSMENT
CLINICAL DIAGNOSIS Preoperative assessment of the patients with a renal lesion has 3 principal aims: to make the diagFrom the Department of Urology, Mayo Clinic, Rochester, Minnesota, USA Reprint requests: Horst Zincke, MD, Department of Urology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected]. © 2005 ELSEVIER INC. 36
ALL RIGHTS RESERVED
nosis of RCC, assess the stage of disease, and delineate the anatomic detail necessary for operative planning. Currently, with the increasing use of cross-sectional imaging, the majority of RCCs are diagnosed incidentally during investigation of unrelated complaints.2,3 The classic clinical triad of pain, hematuria, and a mass is seen less frequently than previously, but RCC remains a great mimic by virtue of its various paraneoplastic manifestations.4 Incidentally diagnosed RCCs are generally of smaller size and lower stage than symptomatic ones, and as such they have a better prognosis.3,5 In our experience, however, after the pathologic features are accounted for, the mode of presentation does not further influence outcome.6 DIFFERENTIAL DIAGNOSIS RCCs comprise ⬎90% of renal masses that are radiologically demonstrated to be solid; therefore they may be presumptively diagnosed on this basis. Differentiation from a renal cyst is usually straightforward, but for cysts exhibiting complex features such as thickness, nodularity or calcification of the wall, internal septation, or heterogeneity, systematic assessment using objective criteria facilitates the estimation of the risk of malignancy.7 Needle biopsy of renal masses is prone to inaccuracy,8,9 and other than for suspected metastases10 or lym0090-4295/05/$30.00 doi:10.1016/j.urology.2005.06.004
phoma,11 it is not recommended for treatment decisions. STAGING Once the diagnosis of RCC has been made, clinical staging requires radiologic assessment of the local extent, venous or nodal involvement, and lungs and liver for potential metastatic deposits.12 Such assessment has been made highly accurate by improvement in cross-sectional imaging, in the form of multidetector computed tomography and magnetic resonance imaging. The advances in imaging technology have also been helpful in providing improved visualization of anatomic detail, so as to facilitate operative planning. This is particularly crucial in more complex cases, such as for planned nephron-sparing surgery (NSS),13 in the presence of anatomical variants,14 or venous tumor thrombus.15 In many such instances, the need for invasive imaging such as by arteriography or venography has been obviated by the reconstructive capability of modern cross-sectional imaging. NEPHRON-SPARING SURGERY RATIONALE The oncologic efficacy of RN led to its rapid recognition as the “gold standard” for the treatment of RCC. However, for patients with RCC arising bilaterally or in a solitary functioning kidney, alternative approaches need to be considered because RN renders them anephric, leading to significant cost and complications. This was the initial impetus that led to the increasing use of NSS, to the point where it could be considered the treatment of choice for the subgroup of patients described above.16 A number of technical prerequisites for NSS, including detailed preoperative imaging, strategies for renal protection against ischemic damage, improved anesthetic and perioperative support, and effective antibiotic prophylaxis, became available during the 1960s and 1970s, thus further contributing to its wider application. RENAL PROTECTION In the context of NSS performed for an imperative indication, the prevention of perioperative nephron damage in the renal remnant is crucial. General factors that contribute to renal protection include adequate hydration, forced diuresis (using agents such as mannitol and furosemide), and avoidance of systemic hypotension or nephrotoxic agents. Additionally, because arterial clamping may be necessary for NSS, the impact of the resulting ischemia needs to be minimized. The duration of ischemia as well as occurrence of intermittent reperfusion are recognized as crucial determinants of nephron damage.17,18 Cooling of the kidney is a UROLOGY 66 (Supplement 5A), November 2005
