J Thorac Cardiovasc Surg 2008;136:605-610
© 2008 The American Association for Thoracic Surgery
The impact of lymph node station on survival in 348 patients with surgically resected malignant pleural mesothelioma: Implications for revision of the American Joint Committee on Cancer staging system
Raja M. Flores, MDa,*,
Tom Routledge, MDa,
Venkatraman E. Seshan, PhDb,
Joseph Dycoco, BAa,
Maureen Zakowski, MDc,
Yael Hirtha,
Valerie W. Rusch, MDa
a Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
b Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
c Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
Received for publication May 3, 2007; revisions received October 18, 2007; accepted for publication February 12, 2008.
* Address for reprints: Raja M. Flores, MD, Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C-879, New York, NY 10021. (Email: floresr{at}mskcc.org).
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Abstract
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Objectives: The propensity of malignant pleural mesothelioma to metastasize to N1 or N2 nodes and their corresponding prognostic value is unclear. The American Joint Committee on Cancer staging system groups N1 and N2 disease together as stage III. The goal of this study was to define the prognostic value of specific nodal stations.
Methods: Patients with malignant pleural mesothelioma who underwent resection were identified from an institutional database. Nodal stations were defined by the American Joint Committee on Cancer lung cancer node map classification. Survival was analyzed by the Kaplan–Meier method, log-rank test, and Cox proportional hazards analysis.
Results: From 1990 to 2006, 348 patients were identified: 279 men and 69 women with a median age of 67 years (range 26–85 years). Extrapleural pneumonectomy was performed in 223 cases, and pleurectomy/decortication was performed in 125 cases. Survival differences (P < .01) were observed between 2 groups: N0 or N1(+) (median survival = 19 months) and N2(+), N2/N1(+) and internal thoracic(+) (median survival = 10 months). Survival was influenced by the number of involved N2 stations (0, 1, 2, or more: P < .001). Multivariate analysis grouping all N2 and internal thoracic(+) versus N1(+) and N0 demonstrated a hazard ratio for survival of 1.7 (P < .0001) controlling for T3/T4 status (hazard ratio = 1.3, P < .01), non-epithelioid histology (hazard ratio = 1.7, P < .0001), extrapleural pneumonectomy (1.1, P = .4), and male gender (hazard ratio 1.4, P < .01).
Conclusion: This study confirms a preferential pattern of drainage of malignant pleural mesothelioma to N2 rather than N1 lymph nodes, but suggests that N1 only nodal involvement should be classified as lower stage disease. Multiple N2 nodal site involvement could potentially be classified as higher stage disease than single station N2. Our results emphasize the need for larger, confirmatory multicenter studies that could lead to revision of the current staging system.
Abbreviations and Acronyms AJCC = American Joint Commission on Cancer; EPP = extrapleural pneumonectomy; HR = hazard ratio; P/D = pleurectomy/decortication; MPM = malignant pleural mesothelioma
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Introduction
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Dr Flores
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The current staging system for malignant pleural mesothelioma (MPM), proposed in 1995 by the International Mesothelioma Interest Group, is based on information about the relationships between T and N status and overall survival.1-7
The staging system has been validated by several reports8-12 and accepted by the Union Internationale Contre le Cancer and American Joint Commission on Cancer (AJCC) as the standard system for MPM. However, it was understood at its inception that revision would be necessary as more data became available.13 Although previous staging systems have suggested separating N1 from N2 nodes, there have been little data to support this distinction. Data are also sparse regarding the influence of internal thoracic nodes on survival.14
The lymph node map for MPM is by default the same used by the AJCC for lung cancer staging.15 However, the lymphatic drainage from the lung is thought to be different from that of the pleura, and this may lead to different patterns of lymph node involvement.9 It is conceivable that N1 nodes could even represent more advanced disease and portend a worse prognosis than N2 nodes in MPM if N2 nodes are actually the first site of drainage from the pleura. The current AJCC staging system groups N1 and N2 disease together as stage III because few data were available on the relative impact of these sites of lymph node involvement when the staging system was developed. The goal of this study was to provide more data regarding the prognostic impact of specific nodal groups, in particular N1 nodes.
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Materials and Methods
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Acquisition of Clinical Data
After approval from the institutional review board of Memorial Sloan-Kettering Cancer Center, all patients with biopsy-proven MPM who underwent surgical resection with complete mediastinal nodal dissection or sampling from 1990 to 2005 at Memorial Sloan-Kettering Cancer Center were identified from the thoracic surgery database. Patients who had incomplete nodal staging information were excluded from this study. Pathological diagnosis was based on histology, immunohistochemical analysis, and, when indicated, electron microscopy. Staging was performed using the sixth edition of the AJCC Cancer Staging Handbook.1 Pathological stage was based on the pathologist's evaluation of the resected specimen and the surgeon's intraoperative findings. Dates of death were verified through the Social Security Death Index.
