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Prognostic value of lymph node metastases and lymph node ratio in esophageal squamous cell carcinoma
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EJSO 36 (2010) 155e159
www.ejso.com
Prognostic value of lymph node metastases and lymph node ratio in esophageal squamous cell carcinoma Y.P. Liu a, L. Ma b, S.J. Wang c, Y.N. Chen a, G.X. Wu a, M. Han d, X.L. Wang a,* a
Department of Pathology, Institute of the Forth Hospital of Hebei Medical University, No.12, Jiankang Road, Shijiazhuang, 050011, PR China Department of Surgery, Institute of the Forth Hospital of Hebei Medical University, No.12, Jiankang Road, Shijiazhuang, 050011, PR China c Department of Endoscopy, Institute of the Forth Hospital of Hebei Medical University, No.12, Jiankang Road, Shijiazhuang, 050011, PR China d Department of Biochemistry and Molecular Biology, Institute of Basic Medical University, No.361, Zhongshan East Road, Shijiazhuang, 050017, PR China b
Accepted 17 September 2009 Available online 25 October 2009
Abstract Aims: Although the positive lymph node (LN) metastasis in patients with thoracic esophageal squamous cell carcinoma carcinoma (SCC) has been reported to be a risk factor to reduce long-term survival, only a few studies have so far evaluated the lymph node metastasis among this group of patients. The purpose of this study was to evaluate the impact of lymph node positivity and ratio on survival of esophageal SCC. Methods: All patients undergoing esophagectomy at the Forth Hospital of Hebei Medical University between January 1986 and December 2002 were reviewed. Survival curves were estimated using the Kaplan-Meier method. Results: Of 1325 patients with invasive cancer, had squamous cell cancer of the esophagus. Median overall survival (OS) of the entire group was 36.7 months and 5-year OS was 39.3%. The most significant prognostic factor for overall survival was the presence of positive LN (P < 0.01). Additionally, patients with zero involved LN had a 5-year survival of 49.1%, while patients with 1e3 positive LN and >3 positive LN had 5-year survival of 19.5% and 11.0%, respectively (P < 0.01). Finally, an increasing ratio of positive to examined LN was linearly associated with a worsening 5-year survival, patients with <25%, 25%e50% and >50% positive LN had 5-year survival of 47.53%, 14.6% and 8.9%, respectively (P < 0.01). Conclusion: Increasing number of positive LN in patients with esophageal cancer and increasing ratio of metastatic to examine LN portend a poor prognosis. These factors should play an important role in predicting prognosis of patients. Ó 2009 Elsevier Ltd. All rights reserved. Keywords: Esophageal cancer; Lymph nodes; Lymph node ratio; Prognosis
Introduction The presence and extent of lymphatic dissemination are among the most important predictors for survival in gastrointestinal malignancies.1e4 Lymph node staging may be further refined by the identification of different anatomic sites of involvement (i.e., proximal versus remote lymph nodes), the absolute number of metastatic lymph nodes (LNM), and/or the lymph node ratio (LNR; i.e., the number of involved nodes over the total number of resected and identified nodes).5 Esophageal carcinoma is a highly
* Corresponding author. Tel.: þ86 86905374. E-mail address: [email protected] (X.L. Wang). 0748-7983/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2009.09.005
aggressive carcinoma with a poor long-term outcome, and surgery is considered the best option for cure. However, even after R0 resection, long-term survival is only about 25% in most Western series.6 Based on reports from China, the 5-year survival is reported to be around 35%.7 LNM in esophageal cancer is characterized by early and widespread dissemination. LNM is closely related to long-term prognosis in patients who undergo esophagectomy, and is considered to be the most important prognostic factor.8e10 Earlier studies have reported significant differences among patients with different degrees of LNM, all following a general trend of an increase in positive nodes associated with a worse prognosis.2,11 Thus, the number of positive lymph nodes in patients with thoracic esophageal carcinoma is an important prognostic factor for long-term survival after
156
Y.P. Liu et al. / EJSO 36 (2010) 155e159
surgery.4,8,10 The LNR has also been investigated as a prognostic indicator, but its significance is less clear. It has been shown that an increasing LNR is associated with increased mortality; however, there is disagreement of what ratios are significant.12,13 Wilson13 reported that an overall increasing LNR was not related to outcome. The goal of the current study was to examine the impact of increasing numbers of pathologically-confirmed positive LN and the LNR on survival in patients undergoing esophagectomy for squamous cell carcinoma (SCC) of the esophagus. Materials and methods Patient selection The medical records of 1538 patients who underwent esophagectomy for esophageal SCC at the Forth Hospital of Hebei Medical University between January 1986 and December 2002 were retrospectively reviewed. The patients selected had the following characteristics: (1) SCC, (2) esophagectomy performed with curative intent, (3) and no neoadjuvant chemotherapy or chemoradiation therapy was administered. Based on these selection criteria, 115 patients were excluded; 98 patients were excluded because of neoadjuvant chemotherapy or chemoradiation. The statastical analyses included a subset of 1325 patients with complete records regarding all known risk factors and complete lymph node information who had not received neoadjuvant chemotherapy or chemoradiation therapy. The patient medical records were