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J Thorac Cardiovasc Surg 2008;135:1022-1028
© 2008 The American Association for Thoracic Surgery
General Thoracic Surgery |
a Department of Surgery, University of Minnesota, Minneapolis, Minn
b Department of Medicine, University of Minnesota, Minneapolis, Minn
c Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minn
Received for publication July 2, 2007; revisions received November 27, 2007; accepted for publication December 18, 2007. * Address for reprints: Michael A. Maddaus, MD, Professor and Program Director, University of Minnesota Department of Surgery, MMC 207, 420 Delaware St SE, Minneapolis, MN 55455. (Email: madda001{at}umn.edu).
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Abstract |
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Patients and Methods: We retrospectively reviewed the charts of all patients with renal cell carcinoma whose histologic specimens were evaluated at our institution from January 1, 2000, through December 31, 2006. Using Kaplan–Meier estimates, we compared the survival of patients who underwent resection of asynchronous mediastinal lymph node metastases with that of patients with stage IV disease.
Results: During the 7-year study period, of the 386 patients with renal cell carcinoma who were evaluated at our institution, 9 underwent resection of asynchronous mediastinal lymph node metastases. After primary tumor resection and before diagnosis of asynchronous mediastinal lymph node metastases, all patients completed chemotherapy, cytokine therapy, or tumor vaccination; 3 underwent radiotherapy. The median age at resection of mediastinal lymph nodes was 57.7 years (range, 39.7–81.2). The median time from primary tumor resection to mediastinal lymph node resection was 2.8 years (range, 0.5–23.3). In all, 4 patients underwent resection of metastases via thoracotomy and 5, via thoracoscopy. The median number of mediastinal lymph nodes pathologically evaluated was 7 (range, 2–28); the median number of positive mediastinal lymph nodes per patient was 1.5 (range, 1–3). We found no surgical complications. The median survival after resection of metastases (3.2 years) was significantly longer (P = .021) than for other patients with stage IV disease at our institution (1.1 years).
Conclusions: Resection of renal cell carcinoma mediastinal lymph node metastases is safe, appears to extend survival, and should be considered an important component of treating patients with renal cell carcinoma who have asynchronous mediastinal lymph node metastases.
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Introduction |
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stage I or II), 25% present as locally advanced disease (stage III), and 30% present with metastatic disease (stage IV).
Patients with asynchronous RCC metastases have a more favorable prognosis (median survival, 21 months)2 than those with synchronous metastases (median survival, 10 months).3 Resection of synchronous metastases does not impart a survival advantage.4 However, resection of isolated abdominal and pulmonary parenchymal asynchronous metastases results in a more favorable prognosis.4-7
In the treatment of patients with RCC with recurrent or advanced disease, the systemic medical therapies used are wide and of limited efficacy. When we began seeing patients with isolated mediasinal lymph node (MLN) metastases, we began offering surgical resection as therapy because of the isolated nature of their disease recurrence and the efficacy of current medical therapies available. We could find no published reports on the efficacy or possible survival advantage of resecting isolated asynchronous MLN metastases in patients with RCC. Traditionally, such patients have been treated with either palliative or experimental chemotherapy.
The aim of this study was to determine whether patients with RCC who undergo resection of isolated asynchronous MLN metastases have a survival advantage as compared with other patients having stage IV disease.
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Methods |
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To establish a control group for comparison with our study cohort, we used the University of Minnesota Cancer Center Registry to collect data (eg, patient characteristics, tumor stage, survival) on all patients with RCC treated at our institution.
Statistical Analysis
For statistical analyses, we used JMP for Windows, version 4.0.4 (SAS Institute, Inc, Cary, NC). Data are reported as mean ± standard deviation unless otherwise noted. For between-group comparisons of ordinal and nominal variables, we used a 
2 test (
=.05); for continuous variables, we used a t test ( =.05). For survival analyses, two survival times were used. The first was the overall survival time, from the time of diagnosis, defined as the time from diagnosis to death or last available follow-up (for those patients with both resectable and unresectable disease). The second survival time employed was the postresection survival time, from the time of resection, defined as the time from surgical resection to death or last available follow-up (as recorded in the University of Minnesota Cancer Center Registry at the time of initial manuscript submission). For survival analyses, we used the Kaplan–Meier method. To compare survival functions, we used a log–rank test ( = .05).
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Results |
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Table 1). All 9 patients had undergone radical nephrectomy before MLN metastases developed (
Table 2); at that time, 6 had stage III disease. The 1 patient with stage IV disease had an isolated humerus metastasis that was treated with (and responded to) radiation therapy. The median age at resection of MLN metastases was 57.7 years (range, 39.7–81.2), and the median interval from primary tumor resection to metastasectomy was 2.8 years (range, 0.5–23.3). New MLN metastases were identified during routine surveillance, as part of the evaluation for other procedures, or incidentally. Selected images (
Figure 1) from a fusion positron emission tomography/computed tomography scan show increased metabolic activity within the mediastinum of 1 patient with MLN metastases.