Surgical and Multimodality Management
Operative intervention was recommended to patients with tumor localized to the hemithorax by computed tomography scan and adequate cardiopulmonary function determined by cardiac stress testing and pulmonary function testing. Routine mediastinoscopy was not performed. Extrapleural pneumonectomy (EPP) was defined as an en bloc resection of the pleura, lung, ipsilateral diaphragm, and pericardium. Pleurectomy/decortication (P/D), which removed all gross tumor without removing underlying lung, was performed in patients who had minimal visceral pleural tumor or poor pulmonary function. The decision to perform an EPP was primarily based on intraoperative findings of confluent visceral tumor not separable from the underlying lung and a partially or totally fused pleural space. Lymph node sampling or dissection was performed in the same manner as would be standard for a lung cancer resection, including lymph node stations 2R, 4R, 7, 8, and 9 on the right, and 5, 6, 7, 8, 9 for left-sided resections.15 The decision to administer chemotherapy or radiation was based on the requirements of sequential clinical trials performed during this time period. When the patient could not participate in a clinical trial, treatment was usually administered according to protocol guidelines.
Statistical Methods
Operative mortality included all patients who died within 30 days of surgery or during the same hospitalization. Survival was calculated from the date of surgery until the date of death or date of last follow-up. Survival according to nodal station involvement (N1 vs N2) was analyzed by the Kaplan–Meier method. The log-rank test was used to assess the statistical significance of potential prognostic factors. A Cox proportional hazard analysis was used to assess the joint influences of known predictors on survival by nodal station. Insignificant variables were then dropped using a stepwise procedure, thus yielding the final model. The STATA 8 (StataCorp, College Station, Tex) statistical package was used.
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Results
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From 1990 to 2006, 348 patients were identified as appropriate for analysis. Patient characteristics are outlined in
Table 1. As is typical for MPM, most patients were male and had epithelioid tumors and stage II or III disease at diagnosis. With a median follow-up of 20 months, the median overall survival for all 348 patients was 15 months, and the 5-year survival was 13%. Tumor histologic subtype and AJCC stage stratified patients by survival. EPP was performed in 223 patients, and P/D was performed in 125 patients, with a mortality of 2% (n = 5/223) for EPP and 2% (n = 3/125) for P/D. There were no significant differences in survival according to the surgical procedure performed (P = .78). The distribution of positive nodal stations for right and left-sided resections is shown in
Figure 1, A and B. The most frequently involved lymph node stations were 4R, 7, and 10R for right-sided tumors and 5, 7, and 10L for left-sided tumors.
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Figure 1. A, Distribution of positive node stations: left lung. Most patients who had lymph node metastases had more than 1 nodal station involved, so the number of metastatic sites exceeds the number of resections. B, Distribution of positive node stations: right lung. Most patients who had lymph node metastases had more than 1 nodal station involved, so the number of metastatic sites exceeds the number of resections.
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Differences in overall survival were observed between patients who were N0 or N1 positive (median survival of 19 months) and those who were N2 positive, N2/N1 positive, and internal thoracic node positive (median survival of 10 months) (
Table 2;
Figure 2). Survivals by solitary N2 versus solitary N1 disease, number of involved nodal stations, and N1/N2 positive versus N2 only positive are shown in
Figures 3, 4, 5, and 6, respectively. When N2 disease was present, survival was not significantly different whether or not N1 disease was also present. Of note, there were differences in survival according to the number of involved N2 nodal stations with a significantly worse survival when 2 or more stations had metastatic disease. Survivals by grouping levels 4 and 7 versus 8 and 9 versus 5 and 6 were no different (P = .36).
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Table 2 Table by positive and negative nodal groups (24 patients with positive internal thoracic nodes are not included)
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Figure 2. Overall survival of patients with N0, N1(+) versus N2(+), N2/N1(+) and internal thoracic(+) nodal disease.
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Only 10 patients who underwent P/D had complete N1 nodal dissection, of whom only 1 patient had a positive N1 node only, 5 patients had positive N1 and N2 nodes, and 4 patients had documented negative N1 nodes. The N2 only and internal thoracic node positive patients (n = 31) were presumed to have negative N1 disease for the purpose of this analysis. Therefore, the same analysis in Figures 1, 2, and 4 was performed exclusively in patients undergoing EPP without demonstrating any change in the final results.