examined and the information was entered into a database following the approval of the Forth Hospital of Hebei Medical University Institutional Review Board. The following data were collected: pre-operative factors (age, co-morbidities, extent of symptoms, and imaging studies), tumor factors (histology, clinical and pathologic staging, and completeness of resection, i.e., R0, R1, or R2), operative and hospital factors (type of operative procedure, blood loss, type of anastomosis, and complications), tumor recurrence (date and location), and long-term survival. All patients were staged both pre- and post-operatively according to the classification scheme of the 6th edition of the American Joint Committee for Cancer Staging3,14 (AJCC; Table 1). Pre-operative evaluation The pre-operative evaluation included history-taking and a physical examination, an endoscopy with biopsy, a barium swallow esophagography, an abdominal ultrasonography, and a bone scan. Those patients with upper thoracic tumors underwent bronchoscopy for the assessment of possible tracheobronchial invasion. A chest MRI was performed in cases with possible great vessel or cardiac invasion. A chest CT scan of the thorax and upper abdomen, PET scan and EUS (endoscopic ultrasound) were not performed routinely.
Table 1 Univariate survival analysis. Variables Gender Male Fermal Age <40 40w60 >60 LNM Positive Negative Location Proxima Middle Distal TNM stage 0 I II a II b III IV
no of patients
Overall 5-year survival rate (%)
P value
899 426
45.50 48.10
0.15
60 938 327
42.5 44.80 43.70
0.85
432 893
18.5 49.1
<0.01
86 704 535
41.2 49.2 43.4
23 73 612 202 188 227
79.2 65.2 51.3 40.7 20.1 16.7
0.42
<0.01
Surgery and pathologic examinations The aim of surgery is to resect the primary tumour with negative microscopic resection margins (R0 resection margins) with the intention of minimizing loco-regional recurrence. The curative intent involves resection of the primary tumor and local lymphadenectomy. All patients with untreated primary tumors underwent esophagectomy via thoracotomy with dissection of at least 10 lymph nodes from the cervical region, thorax, and abdomen. Esophagectomy via thoracotomy with para-esophageal lymph node dissection, including cervical para-esophageal lymph nodes, was offered to all patients. Esophagectomy specimens were grossly- and pathologically-examined to determine the location of the primary tumor, the depth of tumor invasion, the lymph node status, and the status of venous invasion, according to the tumor-node-metastasis (TNM) classification system.20 All resected lymph nodes were histopathologically-assessed by an experienced pathologist in a routine fashion, with one section from each lymph node being analyzed with hematoxylin and eosin (H&E) stain. However, in the present study, lymph node examination was performed using one section stained with H&E, Table 2 Mutivariate survival analysis. Variable
HR
95% CI
P Value
Gender Age LNM Location TNM stage
1.38 1.01 2.65 1.16 1.91
0.76e2.52 0.49e2.02 1.59e4.47 0.74e1.80 1.22e2.99
0.29 0.06 <0.01 0.52 <0.01
HR, hazard ratio; CI, confidence
Y.P. Liu et al. / EJSO 36 (2010) 155e159
therefore, micrometastases may not have been detected. Further analysis on positive LNM using immunohistochemistry might be more accurate than in the present analysis. All patients classified as stage IVA showed cervical or distant abdominal LNM. Follow-up Follow-up data were obtained from the patient charts, the tumor registry, and referring physicians. Numerous patients were treated at other institutions and only underwent surgery at the Forth Hospital of Hebei Medical University. The overall survival (OS) rate was evaluated using the Kaplan-Meier estimator and the log-rank test for univariate and multivariate analyses. The multivariate analyses controlled for all known risk factors, including age, pathologic stage, type of surgery, tumor location (stratification variable), the total number of lymph nodes, and the N category. The primary analysis of lymph node positivity and the LNR was based on pathologic staging information and not preoperative staging information. Statistical analyses were performed using SPSS, version 12.0. Results Patients and survival There were 899 males and 426 females enrolled in the study, ranging in age from 30 to 89 y (mean, 54.8 4.98 y). Fifty-two percent of the patients had a cigarette smoking history (n ¼ 731). Most patients presented with advanced disease (stages II-IV; n ¼ 1229, 92.8%) and greater than one-half of the patients had stage II disease (n ¼ 814; Table 1). Eight hundred fourteen patients had stage IIa or IIb disease (61.4%). According to univariate analysis, metastasis of lymph node, clinical stage were correlated with the prognosis of SCC, (P < 0.01). But age and gender were not significant (P > 0.05, Table 1). A Mutivariate analysis was performed to evalute the impact of the variables on survival. A earlier clinical stwage and a lower number of positive node were identified as independent of good survival. (P < 0.01, Table 2) The operative technique was dictated by the location of the tumor as well as surgeon preference. The number of lymph nodes resected per patient ranged from 10 to 70 (mean 16.1 1.59). The majority of patients (46.9%) underwent a transhiatal esophagectomy. However, approximately 53.9% underwent some type of transthoracic approach. The average number of lymph nodes harvested in the transthoracic group was 21.2, which was higher than those undergoing transhiatal approaches (mean ¼ 11.4 1.02). Follow-up ranged from 1to120 mo (median ¼ 36 mo), and complete follow-up was possible in 86.2% patients. Overall, the median survival for the group was 36.7 months and the 5-year OS rate was 39.3%.