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Perioperative Details
Of the 9 patients who underwent resection of MLN metastases, 5 underwent thoracoscopy and 4, thoracotomy. Blood loss was minimal (range, 25–250 mL). The median operative time was 210 minutes (range, 120–270 minutes). The median number of MLNs pathologically evaluated was 7 (range 2–28). Of those MLNs, a median of 1.5 (range, 1–3) were positive for metastatic RCC, per our final pathologic examination. The median largest dimension of the histologically positive MLN was 3.7 cm (range, 0.8–7.6).
The mean postoperative hospital length of stay was 4.1 ± 3.3 days. Duration of chest tube placement was 2.9 ± 2.1 days. There were no perioperative deaths. The only complication was related to chemotherapy: upper gastrointestinal bleeding (diffuse gastritis on esophagogastroduodenoscopy) in 1 patient resulted in acute blood loss anemia and the need for blood transfusion. The mean survival time after resection of MLN metastases was 3.9 years. The median time after resection was more than 3.2 years (range, 2.8–>3.2 years); of our 9 study cohort patients, at the end of the 7-year study period, 1 had died, 1 had been lost to follow-up, and 7 were alive and well (Table 2).
Neoadjuvant and Adjuvant Therapies
Our 9 study cohort patients completed a variety of neoadjuvant and adjuvant treatment regimens (Table 2): 4 received a large multivalent immunogen vaccine; 3, high-dose interleukin 2 (IL-2); 3, radiation therapy; 3, sunitinib (Sutent; Pfizer Oncology, New York, NY); 3, sorafenib (Nexavar; Onyx Pharmaceuticals, Inc, Emeryville, Calif); 1, cetuximab (Erbitux; ImClone Systems Inc, New York, NY); 1, bevacizumab (Avastin; Genentech, Inc, South San Francisco, Calif); and 1, 852A (an experimental m-toll agonist).
Tumor Characteristics
Per our final histologic evaluation of the MLN specimens, no obvious features distinguished the asynchronous metastases from a typical RCC pattern (
Figure 2). The median Fuhrman grade8 was 3 (range 2–3) (Table 1). Minimal necrosis was seen in the MLNs; however, we noted uniform angiolymphatic invasion.
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Table 3.
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Figure 3, A). Similarly, from the time of resection of MLN metastases, our study cohort had a significantly higher survival (log–rank test, P = .021) than did patients with stage IV disease who were treated at our institution (Figure 3, B).
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Because no directly analogous group of patients with isolated asynchronous MLN metastases who did not undergo resection of metastases was available, we selected these 2 subsets: (1) patients with lung parenchymal lesions who underwent resection of metastases and (2) patients who had stage IV disease with pulmonary metastases when they first came to our institution and who did not undergo resection. From the time of resection (for both our study cohort and the subset with resectable lung parenchymal lesions), the survival was higher (log–rank test; P = .0025) than for the subset with unresectable pulmonary metastases (Figure 3, C). The survival did not significantly differ between our study cohort and the subset with lung parenchymal lesions. The median survival time from the time of resection for the subset with lung parenchymal lesions that were resectable (Figure 3, C, "lung metastasectomy) was 4 years (range, 2.07–> 6.5). For the subset with lung parenchymal lesions that were not resectable (Figure 3, C, "stage IV–lung") the median survival from time of initial treatment was 1.02 years (range, 0.1–5.6). Again, for our study cohort, MLN metastasectomy, the median survival from time of resection was 3.2 years (range, 2.8–> 3.2). The Motzer score for the subset with lung parenchymal lesions was 0.83 ± 0.86, and for the subset of patients with stage IV disease with pulmonary metastases, 0.81 ± 0.75.
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Discussion |
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In our study cohort, the predominant cell type was a clear cell variant.
In addition, the tumor grade provides prognostic information. In 1982, Fuhrman, Lasky, and Limas8 established a grading system (1 through 4) based on increasing nuclear size, cellular irregularity, and nucleolar prominence, that correlates with the survival. Other investigators have confirmed the association between increasing grade and worsening survival.10-12 In particular, a larger tumor size (>8 cm) and a higher number of mitoses per 10 high-power fields (>1) correspond to a worse survival.12 In our cohort of 9 patients, all demonstrated angiolymphatic involvement, not entirely unexpected given metastatic lymph node disease.