A Cox proportional hazards model grouping all N2 and thoracic positive nodes versus N1 positive and N0 nodal stations demonstrated a hazard ratio (HR) of 1.6 (P < .0001) controlling for T3/T4 status (HR = 1.3, P < .01), non-epithelioid histology (HR = 1.7, P < .0001), EPP (1.1, P = .42), and male gender (HR 1.4, P = .01) (
Table 3). Surgical procedure was not significant in the multivariate analysis. The presence of metastasis to nodal areas by histology was not statistically significant by logistic regression, most likely because of the low number of patients with sarcomatoid carcinoma (n = 19).
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Discussion
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The current AJCC staging system was built on previous staging systems but incorporated specific TNM descriptors based on emerging information about their influence on survival.13 The purpose of the staging system was to describe the anatomic extent of disease and group staged subsets by survival, but as with other solid tumor staging systems, it does not take into account tumor biology. It was understood at its inception that revision of the staging system might be appropriate as additional data about the influence of nodal involvement on survival became available.
Little is known about the lymph node drainage pattern of the parietal pleura. Studies from rat and pig experiments suggest preferential drainage to the superior mediastinum.16,17 However, to our knowledge the patterns of lymphatic drainage from the pleura have not been determined in live humans. Cadaveric studies have shown diaphragmatic pleural drainage to the peritracheobronchial lymph nodes via the pulmonary ligament and periesophageal tissue.18 MPM provides a unique clinical scenario from which to gain insight into the pleural nodal drainage patterns in humans.
This study demonstrates the expected characteristics of any MPM cohort: a predominance of male patients, epithelioid histology, and later stage, confirming the adverse impact of N2 disease on overall survival.11,14 This study also confirms our previous data in a smaller number of patients showing that MPM has a greater propensity to metastasize to N2 nodes than N1 nodes, and that nodal involvement is common, occurring in approximately half of patients at surgery.11 Similar percentages of nodal involvement have been reported in other studies by Edwards and colleagues,19 Pass and colleagues,9 de Perrot and colleagues,20 and Aziz and colleagues,21 exceeding the 25% reported by Sugarbaker and colleagues.14 Our data emphasize the importance of performing both N1 and N2 nodal dissections in patients undergoing P/D to ensure complete staging.
Solitary metastasis to N1 nodes demonstrated a trend toward improved survival when compared with solitary metastasis to N2 nodes, thus implying earlier stage disease. In addition, further evidence for separating N1 disease from N2 disease in the staging system is provided by our data showing no further decline in survival in N2/N1 positive patients when compared with patients with solitary N2 disease. Because we demonstrated significantly worse survival for patients with 2 or more positive N2 nodal stations, one would expect survival for the N2/N1 positive (or 2 station nodal disease) patients to be worse than that of the patients with solitary N2. However, the survival was no different, thus supporting a recommendation that N1 be staged differently from N2 disease.
The internal thoracic lymph nodes have been included as N2 disease in the current staging system based on hypothetical reasoning rather than data. Our data confirm that internal thoracic lymph nodes can be appropriately considered N2, stage III disease. There were also no survival differences observed according to involvement of nodal stations 4, 5, 6, 7, 8, and 9. Therefore, it is appropriate to classify all these nodal stations as N2 disease and stage III.
A salient result from our study is the adverse impact of multiple versus single N2 lymph node stations on survival. This finding corroborates our previous data suggesting that the number of involved lymph nodes influences survival.11 Because the counting of lymph nodes is potentially unreliable because of the difficulty for pathologists in identifying nodal fragments from entire nodes in surgical specimens, the number of involved lymph node stations is a more reproducible data point for universally acceptable staging.
Trials investigating induction chemotherapy have sparked increased interest in pre-resectional nodal staging.22,23 Although the routine use of invasive preoperative nodal staging is controversial, newer preoperative staging modalities, such as endobronchial ultrasound to identify N1 disease and esophageal ultrasound to identify N2 disease at levels 8 and 9, may prove useful in clinical trials as more effective chemotherapy becomes available.20,24-27
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Conclusions
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This study confirms a preferential pattern of drainage of MPM to N2 rather than N1 lymph nodes, but suggests that N1 only nodal involvement should be classified as lower stage disease. Multiple N2 nodal site involvement could potentially be classified as higher stage disease than single station N2. Our results emphasize the need for larger, confirmatory multicenter studies that could lead to revision of the Union Internationale Contre le Cancer and AJCC staging systems.
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Footnotes
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Presented at the 87th Annual Meeting of the American Association of Thoracic Surgery 2007, Washington, DC.
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References
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Abstract
Introduction
