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J Thorac Cardiovasc Surg 2007;133:967-972
© 2007 The American Association for Thoracic Surgery
Prognostic role of lymph node involvement in lung metastasectomy
Giulia Veronesi, MDa,*,
Francesco Petrella, MDa,
Francesco Leo, MDa,
Piergiorgio Solli, MDa,
Patrick Maissoneuve, MDb,
Domenico Galetta, MDa,
Roberto Gasparri, MDa,
Giuseppe Pelosi, MDc,
Tommaso De Pas, MDd,
Lorenzo Spaggiari, MDa,e
a Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy
b Division of Epidemiology, European Institute of Oncology, Milan, Italy
c Division of Pathology, European Institute of Oncology, Milan, Italy
d Division of Oncology, European Institute of Oncology, Milan, Italy
e University School of Medicine, Milan, Italy.
Read at the Thirty-second Annual Meeting of the Western Thoracic Surgical Association, June 21-24, 2006, Sun Valley, Idaho.
Received for publication June 14, 2006; revisions received August 22, 2006; accepted for publication September 5, 2006.
* Address for reprints: Giulia Veronesi, MD, Division of Thoracic Surgery, European Institute of Oncology, Via Ripamonti 435, 20143 Milan. (Email: giulia.veronesi{at}ieo.it).
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Abstract
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Objective: The impact of lymph node involvement in lung metastasectomy from extrapulmonary malignancies is uncertain. We assessed the prognostic value of lymph node status in lung metastasectomy and the prevalence of unexpected mediastinal lymph node involvement after lymph node sampling or dissection.
Methods: From May 1998 to October 2005, 388 patients underwent 430 pulmonary metastasectomies with curative intent. The clinical records of all patients who underwent radical lymph node dissection or sampling were reviewed retrospectively. Survival was evaluated using the Kaplan–Meier method and comparison of survival curves by log–rank test.
Results: A total of 124 patients (61 men, mean age 59 years) underwent 139 pulmonary metastasectomies (56 wedge resections, 30 segmentectomies, 49 lobectomies, and 4 pneumonectomies with radical lymph node dissection [88] or sampling [51]). Means of 9.4 lymph nodes and 2 lung metastases per intervention were removed. The median disease-free interval from primary treatment to lung metastasectomy was 49 months. Lymph node involvement was present in 25 patients (20%), in 10 (8%) at N1 stations (hilar or peribronchial) and in 15 (12%) at N2 stations (mediastinal), and in 7 (12.5%) after atypical resection and in 19 (23%) after typical resection. In 15 patients (12%) (60% of N+ patients), lymph node involvement was unexpected. Estimated overall 5-year survival was 46%: It was 60% for subjects with no lymph node metastasis and 17% and 0% for those with N1 and N2 disease, respectively (P = .01).
Conclusions: Lymph node involvement heavily affects prognosis after pulmonary metastasectomies. In most patients, lymph node involvement was not revealed by preoperative workup.
Abbreviations and Acronyms CI = confidence interval; HR = hazard ratio; PET = positron emission tomography
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Introduction
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Although the efficacy of surgical removal of lung metastases has been demonstrated, fewer than 40% of patients benefit.1-5 For this reason there is great interest to identify criteria and prognostic factors to improve selection of surgical candidates and plan further therapeutic approaches. The main factor predicting survival is complete surgical removal of all metastases2; others are the disease-free interval, number of metastases, primary tumor type, presence of extrathoracic metastases, and levels of biological markers, such as carcinoembryonic antigen for gastrointestinal cancers and alpha-fetoprotein for germ cell-cancers.1-8
Lymph node staging was recently introduced as a prognostic factor for patients with resectable lung metastases.9-11 However, few data are available in the literature on the prevalence of nodal involvement in these patients and its prognostic significance, so there is no agreement whether lymph node dissection should be routinely performed as part of metastasectomy.6-10,12
The aim of the present study was to determine the prevalence of occult regional lymph node metastasis and the prognostic value in a retrospective series of patients who underwent radical lymph node dissection or sampling during lung metastasectomy.