further protective factor that enables the ischemic time to be safely prolonged beyond the 30 minutes permitted at body temperature.19 INDICATIONS The indications for NSS have broadened significantly over time, to now include many patients without the imperative to avoid extirpation of the whole kidney. The most obvious group of patients who benefit from such elective NSS are those individuals in whom the normal contralateral kidney is under potential future threat, such as from hypertension, diabetes mellitus, or a hereditary cancer diathesis like von Hippel-Lindau syndrome. In addition, for the increasing number of small, earlystage RCCs detected incidentally on imaging, RN represents overtreatment. For such lesions, NSS is often more appropriate, because it may prevent potential problems such as hyperfiltration injury to the contralateral kidney20 and may simplify management of metachronous contralateral RCC. TECHNIQUE The technique for NSS has also evolved over time, in part because of a change in the spectrum of tumors being treated. Thus, the early application of NSS was frequently for large tumors, with complex resection and reconstruction that often called for extracorporeal bench surgery.21,22 Subsequently, various approaches other than partial nephrectomy, including wedge resection and enucleation, have become established,16 thereby allowing greater preservation of renal parenchyma. Despite initial concerns regarding the risk of recurrence after enucleation,23,24 NSS has become established as a safe technique that is now widely used, with outcomes similar to those with partial nephrectomy.25–27 In contrast, ex vivo surgery is now rarely performed, not only because of its poorer outcomes26,28 but also because improved surgical expertise and decreased frequency of large, complex tumors have reduced its need. MORBIDITY Although NSS is surgically more challenging than RN, in experienced hands it can be carried out with low morbidity.18,20,29,30 Urinary leakage and hemorrhage are potential complications of specific concern, but the risk may be minimized by appropriate attention to surgical technique.30 Additionally, the availability of minimally invasive modalities for managing these sequelae— by ureteric stenting for urinary leakage and angioembolization for hemorrhage— has reduced the risk of completion nephrectomy in this context. On the other hand, there is evidence to suggest that long-term complications such as proteinuria and renal impairment are less common after NSS than after RN 37
for unilateral RCC in the presence of a normal contralateral kidney,20 thus providing support in favor of elective NSS. ONCOLOGIC EFFICACY Justifiably, the oncologic efficacy of NSS has been closely scrutinized, with a major concern being tumor involvement of the surgical margin. With NSS, traditionally it has been recommended that the tumor be resected with a ⱖ10-mm margin of normal parenchyma, so as to minimize the risk of a positive surgical margin16; however, recent data provide evidence that a much smaller margin may be adequate.26,31,32 The use of intraoperative pathologic assessment based on frozen tissue sections allows the identification of tumor at the surgical margin and consequent resection of further tissue in order to achieve a negative margin.21 Notably, although local recurrence is more likely in the presence of RCC at the surgical margin, it is not inevitable,32 and it may be successfully treated by surgical resection33 or radiofrequency ablation34 if it occurs. The second concern regarding NSS relates to the possibility of multifocal RCC afflicting the remainder of the kidney. Although the risk of multifocal RCC has been estimated to be as high as 20%,35 it is much lower (3% to 7%) among patients with smaller and lower stage tumors who may be candidates for elective NSS.36 –38 Additionally, most multifocal lesions are identifiable, either on preoperative radiology or intraoperative examination of the kidney, and the overall incidence of unrecognized multifocality is only 6%.38 Notably, the risk of multifocal disease is much greater among RCC of the papillary subtype (11%) than it is for clear cell or chromophobe subtypes (2% each).39 Two recent observations provide a further rationale for preferential NSS for multiple renal tumors. First, in 25% of cases additional ipsilateral tumors associated with an index RCC are of benign histology, and therefore they should be treated by NSS if appropriate.40 Second, multifocal clear-cell RCCs are associated with a 5-time greater risk of subsequent contralateral recurrence, in which case ipsilateral nephron preservation may become crucial.41 Notwithstanding the above issues, the oncologic efficacy of NSS was demonstrated as early as the 1980s,21,42 and has since been confirmed in multiple studies with long-term follow-up.20,29,43 In the imperative setting, the tumors being treated are often of more adverse pathology; nevertheless, 5-year overall survival rates of 60% to 75% and cancer-specific survival rates of 70% to 80% are achievable.27,42 On the other hand, outcomes following NSS for small tumors (including those performed for imperative indications) appear to be much better than this, and they are comparable to 38