157
The relationship of the number of LMN and survival LNM were found in 32.5% of the patients (n ¼ 431) and played a role in OS; patients without nodal involvement had a median survival of 38 mo versus 24 mo for node-positive patients (P ¼ 0.01). In the initial analysis of lymph node positivity, a dichotomized cut-off of < or >3 was determined to be a statistically significant predictor of OS by univariate analysis (P < 0.01). We then analyzed the lymph nodes in a manner similar to the method used by Wilson,13 specifically, LNM ¼ 0, LNM ¼ 1e3, and LNM > 4. In this manner, patients with no involved LN had a 5-year survival of 49.1%, while patients with 1e3 positive LN and >3 positive LN had 5-year survivals of 19.5 and 11.0%, respectively. Fig. 1A presents the Kaplan-Meier survival curves for the groups of patients with 0, 1e3, and >3 positive lymph nodes. The difference in survival among these three groups was significant (P < 0.01, Table 3). The relationship of the ratio of LNM and survival Finally, we examined the impact of an increasing LNR. The proportion of positive lymph nodes was analyzed using the following categories: none, <25%, >25% but <50%, and >50%. In this manner, patients with <25% involved LN had a 5-year survival of 29.7%, while patients with 25e50% and >50% positive LN had 5-year survivals of 14.6 and 8.2%, respectively. The difference in survival among these four groups was significant (P < 0.05); the corresponding KaplaneMeier survival curves are shown in Fig. 1B. Discussion In the present study, we investigated the positive LNM and LNR in patients with thoracic esophageal carcinoma. Positive nodes were found in 32.5% of the patients.Tumors with a positive node revealed more deep tumors and more frequent venous invasion, even a solitary positive node reflects tumor progression, so the presence of a positive node worsens the patient’s survival. Therefore, the poor prognosis in patients with thoracic esophageal SCC is mainly clue to high incidence of lymph node metastasis, including metasteses in the distant field, and lymph node dissection is a promising approach for the treatment of esophageal cancer. Comparison with previous studies assessing LNM and prognosis in oesophageal cancer Lymphatic dissemination is an early event in esophageal cancer, and lymph node involvement is known to be the most important prognostic factor with respect to esophageal cancer. Ellis and colleagues6 suggested that LNM is strongly associated with poor long-term survival. Other reports have concluded that nodal involvement is the single
Y.P. Liu et al. / EJSO 36 (2010) 155e159
158
Figure 1. Kaplan-Meier curve analysis. A: Kaplan-Meier curve demonstrating overall survival for patients by lymph node category; B: Kaplan-Meier curve demonstrating overall survival for patients by lymph node ratio category.
most important prognostic factor for both loco-regional and systemic recurrence after complete resection.7,15,16 Nakagawa and colleagues17 also reported that a higher number of positive lymph nodes increased the risk of hematogenous recurrence, which implies that the extent of lymph node involvement is related to prognosis. The main goal of this study was to examine the utility of the number of LNM and the ratio of positive lymph nodes to excised lymph nodes as prognostic factors in survival of patients with tumors of the esophagus. The number of positive lymph nodes is a recognized factor of long-term survival. However, a nodal involvement of <4 and a positive LNR of <0.2 are regarded as favorable prognostic factors in N1 disease.18,19 In this study, the number of LNM proved to be an important indicator of survival. Patients with more than 3 LNM fared worse than patients with 3 or fewer LNM.