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Materials and Methods
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From May 1998 to October 2005, 388 patients underwent 430 lung metastasectomies with curative intent at the European Institute of Oncology. The records of all patients who received radical lymph node dissection or lymph node sampling were reviewed. Age, sex, disease-free interval, primary tumor type, type of resection, number and size of lung metastases, number of lymph nodes resected, presence of hilar and mediastinal node metastases, and length of follow-up were abstracted and analyzed.
Indications for lung metastasectomy were controlled: primary tumor, absence of extrapulmonary metastasis or local recurrence at the preoperative staging, and complete lung resection considered possible from chest computed tomography.
Positron emission tomography (PET) scan was not available during the entire time frame of the study period. All lesions that were suitable for nonanatomic resection on the basis of their size and position were removed by a wedge resection or tumorectomy; in all other cases (large or centrally located metastases), an anatomic resection was performed (segmentectomy, lobectomy, or pneumonectomy). Videothoracoscopy was not used because a manual palpation of all lungs was routinely performed. The standard approach was lateral muscle-sparing thoracotomy. Only in case of apical chest tumors with suspicious invasion of cervicothoracic junction structures was a transmanubrial approach or hemiclamshell performed.
Although our previous experience indicated that 14% of patients undergoing lung metastasectomy had lymph node involvement,13 regional lymph node dissection in clinically negative cases was not performed routinely but according to the preference of each surgeon.
We considered a lymph node sampling to be the exploration of all ipsilateral mediastinal stations with lymph node biopsy at the level of at least 2 of them. We considered a radical lymph node dissection to be performed at the following stations: R2, R4, 7, and R9 for right lung metastasis and 5, 6, 7, and L9 for left lung metastasis.
The institutional review board was notified of our study, and informed consent to treat clinical data for research was obtained from the patients at the time of surgical resection.
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Statistical Analysis
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Time to death was defined as the time from surgery until death from any cause. All patients alive at last follow-up were right censored. Survival curves were estimated by the Kaplan–Meier method, and the log–rank test was used to compare survival between groups. The chi-square or Fisher exact test was used to analyze associations between categoric variables. A Cox proportional hazards model was used to identify independent predictors of survival, with adjustment for relevant clinical covariates. All statistical tests were 2-sided. The analyses were performed with the SAS statistical package version 8.2 (SAS Institute, Cary, NC).
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Results
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Mediastinal lymph node dissection or sampling was performed in 124 patients. The mean age was 59 years (range 24-82 years); 61 were men and 63 were women. The median disease-free time from primary tumor resection to first pulmonary metastasectomy was 49 months (range 2-371 months). A total of 139 pulmonary metastasectomies were performed in these patients: 56 wedge resections, 30 segmentectomies, 49 lobectomies, and 4 pneumonectomies. Radical lymph node dissection was performed in 88 procedures, and sampling was performed in 51 procedures. A mean of 9.4 (1308/139) lymph nodes were removed per operation (4.6 lymph nodes for sampling and 12.1 lymph nodes for radical dissection). A mean of 2 lung metastases were resected per operation. Table 1
shows the frequency of lymph node metastases and other characteristics. Lymph node involvement was found in 25 patients (20%); 10 patients (8%) had hilar station and 15 patients (12%) had mediastinal station involvement (among these, 7 patients had both hilar and mediastinal metastases). In 10 of these cases, involvement (hilar 6, mediastinal 4) was suspected from the presurgical workup, and in 15 of these cases (12%), lymph node metastasis was not revealed by staging procedures and was totally unexpected. Another 5 patients had clinically positive lymph nodes (among the group with pathologic negative lymph nodes). Overall, there were 109 patients with clinically negative lymph nodes, and the true rate of occult nodal involvement was 13.7% (15/109). Even if a small number of patients were available for each tumor type, we could observe that the frequency of nodal involvement varied significantly according to primary site (Table 1). Patients with lung metastases from breast cancer, germ cell cancers, and epithelial gynecologic cancers had significantly higher frequencies of nodal involvement than those with metastases from colon cancer. Nodal metastases were found in 7 of 56 (12.5%) atypical lung resections and in 19 of 83 (22.9%) typical resections (per procedure analysis; P = .18). Peribronchial or hilar node (N1) metastases occurred in 3.5% and 9% of atypical and typical resections, respectively, whereas mediastinal node metastases occurred in 9% and 12% of atypical and typical resections, respectively. Fifteen (4.9%) of the 303 lymph nodes removed during atypical resection were metastatic, compared with 71 (6.7%) of the 998 lymph nodes removed by typical resection (P = .29).