RN.26,29,44 Similarly, elective NSS performed for solitary unilateral RCC in the presence of a normal contralateral kidney results in overall and cancerspecific survival rates that are similar to patients undergoing RN, despite a somewhat higher risk of local recurrence.20,45 MINIMALLY INVASIVE APPROACHES LAPAROSCOPIC SURGERY Since demonstration of the feasibility of laparoscopic nephrectomy in 1991,46 there has been a steadily increasing use of a laparoscopic approach for the surgical treatment of RCC. The principal benefits of laparoscopic nephrectomy relate to reductions in postoperative pain, shortened length of hospitalization and duration of convalescence, and improved cosmesis. The main problem with this approach relates to the long learning curve, which is often associated with higher complication rates. Nonetheless, multiple series have now demonstrated that with appropriate patient selection and adequate training, laparoscopic RN can be carried out with complication rates and medium-term oncologic outcomes that are similar to open surgery.47–52 There remains some controversy surrounding the extraction of the tumor-bearing kidney after it has been laparoscopically resected, which is achieved by morcellation at some centers. However, this precludes an adequate pathologic assessment53 and appears not to confer any benefit in terms of postoperative pain or recovery.54 As such, it cannot be recommended. A further discussion point relating to laparoscopic surgery for RCC relates to the choice between laparoscopic RN and open NSS for small unilateral RCC with a normal contralateral kidney. In such instances, laparoscopic RN leads to short-term benefits in terms of blood loss, hospital stay, and recovery, but at the cost of worse renal function in the long run.55 Laparoscopic NSS is developing as a surgical approach that may combine the benefits of both techniques,56 –59 but at present it remains a challenging undertaking.60 Additionally, laparoscopic surgery is also being applied to an ever-increasing spectrum of patients with RCC, with reports of laparoscopic nephrectomy for large tumors,61 for those involving venous tumor thrombus,62 or for cytoreduction in the setting of local extension or distant metastases.63– 65 However, for most urologic laparoscopists, currently accepted exclusion criteria would include the presence of extrarenal spread, venous extension, or lymphadenopathy.53 ABLATIVE TECHNIQUES A number of tissue ablative techniques, including cryotherapy66 and radiofrequency ablation,34,67 UROLOGY 66 (Supplement 5A), November 2005
have also been used to treat RCC. The great advantage of such techniques is the ability to percutaneously or laparoscopically68 treat small exophytic tumors. To date, encouraging results have been reported,34,66 – 68 although follow-up has been short and tumor persistence and recurrence were assessed radiologically rather than histologically in the majority of series. The principal applications of such technologies may be in patients who require repeated intervention for small tumors, such as in the case of von Hippel-Lindau syndrome,69 especially in the setting of a solitary kidney70 or after multiple surgical resections.34 Additionally, it may be an alternative to surgical resection for elderly or frail patients,34 although small tumors in such patients may also be safely observed,71 particularly given the lower risk of malignancy.72 MANAGEMENT OF ADVANCED DISEASE TUMOR THROMBUS At the other end of the spectrum, the surgical treatment of advanced RCC now has wider scope and better results than ever before. The area where this is most clearly evident is in the management of RCC with venous tumor thrombus. Improvements in perioperative monitoring and management, surgical expertise, and vascular bypass techniques have allowed progressively more difficult thrombus cases to be managed with lower complication rates.73,74 Furthermore, it has been demonstrated that patients with venous tumor thrombus but without nodal or distant metastases have good oncologic outcomes and therefore merit aggressive surgical treatment.73–76 The feasibility of venous tumor thrombectomy for RCC arising in a solitary kidney has also been demonstrated.77,78 LYMPHADENECTOMY Although Robson et al.’s1 description of RN included removal of some draining lymph nodes, the exact role of lymphadenectomy in the surgical treatment of RCC remains controversial. In a randomized controlled trial conducted by the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC), the prevalence of lymph nodes involved by tumor was low, reflecting the preponderance of low-risk disease.79 This is similar to reports of single-institution experience,80,81 although specific subgroups can be identified that have a higher risk of nodal involvement.80 Although lymphadenectomy has been shown to add minimal morbidity to nephrectomy for clinically localized RCC, to date a benefit in terms of oncologic outcomes has not.79 METASTATIC DISEASE In contrast, the resection of involved lymph nodes in patients with metastatic RCC results in UROLOGY 66 (Supplement 5A), November 2005