Table 3 Analysis of lymph node and prognostic. Median survival time (months) n
Kaplan-Meier 95% estimate confidence limits
P-value 5-year survival
Comparison with previous studies assessing LNR and prognosis in oesophageal cancer In the Wilson study,13 LNR examination did not reach significance, most likely due to the small number of patients per group with <20 patients per positive lymph node group. However, in our results, patients with more than 50% positive lymph nodes LNM fared worse than patients with 25e50% or fewer LNR. This finding has been previously reported for other malignancies, such as colon cancer, but not in esophageal cancer.18 Eloubeidi reported a similar finding that increasing LNR was associated with a poorer prognosis.2 Other authors have had differing cutoff points for LNR. Bollschweiler reported that LNR only became significant if it exceeded (P < 0.01) and Nigro showed patients with a LNR < 0.1 fared significantly better than those who had a LNR 0.1.4,10 Further investigation should examine the locations of the node prior to removal and compare that date with the LNR to see if a positive node at one anatomical site differs from a positive node at another site in terms of survival relative to the tumor location. Unfortunately, we were unable to examine the exact location of lymph node metastases in this study due to its retrospective nature.
Lower Upper LNþ category OLNþ 893 1e3 LNþ 359 >3 LNþ 73 % LNþ category 0 LNþ 893 0%e25% 160 LNþ 25%e50% 178 LNþ >50% LNþ 94
Conclusion 96 30 24
75 26 18
117 34 30
0.00
49.1% 19.5% 11.0%
96 56
75 48
117 64
0.00
39
34
45
14.6%
24
18
30
8.21%
49.1% 29.7%
Our experience has shown that the number of positive lymph nodes and the ratio of positive lymph nodes to examined lymph nodes are significant prognostic factors for esophageal carcinoma. It is thus recommended that the AJCC revise the TNM staging scheme to incorporate these two factors, so as to give a more complete assessment of a particular patient’s disease state to guide clinical decision-making.
Y.P. Liu et al. / EJSO 36 (2010) 155e159
Conflict of interest All authors have read and approved to submit it to your journal. There is no conflict of interest of any authors in relation to the submission. This paper has not been submitted elsewhere for consideration of publication. Acknowledgement This work has supported by Key Oncologic Subject Foundation of Hebei Province (No.200552), Youth Natural Science Foundation of Hebei Province (No.C2009001212).
References 1. de Manzoni G, Pedrazzani C, Verlato G, et al. Comparison of old and new TNM systems for nodal staging in adenocarcinoma of the gastrooesophageal junction. Br J Surg 2004;91:296–303. 2. Eloubeidi MA, Desmond R, Arguedas MR, et al. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 2002;95:1434–43. 3. Korst RJ, Rusch VW, Venkatraman E, et al. Proposed revision of the staging classification for esophageal cancer. J Thorac Cardiovasc Surg 1998;115:660–9. 4. Nigro JJ, DeMeester SR, Hagen JA, et al. Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy. J Thorac Cardiovasc Surg 1999;117:960–8. 5. Greenstein AJ, Litle VR, Swanson SJ, et al. Prognostic significance of the number of lymph node metastases in esophageal cancer. J Am Coll Surg 2008;206:239–46. 6. Ellis Jr FH, Heatley GJ, Krasna MJ, et al. Esophagogastrectomy for carcinoma of the esophagus and cardia: a comparison of findings and results after standard resection in three consecutive eight-year intervals with improved staging criteria. J Thorac Cardiovasc Surg 1997;113:836–48.
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7. Chen G, Wang Z, Liu XY, et al. Recurrence pattern of squamous cell carcinoma in the middle thoracic esophagus after modified Ivor-Lewis esophagectomy. World J Surg 2007;31:1107–14. 8. Lerut T. Esophageal surgery at the end of the millennium. J Thorac Cardiovasc Surg 1998;116:1–20. 9. Lin CS, Chang SC, Wei YH, et al. Prognostic variables in thoracic esophageal squamous cell carcinoma. Ann Thorac Surg 2009;87:1056–65. 10. Bollschweiler E, Baldus SE, Schroder W, et al. Staging of esophageal carcinoma: length of tumor and number of involved regional lymph nodes. Are these independent prognostic factors? J Surg Oncol 2006;94:355–63. 11. Kawahara K, Maekawa T, Okabayashi K, et al. The number of lymph node metastases influences survival in esophageal cancer. J Surg Oncol 1998;67:160–3. 12. Nishimaki T, Suzuki T, Kanda T, et al. Extended radical esophagectomy for superficially invasive carcinoma of the esophagus. Surgery 1999;125:142–7. 13. Wilson M, Rosato EL, Chojnacki KA, et al. Prognostic significance of lymph node metastases and ratio in esophageal cancer. J Surg Res 2008;146:11–5. 14. Hofstetter W, Correa AM, Bekele N, et al. Proposed modification of nodal status in AJCC esophageal cancer staging system. Ann Thorac Surg 2007;84:365–75. 15. Holscher AH, Bollschweiler E, Bumm R, et al. Prognostic factors of resected adenocarcinoma of the esophagus. Surgery 1995;118:845–55. 16. Clark GW, Peters JH, Ireland AP, et al. Nodal metastasis and sites of recurrence after en bloc esophagectomy for adenocarcinoma. Ann Thorac Surg 1994;58:646–54. 17. Nakagawa S, Kanda T, Kosugi S, et al. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg 2004;198:205–11. 18. Berger AC, Sigurdson ER, LeVoyer T, et al. Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. J Clin Oncol 2005;23:8706–12. 19. Alidina A, Gaffar A, Hussain F, et al. Survival data and prognostic factors seen in Pakistani patients with esophageal cancer. Ann Oncol 2004;15:118–22. 20. Iizuka T, Onoda T. TNM classification of carcinoma of the esophagus. Gan To Kagaku Ryoho 1997;24:893–901.