Motzer and associates developed a simple prognostic scoring system for patients with RCC and asynchronous disease. Patients receive a score of 0 to 3 on the basis of the presence of each of the following risk factors (1 point for each risk factor): low Karnofsky performance status (<80), anemia (hemoglobin 
13 g/dL for men and 11.5 g/dL for women), and hypercalcemia (serum calcium >10 mg/dL). Patients with no risk factors have a 25% 3-year survival. Patients with 1 risk factor have an 11% 3-year survival, and those with 2 or 3 risk factors, a 0% 3-year survival.3 In our study cohort (Table 1), only 1 patient (male) had anemia (Motzer score of 1). All other patients had a score of 0. On the basis of this scoring system, our study cohort had a good prognosis. Of interest, lymph node involvement has been associated with a worse survival.6,7,10,11
Most RCC recurrences or metastases occur within 5 years after initial treatment; patients who are disease-free at 5 years are traditionally considered to be cured. Although isolated asynchronous metastases developed within 7 years after radical nephrectomy in most of our 9 study cohort patients, in 1 patient metastases developed 23 years after radical nephrectomy. This patient had a low Furhman grade and a low Motzer score, likely indicative of the indolent nature of that particular tumor.
Resection of Metastases
Because resection of synchronous metastases does not impart a significant survival advantage,4 patients with stage IV RCC are usually treated with either palliative or experimental chemotherapy or with radiation therapy. Often, patients with isolated asynchronous metastatic disease are erroneously treated like patients with synchronous metastatic disease. However, the 2 groups have different prognoses and different responses to treatment. Possibly because of differences in tumor burden, patients who have RCC with asynchronous RCC metastases have a more favorable prognosis (median survival, 21 months)2 than patients with synchronous metastases (median survival, 10 months).3 Furthermore, evidence is accumulating regarding the efficacy of resection of metastases.
Cytoreduction through complete resection of locally recurrent RCC13 or asynchronous metastases5,7, 3-15 improves the patient survivals. Resection of lung parenchymal metastases is feasible6,7,16,17 and improves survival time (median, 35 months).4,6,7,16 Furthermore, unlike resection of locally recurrent RCC, which often requires extensive intra-abdominal resection,15 resection of pulmonary metastases is associated with minimal morbidity.4,6,7
Thus far, 1 previous case report has been published describing resection of RCC MLN.18 In that report, from Japan, the patient survived at least 6 years after resection of metastases. In our series of 9 patients, we have now demonstrated that resection of metastases can be performed safely via thoracotomy or thoracoscopy with a brief hospital length of stay, with minimal morbidity, with no postoperative mortality, and with excellent long-term results. In skilled hands, a thoracoscopic approach is adequate. At both a median and mean follow-up period of 3.2 years, of our 9 patients, 7 were alive and well. These 7 patients had a significantly longer survival time (mean, 47 months) than other patients with stage IV disease treated at our institution.
Chemoradiation, Tumor Vaccines, and Cytokine Therapy
In general, all patients with RCC are treated with a nephrectomy. For stage I and II, this could be a simple nephrectomy or a radical nephrectomy (the standard for stages III and IV). Limited clinical data are available for the use of standardized chemotherapeutic regimens for patients with advanced RCC.19 However, the use of IL-2 and interferon-alpha was associated in one study with a response rate of around 15%.20 In other studies, a tendency to relapse was noted in patients treated with IL-2 alone, whereas relapse was less likely in patients who underwent cytoreduction via resection of metastases (ie, metastasectomy) and subsequent IL-2 therapy with a complete response.14,21
Recently, novel chemotherapeutic agents have been added to the standard regimen for patients with metastatic RCC: sorafenib in December 2005 and sunitinib in January 2006. Two additional agents, far along in clinical phase trials, show potential: bevacizumab, an antibody against vascular endothelial growth factor, and temsirolimus, a mammalian target of rapamycin inhibitor.
The large multivalent immunogen vaccine, an autologous vaccine strategy developed at the University of Minnesota, continues to be experimental. Additionally, 852A, an m-toll agonist, and cetuximab, an antibody against epidermal growth factor receptor, are both experimental agents that currently are used at our institution as part of another protocol. At the time of RCC recurrence, cytokine therapy with high-dose IL-2 can be used (if not used before); sunitinib or sorafenib can be employed.
Sunitinib, a small molecule receptor tyrosine kinase inhibitor, has a possible mechanism of action through the vascular endothelial growth factor receptor. Sorafenib, a small molecule inhibitor of the Raf kinase, potentially works through the vascular endothelial growth factor receptor as well as platelet-derived growth factor. Both chemotherapeutic agents target vascular invasion.
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Conclusion |
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Acknowledgments |
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References |
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  M. Riquet, P. Berna, E. Brian, A. Badia, C. Vlas, P. Bagan, and F. Le Pimpec Barthes Intrathoracic Lymph Node Metastases From Extrathoracic Carcinoma: The Place for Surgery Ann. Thorac. Surg., July 1, 2009; 88(1): 200 - 205. [Abstract] [Full Text] [PDF]
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 R. Kanzaki, M. Higashiyama, J. Okami, and K. Kodama Surgical treatment for patients with solitary metastasis in the mediastinal lymph node from renal cell carcinoma Interact CardioVasc Thorac Surg, April 1, 2009; 8(4): 485 - 487. [Abstract] [Full Text] [PDF]
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