improved response to immunotherapy and longer survival.82 This forms part of the growing body of evidence suggesting that surgical reduction of tumor bulk before systemic immunotherapy improves outcomes in patients with metastatic RCC, including numerous single-institution reports83– 86 and 2 large randomized controlled trials87,88 of cytoreductive nephrectomy. As an alternative, some centers have advocated consolidative nephrectomy after induction immunotherapy, in an effort to best target surgical therapy to responders.89,90 At present the optimal timing of nephrectomy in relation to immunotherapy remains uncertain, as do the ideal immunotherapy regimen and appropriate patient selection. Occasionally, nephrectomy may be required for the palliation of local symptoms or paraneoplastic phenomena in patients with metastatic RCC.91 Spontaneous regression of metastases, although reported,92 is a rare occurrence and should not serve as an indication for surgery. Additionally, the surgical treatment of metastatic RCC may also encompass the resection of secondary tumor deposits. For a single site of recurrent disease (particularly if pulmonary) that occurs after a disease-free interval and is amenable to complete resection, excellent outcomes may be achieved.93–97 CONCLUSION The surgical treatment of RCC has evolved significantly over the preceding 4 decades, and it continues to do so as of this writing. Preoperative assessment, particularly by radiologic modalities, has become less invasive but more detailed and accurate. Perioperative supportive management in terms of anesthetic administration, vital monitoring, antibiotic prophylaxis, and fluid resuscitation offers greater choice and sophistication, thus catering to more complex procedures and older or frailer patients. A variety of operative approaches is now available, and it can be tailored on a case-bycase basis, depending on the tumor characteristics and patient wishes. In the future, further options are likely to emerge as currently available techniques become more widespread in their availability. Limitations that remain in the surgical management of RCC include the high rate of failure after treatment with curative intent for localized disease.98 Prognostic models may help identify such patients and may facilitate appropriate surveillance99 or trials of adjuvant therapy.100 At present, the efficacy of salvage treatments for such patients is limited,101 but complete surgical resection may lead to favorable outcomes in some instances.95,97 Disappointingly, currently available systemic therapies appear to be ineffective in the adjuvant set39
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83. Rackley R, Novick A, Klein E, et al: The impact of adjuvant nephrectomy on multimodality treatment of metastatic renal cell carcinoma. J Urol 152: 1399 –1403, 1994. 84. Mani S, Todd MB, Katz K, et al: Prognostic factors for survival in patients with metastatic renal cancer treated with biological response modifiers. J Urol 154: 35– 40, 1995. 85. Wagner JR, Walther MM, Linehan WM, et al: Interleukin-2 based immunotherapy for metastatic renal cell carcinoma with the kidney in place. J Urol 162: 43– 45, 1999. 86. Walther MM, Yang JC, Pass HI, et al: Cytoreductive surgery before high dose interleukin-2 based therapy in patients with metastatic renal cell carcinoma. J Urol 158: 1675– 1678, 1997. 87. Mickisch GH, Garin A, van Poppel H, et al, for the European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 358: 966 –970, 2001. 88. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345: 1655–1659, 2001. 89. Sella A, Swanson DA, Ro JY, et al: Surgery following response to interferon-alpha-based therapy for residual renal cell carcinoma. J Urol 149: 19 –22, 1993. 90. Krishnamurthi V, Novick AC, and Bukowski RM: Efficacy of multimodality therapy in advanced renal cell carcinoma. Urology 51: 933–937, 1998. 91. Wood CG: The role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma. Urol Clin North Am 30: 581–588, 2003. 92. Lokich J: Spontaneous regression of metastatic renal cancer: case report and literature review. Am J Clin Oncol 20: 416 – 418, 1997. 93. Kavolius JP, Mastorakos DP, Pavlovich C, et al: Resection of metastatic renal cell carcinoma. J Clin Oncol 16: 2261– 2266, 1998. 94. O’Dea MJ, Zincke H, Utz DC, et al: The treatment of renal cell carcinoma with solitary metastasis. J Urol 120: 540 – 542, 1978. 95. Kierney PC, van Heerden JA, Segura JW, et al: Surgeon’s role in the management of solitary renal cell carcinoma metastases occurring subsequent to initial curative nephrectomy: an institutional review. Ann Surg Oncol 1: 345–352, 1994.