EJSO 36 (2010) 155e159
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Prognostic value of lymph node metastases and lymph node ratio in esophageal squamous cell carcinoma Y.P. Liu a, L. Ma b, S.J. Wang c, Y.N. Chen a, G.X. Wu a, M. Han d, X.L. Wang a,* a
Department of Pathology, Institute of the Forth Hospital of Hebei Medical University, No.12, Jiankang Road, Shijiazhuang, 050011, PR China Department of Surgery, Institute of the Forth Hospital of Hebei Medical University, No.12, Jiankang Road, Shijiazhuang, 050011, PR China c Department of Endoscopy, Institute of the Forth Hospital of Hebei Medical University, No.12, Jiankang Road, Shijiazhuang, 050011, PR China d Department of Biochemistry and Molecular Biology, Institute of Basic Medical University, No.361, Zhongshan East Road, Shijiazhuang, 050017, PR China b
Accepted 17 September 2009 Available online 25 October 2009
Abstract Aims: Although the positive lymph node (LN) metastasis in patients with thoracic esophageal squamous cell carcinoma carcinoma (SCC) has been reported to be a risk factor to reduce long-term survival, only a few studies have so far evaluated the lymph node metastasis among this group of patients. The purpose of this study was to evaluate the impact of lymph node positivity and ratio on survival of esophageal SCC. Methods: All patients undergoing esophagectomy at the Forth Hospital of Hebei Medical University between January 1986 and December 2002 were reviewed. Survival curves were estimated using the Kaplan-Meier method. Results: Of 1325 patients with invasive cancer, had squamous cell cancer of the esophagus. Median overall survival (OS) of the entire group was 36.7 months and 5-year OS was 39.3%. The most significant prognostic factor for overall survival was the presence of positive LN (P < 0.01). Additionally, patients with zero involved LN had a 5-year survival of 49.1%, while patients with 1e3 positive LN and >3 positive LN had 5-year survival of 19.5% and 11.0%, respectively (P < 0.01). Finally, an increasing ratio of positive to examined LN was linearly associated with a worsening 5-year survival, patients with <25%, 25%e50% and >50% positive LN had 5-year survival of 47.53%, 14.6% and 8.9%, respectively (P < 0.01). Conclusion: Increasing number of positive LN in patients with esophageal cancer and increasing ratio of metastatic to examine LN portend a poor prognosis. These factors should play an important role in predicting prognosis of patients. Ó 2009 Elsevier Ltd. All rights reserved. Keywords: Esophageal cancer; Lymph nodes; Lymph node ratio; Prognosis
Introduction The presence and extent of lymphatic dissemination are among the most important predictors for survival in gastrointestinal malignancies.1e4 Lymph node staging may be further refined by the identification of different anatomic sites of involvement (i.e., proximal versus remote lymph nodes), the absolute number of metastatic lymph nodes (LNM), and/or the lymph node ratio (LNR; i.e., the number of involved nodes over the total number of resected and identified nodes).5 Esophageal carcinoma is a highly
* Corresponding author. Tel.: þ86 86905374. E-mail address: [email protected] (X.L. Wang). 0748-7983/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2009.09.005
aggressive carcinoma with a poor long-term outcome, and surgery is considered the best option for cure. However, even after R0 resection, long-term survival is only about 25% in most Western series.6 Based on reports from China, the 5-year survival is reported to be around 35%.7 LNM in esophageal cancer is characterized by early and widespread dissemination. LNM is closely related to long-term prognosis in patients who undergo esophagectomy, and is considered to be the most important prognostic factor.8e10 Earlier studies have reported significant differences among patients with different degrees of LNM, all following a general trend of an increase in positive nodes associated with a worse prognosis.2,11 Thus, the number of positive lymph nodes in patients with thoracic esophageal carcinoma is an important prognostic factor for long-term survival after
156
Y.P. Liu et al. / EJSO 36 (2010) 155e159