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TABLE 1 Prevalence of nodal involvement in lung metastasectomies in relation to primary cancer site, type of resection, number of lymph nodes removed, number of lung metastases, and maximum diameter of lung metastasis
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The prevalence of nodal metastasis was not significantly correlated with the size of resected metastasis (P = .17).
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Survival
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The mean postoperative follow-up was 31 months (range 2-82 months). Estimated 5-year survival was 46% overall, 60% in N0, 17% in N1, and 0% in N2 (or N1 + N2) cases (P = .01; Figure 1). Estimated 5-year survival was 47% in those with 1 lung metastasis, 57% in those 2 lung metastases, and 31% in those with 3 or more metastases (P = .024; Figure 2).
By univariate analyses, age, sex, primary tumor site, disease-free interval, type of resection, type of lymph node dissection, and size of the largest metastasis had no impact on survival (Table 2).
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TABLE 2 Univariate and multivariate analysis of 124 patients undergoing 139 lung metastasectomies with lymph node sampling
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Among patients with positive nodes, no significant difference in overall survival was observed in cases of radical lymph node dissection or sampling (P = .36).
The multivariate analysis showed that the nodal status and number of lung metastases were independent prognostic factors for overall survival. For involved nodes, the hazard ratio (HR) for death was 2.62 (95% confidence interval [CI] 1.14-6.01) for 3 or more lung metastases, and the HR of death was 5.83 (95% CI 2.35-14.5) (Table 2). The combination of nodal status and number of lung metastases produced 2 groups of patients with markedly differing prognoses: Those with pN0 and 1 or 2 metastases had a 5-year survival of 55%; those with pN+ and 3 or more metastases (most with 1 had the other) had a 5-year survival of 12% (P < .0001, log rank; HR of death 3.1, 95% CI 1.78-5.4, Figure 3).
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Figure 3. Survival according to combination of the 2 independent prognostic variables (pN status and number of metastases).
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Discussion
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The role of lymph node dissection in lung metastasectomy and the prognostic role of nodal involvement are still controversial (Table 3). In a series of 100 patients with colon cancer who underwent routine lymph node dissection during lung metastasectomy, involved lymph nodes were associated with poorer prognosis (5-year survival 7% vs 50% in those with no positive nodes).6 Similarly, in a series of 70 lung metastasectomies with complete lymph node dissection,9 the 3-year survival of patients with negative nodes was 69%, but only 38% in those with positive nodes (P < .001); nodal status was the only prognostic factor for survival in this series. Lymph node metastasis was also an independent predictor of survival in the studies of Pfannschmidt and colleagues.12,14 In contrast, the recent study of Loehe and colleagues10 found that lymph node status had no effect on survival in a series of 71 lung metastasectomies from various primaries, 14.5% of which had mediastinal metastasis. Kamiyoshihara and associates15 found no survival difference between patients with and without lymph node involvement in a retrospective review of 28 patients undergoing lung metastasectomy and nodal dissection.