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96. Frydenberg M, Gunderson L, Hahn G, et al: Preoperative external beam radiotherapy followed by cytoreductive surgery and intraoperative radiotherapy for locally advanced primary or recurrent renal malignancies. J Urol 152: 15–21, 1994. 97. Itano NB, Blute ML, Spotts B, et al: Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy. J Urol 164: 322–325, 2000. 98. Leibovich BC, Blute ML, Cheville JC, et al: Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 97: 1663–1671, 2003. 99. Frank I, Blute ML, Cheville JC, et al: A multifactorial postoperative surveillance model for patients with surgically treated clear cell renal cell carcinoma. J Urol 170: 2225–2232, 2003. 100. Motzer RJ, Mazumdar M, Bacik J, et al: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17: 2530 –2540, 1999. 101. Janzen NK, Kim HL, Figlin RA, et al: Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 30: 843– 852, 2003. 102. Clark JI, Atkins MB, Urba WJ, et al: Adjuvant highdose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol 21: 3133–3140, 2003. 103. Atzpodien J, Schmitt E, Gertenbach U, et al: Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer 92: 843– 846, 2005. 104. Fisher RI, Rosenberg SA, and Fyfe G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 6(suppl 1): S55–S57, 2000. 105. Medical Research Council Renal Cancer Collaborators: Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 353: 14 –17, 1999. 106. Thompson RH, Gillett MD, Cheville JC, et al: Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 101: 17174 –17179, 2004.
UROLOGY 66 (Supplement 5A), November 2005
AND
HORST ZINCKE
ABSTRACT Surgical excision, the mainstay of management of renal cell carcinoma (RCC), has evolved significantly over the last 4 decades. Radiological imaging is crucial to the diagnosis and staging of RCC, and technological advances have facilitated more precise preoperative assessment. Additionally, wider use of cross-sectional imaging modalities has led to increasing incidental diagnosis of small, early-stage RCC. Nephron-sparing surgery (NSS), originally developed to treat RCC arising in a solitary functioning kidney, has been demonstrated to be a safe and effective alternative to radical nephrectomy. NSS is now also applicable to tumors of suitable size and anatomy in patients with a normal contralateral kidney, thus facilitating preservation of renal function and management of metachronous contralateral pathology. Laparoscopic and percutaneous approaches have developed over the last decade, thus providing minimally invasive modalities, with shortened convalescence and improved cosmesis. Advanced RCC, involving venous extension or nodal spread, is increasingly amenable to surgical management, although appropriate patient selection is crucial. Furthermore, surgical excision of the primary lesion appears to be an integral part of systemic therapy for metastatic RCC. UROLOGY 66 (Suppl 5A): 36–42, 2005. © 2005 Elsevier Inc.
R
enal cell carcinoma (RCC), the most common adult neoplasm in the kidney, is relatively resistant to nonsurgical modalities and therefore is primarily managed by surgery. The modern surgical management of RCC can be said to have originated from Robson et al.’s1 description of radical nephrectomy (RN) in the 1960s. In the subsequent 4 decades, the surgical armamentarium for treatment of RCC has expanded with the development of nephronsparing and minimally invasive approaches, which complement traditional open RN. Additionally, the spectrum of disease being considered for surgical management has become much broader than in the past, from small incidentally detected tumors to large lesions with associated local or distant spread. Herein we review the lessons learned in the surgical management of RCC and discuss currently available surgical options. PREOPERATIVE ASSESSMENT
CLINICAL DIAGNOSIS Preoperative assessment of the patients with a renal lesion has 3 principal aims: to make the diagFrom the Department of Urology, Mayo Clinic, Rochester, Minnesota, USA Reprint requests: Horst Zincke, MD, Department of Urology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected]. © 2005 ELSEVIER INC. 36
ALL RIGHTS RESERVED
nosis of RCC, assess the stage of disease, and delineate the anatomic detail necessary for operative planning. Currently, with the increasing use of cross-sectional imaging, the majority of RCCs are diagnosed incidentally during investigation of unrelated complaints.2,3 The classic clinical triad of pain, hematuria, and a mass is seen less frequently than previously, but RCC remains a great mimic by virtue of its various paraneoplastic manifestations.4 Incidentally diagnosed RCCs are generally of smaller size and lower stage than symptomatic ones, and as such they have a better prognosis.3,5 In our experience, however, after the pathologic features are accounted for, the mode of presentation does not further influence outcome.6 DIFFERENTIAL DIAGNOSIS RCCs comprise ⬎90% of renal masses that are radiologically demonstrated to be solid; therefore they may be presumptively diagnosed on this basis. Differentiation from a renal cyst is usually straightforward, but for cysts exhibiting complex features such as thickness, nodularity or calcification of the wall, internal septation, or heterogeneity, systematic assessment using objective criteria facilitates the estimation of the risk of malignancy.7 Needle biopsy of renal masses is prone to inaccuracy,8,9 and other than for suspected metastases10 or lym0090-4295/05/$30.00 doi:10.1016/j.urology.2005.06.004