surgery.4,8,10 The LNR has also been investigated as a prognostic indicator, but its significance is less clear. It has been shown that an increasing LNR is associated with increased mortality; however, there is disagreement of what ratios are significant.12,13 Wilson13 reported that an overall increasing LNR was not related to outcome. The goal of the current study was to examine the impact of increasing numbers of pathologically-confirmed positive LN and the LNR on survival in patients undergoing esophagectomy for squamous cell carcinoma (SCC) of the esophagus. Materials and methods Patient selection The medical records of 1538 patients who underwent esophagectomy for esophageal SCC at the Forth Hospital of Hebei Medical University between January 1986 and December 2002 were retrospectively reviewed. The patients selected had the following characteristics: (1) SCC, (2) esophagectomy performed with curative intent, (3) and no neoadjuvant chemotherapy or chemoradiation therapy was administered. Based on these selection criteria, 115 patients were excluded; 98 patients were excluded because of neoadjuvant chemotherapy or chemoradiation. The statastical analyses included a subset of 1325 patients with complete records regarding all known risk factors and complete lymph node information who had not received neoadjuvant chemotherapy or chemoradiation therapy. The patient medical records were examined and the information was entered into a database following the approval of the Forth Hospital of Hebei Medical University Institutional Review Board. The following data were collected: pre-operative factors (age, co-morbidities, extent of symptoms, and imaging studies), tumor factors (histology, clinical and pathologic staging, and completeness of resection, i.e., R0, R1, or R2), operative and hospital factors (type of operative procedure, blood loss, type of anastomosis, and complications), tumor recurrence (date and location), and long-term survival. All patients were staged both pre- and post-operatively according to the classification scheme of the 6th edition of the American Joint Committee for Cancer Staging3,14 (AJCC; Table 1). Pre-operative evaluation The pre-operative evaluation included history-taking and a physical examination, an endoscopy with biopsy, a barium swallow esophagography, an abdominal ultrasonography, and a bone scan. Those patients with upper thoracic tumors underwent bronchoscopy for the assessment of possible tracheobronchial invasion. A chest MRI was performed in cases with possible great vessel or cardiac invasion. A chest CT scan of the thorax and upper abdomen, PET scan and EUS (endoscopic ultrasound) were not performed routinely.
Table 1 Univariate survival analysis. Variables Gender Male Fermal Age <40 40w60 >60 LNM Positive Negative Location Proxima Middle Distal TNM stage 0 I II a II b III IV
no of patients
Overall 5-year survival rate (%)
P value
899 426
45.50 48.10
0.15
60 938 327
42.5 44.80 43.70
0.85
432 893
18.5 49.1
<0.01
86 704 535
41.2 49.2 43.4
23 73 612 202 188 227
79.2 65.2 51.3 40.7 20.1 16.7
0.42
<0.01
Surgery and pathologic examinations The aim of surgery is to resect the primary tumour with negative microscopic resection margins (R0 resection margins) with the intention of minimizing loco-regional recurrence. The curative intent involves resection of the primary tumor and local lymphadenectomy. All patients with untreated primary tumors underwent esophagectomy via thoracotomy with dissection of at least 10 lymph nodes from the cervical region, thorax, and abdomen. Esophagectomy via thoracotomy with para-esophageal lymph node dissection, including cervical para-esophageal lymph nodes, was offered to all patients. Esophagectomy specimens were grossly- and pathologically-examined to determine the location of the primary tumor, the depth of tumor invasion, the lymph node status, and the status of venous invasion, according to the tumor-node-metastasis (TNM) classification system.20 All resected lymph nodes were histopathologically-assessed by an experienced pathologist in a routine fashion, with one section from each lymph node being analyzed with hematoxylin and eosin (H&E) stain. However, in the present study, lymph node examination was performed using one section stained with H&E, Table 2 Mutivariate survival analysis. Variable
HR
95% CI
P Value
Gender Age LNM Location TNM stage
1.38 1.01 2.65 1.16 1.91
0.76e2.52 0.49e2.02 1.59e4.47 0.74e1.80 1.22e2.99
0.29 0.06 <0.01 0.52 <0.01
HR, hazard ratio; CI, confidence
Y.P. Liu et al. / EJSO 36 (2010) 155e159
therefore, micrometastases may not have been detected. Further analysis on positive LNM using immunohistochemistry might be more accurate than in the present analysis. All patients classified as stage IVA showed cervical or distant abdominal LNM. Follow-up Follow-up data were obtained from the patient charts, the tumor registry, and referring physicians. Numerous patients were treated at other institutions and only underwent surgery at the Forth Hospital of Hebei Medical University. The overall survival (OS) rate was evaluated using the Kaplan-Meier estimator and the log-rank test for univariate and multivariate analyses. The multivariate analyses controlled for all known risk factors, including age, pathologic stage, type of surgery, tumor