The main finding of our study is that involved lymph nodes identified during radical lymphadenectomy or sampling as part of lung metastasectomy for extrapulmonary primaries had a major impact on survival: The nodal status and number of lung metastases were independent prognostic factors. The combination of these 2 factors defined 2 groups with different prognoses: those with 1 or 2 metastases and no nodal involvement (5-year survival, 60%) and those with 3 or more lung metastases and nodal involvement (5-year survival, 12%). An important issue in patients proposed for lung metastasectomy is the frequency of nodal involvement, particularly in view of the finding by most studies that nodal involvement has a strong negative impact on survival. The frequency was 5% in the International Registry Report3 and approximately 15% in most reports,6,10,11 but sometimes higher (28.6% and 37%).9,12 Twenty percent of our patients (18% of procedures) had lymph node involvement. More revealing, however, is the frequency of unexpected (not identified in preoperative workup) lymph node involvement, which was 13.5% in our study.
The incidence of lymph node metastasis was significantly influenced by primary tumor site, being low for colorectal cancer and sarcoma (9% and 6.6%, respectively), moderate for head and neck and urinary tract tumors (12% and 18%, respectively), and high for melanoma, gynecologic tract cancers, breast cancers, and germ cell cancers (33%, 38%, 54% and 100%, respectively). Even if a small number of cases are reported for each tumor type, these findings are in line with previous experience of high rates of lymph node involvement in lung metastases from melanoma16,17 and gynecologic tract tumors10 and a low rate for sarcoma.9,18
We found that the frequency of nodal involvement did not correlate with the number of resected lung metastases as reported by others9,10 or the maximum diameter of the lung lesions. In contrast, the frequency of nodal involvement tended to be higher for typical resections (23%) than for atypical resections (12%) (P = .18). In particular, patients undergoing typical resections had a higher frequency of N1 metastases than those who received atypical resection (11% vs 3.5%, respectively), suggesting differences in the extent of lymph node resection at hilar, lobar, or segmental stations by the 2 procedures (no segmental and peribronchial lymph node can be removed in case of wedge resection). In fact, when the number of positive nodes is divided by the total number of resected lymph nodes in the 2 groups of patients (typical vs atypical resection), a similar proportion of involved nodes was found at N1 and N2 stations.
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Conclusions
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Although our study is limited by its retrospective nature and the absence of evaluation of preoperative PET results, it provides strong evidence that N2 and N1 node involvement in patients undergoing lung metastasectomy has a significant impact on survival. The implication is that preoperatively confirmed involvement is a relative contraindication for lung metastasectomy. Our second major finding was that at least 13% of patients undergoing metastasectomy had lymph node metastases that were not suspected from preoperative workup and that the frequency of involvement correlated with the primary site.
More accurate and sensitive preoperative staging procedures are required. There is evidence that PET or computed tomography/PET may partially fulfill this requirement,13 although this requires confirmation by prospective study with the aim to avoid useless surgery and to identify patients who are candidates for multimodality treatments that may offer longer survival. Mediastinoscopy can also be considered in some histologic subtypes. Considering the standard methods of staging available today, we can affirm that the pathologic examination of regional lymph nodes offers patients with resectable lung metastasis a more accurate staging and better determination of prognosis with the possibility to administrate potentially beneficial multimodality treatment.
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References
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- The International Registry of Lung Metastases Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37-49.[Abstract/Free Full Text]
- Girard P, Baldeyrou P, Le Chevalier T, et al. Surgery for pulmonary metastases: who are the 10-year survivors?. Cancer 1994;74:2791-2797.[Medline]
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- Okumura S, Kondo H, Tsuboi M, et al. Pulmonary resection for metastatic colorectal cancer: experiences with 159 patients. J Thorac Cardiovasc Surg 1996;12:867-874.
- Cerfolio RJ, Allen MS, Deschamps C, et al. Pulmonary resection of metastatic renal cell carcinoma. Ann Thorac Surg 1994;57:339-344.[Abstract]
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Abstract
Introduction