phoma,11 it is not recommended for treatment decisions. STAGING Once the diagnosis of RCC has been made, clinical staging requires radiologic assessment of the local extent, venous or nodal involvement, and lungs and liver for potential metastatic deposits.12 Such assessment has been made highly accurate by improvement in cross-sectional imaging, in the form of multidetector computed tomography and magnetic resonance imaging. The advances in imaging technology have also been helpful in providing improved visualization of anatomic detail, so as to facilitate operative planning. This is particularly crucial in more complex cases, such as for planned nephron-sparing surgery (NSS),13 in the presence of anatomical variants,14 or venous tumor thrombus.15 In many such instances, the need for invasive imaging such as by arteriography or venography has been obviated by the reconstructive capability of modern cross-sectional imaging. NEPHRON-SPARING SURGERY RATIONALE The oncologic efficacy of RN led to its rapid recognition as the “gold standard” for the treatment of RCC. However, for patients with RCC arising bilaterally or in a solitary functioning kidney, alternative approaches need to be considered because RN renders them anephric, leading to significant cost and complications. This was the initial impetus that led to the increasing use of NSS, to the point where it could be considered the treatment of choice for the subgroup of patients described above.16 A number of technical prerequisites for NSS, including detailed preoperative imaging, strategies for renal protection against ischemic damage, improved anesthetic and perioperative support, and effective antibiotic prophylaxis, became available during the 1960s and 1970s, thus further contributing to its wider application. RENAL PROTECTION In the context of NSS performed for an imperative indication, the prevention of perioperative nephron damage in the renal remnant is crucial. General factors that contribute to renal protection include adequate hydration, forced diuresis (using agents such as mannitol and furosemide), and avoidance of systemic hypotension or nephrotoxic agents. Additionally, because arterial clamping may be necessary for NSS, the impact of the resulting ischemia needs to be minimized. The duration of ischemia as well as occurrence of intermittent reperfusion are recognized as crucial determinants of nephron damage.17,18 Cooling of the kidney is a UROLOGY 66 (Supplement 5A), November 2005
further protective factor that enables the ischemic time to be safely prolonged beyond the 30 minutes permitted at body temperature.19 INDICATIONS The indications for NSS have broadened significantly over time, to now include many patients without the imperative to avoid extirpation of the whole kidney. The most obvious group of patients who benefit from such elective NSS are those individuals in whom the normal contralateral kidney is under potential future threat, such as from hypertension, diabetes mellitus, or a hereditary cancer diathesis like von Hippel-Lindau syndrome. In addition, for the increasing number of small, earlystage RCCs detected incidentally on imaging, RN represents overtreatment. For such lesions, NSS is often more appropriate, because it may prevent potential problems such as hyperfiltration injury to the contralateral kidney20 and may simplify management of metachronous contralateral RCC. TECHNIQUE The technique for NSS has also evolved over time, in part because of a change in the spectrum of tumors being treated. Thus, the early application of NSS was frequently for large tumors, with complex resection and reconstruction that often called for extracorporeal bench surgery.21,22 Subsequently, various approaches other than partial nephrectomy, including wedge resection and enucleation, have become established,16 thereby allowing greater preservation of renal parenchyma. Despite initial concerns regarding the risk of recurrence after enucleation,23,24 NSS has become established as a safe technique that is now widely used, with outcomes similar to those with partial nephrectomy.25–27 In contrast, ex vivo surgery is now rarely performed, not only because of its poorer outcomes26,28 but also because improved surgical expertise and decreased frequency of large, complex tumors have reduced its need. MORBIDITY Although NSS is surgically more challenging than RN, in experienced hands it can be carried out with low morbidity.18,20,29,30 Urinary leakage and hemorrhage are potential complications of specific concern, but the risk may be minimized by appropriate attention to surgical technique.30 Additionally, the availability of minimally invasive modalities for managing these sequelae— by ureteric stenting for urinary leakage and angioembolization for hemorrhage— has reduced the risk of completion nephrectomy in this context. On the other hand, there is evidence to suggest that long-term complications such as proteinuria and renal impairment are less common after NSS than after RN 37