location (stratification variable), the total number of lymph nodes, and the N category. The primary analysis of lymph node positivity and the LNR was based on pathologic staging information and not preoperative staging information. Statistical analyses were performed using SPSS, version 12.0. Results Patients and survival There were 899 males and 426 females enrolled in the study, ranging in age from 30 to 89 y (mean, 54.8 4.98 y). Fifty-two percent of the patients had a cigarette smoking history (n ¼ 731). Most patients presented with advanced disease (stages II-IV; n ¼ 1229, 92.8%) and greater than one-half of the patients had stage II disease (n ¼ 814; Table 1). Eight hundred fourteen patients had stage IIa or IIb disease (61.4%). According to univariate analysis, metastasis of lymph node, clinical stage were correlated with the prognosis of SCC, (P < 0.01). But age and gender were not significant (P > 0.05, Table 1). A Mutivariate analysis was performed to evalute the impact of the variables on survival. A earlier clinical stwage and a lower number of positive node were identified as independent of good survival. (P < 0.01, Table 2) The operative technique was dictated by the location of the tumor as well as surgeon preference. The number of lymph nodes resected per patient ranged from 10 to 70 (mean 16.1 1.59). The majority of patients (46.9%) underwent a transhiatal esophagectomy. However, approximately 53.9% underwent some type of transthoracic approach. The average number of lymph nodes harvested in the transthoracic group was 21.2, which was higher than those undergoing transhiatal approaches (mean ¼ 11.4 1.02). Follow-up ranged from 1to120 mo (median ¼ 36 mo), and complete follow-up was possible in 86.2% patients. Overall, the median survival for the group was 36.7 months and the 5-year OS rate was 39.3%.
157
The relationship of the number of LMN and survival LNM were found in 32.5% of the patients (n ¼ 431) and played a role in OS; patients without nodal involvement had a median survival of 38 mo versus 24 mo for node-positive patients (P ¼ 0.01). In the initial analysis of lymph node positivity, a dichotomized cut-off of < or >3 was determined to be a statistically significant predictor of OS by univariate analysis (P < 0.01). We then analyzed the lymph nodes in a manner similar to the method used by Wilson,13 specifically, LNM ¼ 0, LNM ¼ 1e3, and LNM > 4. In this manner, patients with no involved LN had a 5-year survival of 49.1%, while patients with 1e3 positive LN and >3 positive LN had 5-year survivals of 19.5 and 11.0%, respectively. Fig. 1A presents the Kaplan-Meier survival curves for the groups of patients with 0, 1e3, and >3 positive lymph nodes. The difference in survival among these three groups was significant (P < 0.01, Table 3). The relationship of the ratio of LNM and survival Finally, we examined the impact of an increasing LNR. The proportion of positive lymph nodes was analyzed using the following categories: none, <25%, >25% but <50%, and >50%. In this manner, patients with <25% involved LN had a 5-year survival of 29.7%, while patients with 25e50% and >50% positive LN had 5-year survivals of 14.6 and 8.2%, respectively. The difference in survival among these four groups was significant (P < 0.05); the corresponding KaplaneMeier survival curves are shown in Fig. 1B. Discussion In the present study, we investigated the positive LNM and LNR in patients with thoracic esophageal carcinoma. Positive nodes were found in 32.5% of the patients.Tumors with a positive node revealed more deep tumors and more frequent venous invasion, even a solitary positive node reflects tumor progression, so the presence of a positive node worsens the patient’s survival. Therefore, the poor prognosis in patients with thoracic esophageal SCC is mainly clue to high incidence of lymph node metastasis, including metasteses in the distant field, and lymph node dissection is a promising approach for the treatment of esophageal cancer. Comparison with previous studies assessing LNM and prognosis in oesophageal cancer Lymphatic dissemination is an early event in esophageal cancer, and lymph node involvement is known to be the most important prognostic factor with respect to esophageal cancer. Ellis and colleagues6 suggested that LNM is strongly associated with poor long-term survival. Other reports have concluded that nodal involvement is the single
Y.P. Liu et al. / EJSO 36 (2010) 155e159
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Figure 1. Kaplan-Meier curve analysis. A: Kaplan-Meier curve demonstrating overall survival for patients by lymph node category; B: Kaplan-Meier curve demonstrating overall survival for patients by lymph node ratio category.