for unilateral RCC in the presence of a normal contralateral kidney,20 thus providing support in favor of elective NSS. ONCOLOGIC EFFICACY Justifiably, the oncologic efficacy of NSS has been closely scrutinized, with a major concern being tumor involvement of the surgical margin. With NSS, traditionally it has been recommended that the tumor be resected with a ⱖ10-mm margin of normal parenchyma, so as to minimize the risk of a positive surgical margin16; however, recent data provide evidence that a much smaller margin may be adequate.26,31,32 The use of intraoperative pathologic assessment based on frozen tissue sections allows the identification of tumor at the surgical margin and consequent resection of further tissue in order to achieve a negative margin.21 Notably, although local recurrence is more likely in the presence of RCC at the surgical margin, it is not inevitable,32 and it may be successfully treated by surgical resection33 or radiofrequency ablation34 if it occurs. The second concern regarding NSS relates to the possibility of multifocal RCC afflicting the remainder of the kidney. Although the risk of multifocal RCC has been estimated to be as high as 20%,35 it is much lower (3% to 7%) among patients with smaller and lower stage tumors who may be candidates for elective NSS.36 –38 Additionally, most multifocal lesions are identifiable, either on preoperative radiology or intraoperative examination of the kidney, and the overall incidence of unrecognized multifocality is only 6%.38 Notably, the risk of multifocal disease is much greater among RCC of the papillary subtype (11%) than it is for clear cell or chromophobe subtypes (2% each).39 Two recent observations provide a further rationale for preferential NSS for multiple renal tumors. First, in 25% of cases additional ipsilateral tumors associated with an index RCC are of benign histology, and therefore they should be treated by NSS if appropriate.40 Second, multifocal clear-cell RCCs are associated with a 5-time greater risk of subsequent contralateral recurrence, in which case ipsilateral nephron preservation may become crucial.41 Notwithstanding the above issues, the oncologic efficacy of NSS was demonstrated as early as the 1980s,21,42 and has since been confirmed in multiple studies with long-term follow-up.20,29,43 In the imperative setting, the tumors being treated are often of more adverse pathology; nevertheless, 5-year overall survival rates of 60% to 75% and cancer-specific survival rates of 70% to 80% are achievable.27,42 On the other hand, outcomes following NSS for small tumors (including those performed for imperative indications) appear to be much better than this, and they are comparable to 38
RN.26,29,44 Similarly, elective NSS performed for solitary unilateral RCC in the presence of a normal contralateral kidney results in overall and cancerspecific survival rates that are similar to patients undergoing RN, despite a somewhat higher risk of local recurrence.20,45 MINIMALLY INVASIVE APPROACHES LAPAROSCOPIC SURGERY Since demonstration of the feasibility of laparoscopic nephrectomy in 1991,46 there has been a steadily increasing use of a laparoscopic approach for the surgical treatment of RCC. The principal benefits of laparoscopic nephrectomy relate to reductions in postoperative pain, shortened length of hospitalization and duration of convalescence, and improved cosmesis. The main problem with this approach relates to the long learning curve, which is often associated with higher complication rates. Nonetheless, multiple series have now demonstrated that with appropriate patient selection and adequate training, laparoscopic RN can be carried out with complication rates and medium-term oncologic outcomes that are similar to open surgery.47–52 There remains some controversy surrounding the extraction of the tumor-bearing kidney after it has been laparoscopically resected, which is achieved by morcellation at some centers. However, this precludes an adequate pathologic assessment53 and appears not to confer any benefit in terms of postoperative pain or recovery.54 As such, it cannot be recommended. A further discussion point relating to laparoscopic surgery for RCC relates to the choice between laparoscopic RN and open NSS for small unilateral RCC with a normal contralateral kidney. In such instances, laparoscopic RN leads to short-term benefits in terms of blood loss, hospital stay, and recovery, but at the cost of worse renal function in the long run.55 Laparoscopic NSS is developing as a surgical approach that may combine the benefits of both techniques,56 –59 but at present it remains a challenging undertaking.60 Additionally, laparoscopic surgery is also being applied to an ever-increasing spectrum of patients with RCC, with reports of laparoscopic nephrectomy for large tumors,61 for those involving venous tumor thrombus,62 or for cytoreduction in the setting of local extension or distant metastases.63– 65 However, for most urologic laparoscopists, currently accepted exclusion criteria would include the presence of extrarenal spread, venous extension, or lymphadenopathy.53 ABLATIVE TECHNIQUES A number of tissue ablative techniques, including cryotherapy66 and radiofrequency ablation,34,67 UROLOGY 66 (Supplement 5A), November 2005
have also been used to treat RCC. The great advantage of such techniques is the ability to percutaneously or laparoscopically68 treat small exophytic tumors. To date, encouraging results have been reported,34,66 – 68 although follow-up has been short and tumor persistence and recurrence were assessed radiologically rather than histologically in the majority of series. The principal applications of such technologies may be in patients who require repeated intervention for small tumors, such as in the case of von Hippel-Lindau syndrome,69 especially in the setting of a solitary kidney70 or after multiple surgical resections.34 Additionally, it may be an alternative to surgical resection for elderly or frail patients,34 although small tumors in such patients may also be safely observed,71 particularly given the lower risk of malignancy.72 MANAGEMENT OF ADVANCED DISEASE TUMOR THROMBUS At the other end of the spectrum, the surgical treatment of advanced RCC now has wider scope and better results than ever before. The area where this is most clearly evident is in the management of RCC with venous tumor thrombus. Improvements in perioperative monitoring and management, surgical expertise, and vascular bypass techniques have allowed progressively more difficult thrombus cases to be managed with lower complication rates.73,74 Furthermore, it has been demonstrated that patients with venous tumor thrombus but without nodal or distant metastases have good oncologic outcomes and therefore merit aggressive surgical treatment.73–76 The feasibility of venous tumor thrombectomy for RCC arising in a solitary kidney has also been demonstrated.77,78 LYMPHADENECTOMY Although Robson et al.’s1 description of RN included removal of some draining lymph nodes, the exact role of lymphadenectomy in the surgical treatment of RCC remains controversial. In a randomized controlled trial conducted by the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC), the prevalence of lymph nodes involved by tumor was low, reflecting the preponderance of low-risk disease.79 This is similar to reports of single-institution experience,80,81 although specific subgroups can be identified that have a higher risk of nodal involvement.80 Although lymphadenectomy has been shown to add minimal morbidity to nephrectomy for clinically localized RCC, to date a benefit in terms of oncologic outcomes has not.79 METASTATIC DISEASE In contrast, the resection of involved lymph nodes in patients with metastatic RCC results in UROLOGY 66 (Supplement 5A), November 2005
improved response to immunotherapy and longer survival.82 This forms part of the growing body of evidence suggesting that surgical reduction of tumor bulk before systemic immunotherapy improves outcomes in patients with metastatic RCC, including numerous single-institution reports83– 86 and 2 large randomized controlled trials87,88 of cytoreductive nephrectomy. As an alternative, some centers have advocated consolidative nephrectomy after induction immunotherapy, in an effort to best target surgical therapy to responders.89,90 At present the optimal timing of nephrectomy in relation to immunotherapy remains uncertain, as do the ideal immunotherapy regimen and appropriate patient selection. Occasionally, nephrectomy may be required for the palliation of local symptoms or paraneoplastic phenomena in patients with metastatic RCC.91 Spontaneous regression of metastases, although reported,92 is a rare occurrence and should not serve as an indication for surgery. Additionally, the surgical treatment of metastatic RCC may also encompass the resection of secondary tumor deposits. For a single site of recurrent disease (particularly if pulmonary) that occurs after a disease-free interval and is amenable to complete resection, excellent outcomes may be achieved.93–97 CONCLUSION The surgical treatment of RCC has evolved significantly over the preceding 4 decades, and it continues to do so as of this writing. Preoperative assessment, particularly by radiologic modalities, has become less invasive but more detailed and accurate. Perioperative supportive management in terms of anesthetic administration, vital monitoring, antibiotic prophylaxis, and fluid resuscitation offers greater choice and sophistication, thus catering to more complex procedures and older or frailer patients. A variety of operative approaches is now available, and it can be tailored on a case-bycase basis, depending on the tumor characteristics and patient wishes. In the future, further options are likely to emerge as currently available techniques become more widespread in their availability. Limitations that remain in the surgical management of RCC include the high rate of failure after treatment with curative intent for localized disease.98 Prognostic models may help identify such patients and may facilitate appropriate surveillance99 or trials of adjuvant therapy.100 At present, the efficacy of salvage treatments for such patients is limited,101 but complete surgical resection may lead to favorable outcomes in some instances.95,97 Disappointingly, currently available systemic therapies appear to be ineffective in the adjuvant set39
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