most important prognostic factor for both loco-regional and systemic recurrence after complete resection.7,15,16 Nakagawa and colleagues17 also reported that a higher number of positive lymph nodes increased the risk of hematogenous recurrence, which implies that the extent of lymph node involvement is related to prognosis. The main goal of this study was to examine the utility of the number of LNM and the ratio of positive lymph nodes to excised lymph nodes as prognostic factors in survival of patients with tumors of the esophagus. The number of positive lymph nodes is a recognized factor of long-term survival. However, a nodal involvement of <4 and a positive LNR of <0.2 are regarded as favorable prognostic factors in N1 disease.18,19 In this study, the number of LNM proved to be an important indicator of survival. Patients with more than 3 LNM fared worse than patients with 3 or fewer LNM.
Table 3 Analysis of lymph node and prognostic. Median survival time (months) n
Kaplan-Meier 95% estimate confidence limits
P-value 5-year survival
Comparison with previous studies assessing LNR and prognosis in oesophageal cancer In the Wilson study,13 LNR examination did not reach significance, most likely due to the small number of patients per group with <20 patients per positive lymph node group. However, in our results, patients with more than 50% positive lymph nodes LNM fared worse than patients with 25e50% or fewer LNR. This finding has been previously reported for other malignancies, such as colon cancer, but not in esophageal cancer.18 Eloubeidi reported a similar finding that increasing LNR was associated with a poorer prognosis.2 Other authors have had differing cutoff points for LNR. Bollschweiler reported that LNR only became significant if it exceeded (P < 0.01) and Nigro showed patients with a LNR < 0.1 fared significantly better than those who had a LNR 0.1.4,10 Further investigation should examine the locations of the node prior to removal and compare that date with the LNR to see if a positive node at one anatomical site differs from a positive node at another site in terms of survival relative to the tumor location. Unfortunately, we were unable to examine the exact location of lymph node metastases in this study due to its retrospective nature.
Lower Upper LNþ category OLNþ 893 1e3 LNþ 359 >3 LNþ 73 % LNþ category 0 LNþ 893 0%e25% 160 LNþ 25%e50% 178 LNþ >50% LNþ 94
Conclusion 96 30 24
75 26 18
117 34 30
0.00
49.1% 19.5% 11.0%
96 56
75 48
117 64
0.00
39
34
45
14.6%
24
18
30
8.21%
49.1% 29.7%
Our experience has shown that the number of positive lymph nodes and the ratio of positive lymph nodes to examined lymph nodes are significant prognostic factors for esophageal carcinoma. It is thus recommended that the AJCC revise the TNM staging scheme to incorporate these two factors, so as to give a more complete assessment of a particular patient’s disease state to guide clinical decision-making.
Y.P. Liu et al. / EJSO 36 (2010) 155e159
Conflict of interest All authors have read and approved to submit it to your journal. There is no conflict of interest of any authors in relation to the submission. This paper has not been submitted elsewhere for consideration of publication. Acknowledgement This work has supported by Key Oncologic Subject Foundation of Hebei Province (No.200552), Youth Natural Science Foundation of Hebei Province (No.C2009001212).
References 1. de Manzoni G, Pedrazzani C, Verlato G, et al. Comparison of old and new TNM systems for nodal staging in adenocarcinoma of the gastrooesophageal junction. Br J Surg 2004;91:296–303. 2. Eloubeidi MA, Desmond R, Arguedas MR, et al. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 2002;95:1434–43. 3. Korst RJ, Rusch VW, Venkatraman E, et al. Proposed revision of the staging classification for esophageal cancer. J Thorac Cardiovasc Surg 1998;115:660–9. 4. Nigro JJ, DeMeester SR, Hagen JA, et al. Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy. J Thorac Cardiovasc Surg 1999;117:960–8. 5. Greenstein AJ, Litle VR, Swanson SJ, et al. Prognostic significance of the number of lymph node metastases in esophageal cancer. J Am Coll Surg 2008;206:239–46. 6. Ellis Jr FH, Heatley GJ, Krasna MJ, et al. Esophagogastrectomy for carcinoma of the esophagus and cardia: a comparison of findings and results after standard resection in three consecutive eight-year intervals with improved staging criteria. J Thorac Cardiovasc Surg 1997;113:836–48.
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7. Chen G, Wang Z, Liu XY, et al. Recurrence pattern of squamous cell carcinoma in the middle thoracic esophagus after modified Ivor-Lewis esophagectomy. World J Surg 2007;31:1107–14. 8. Lerut T. Esophageal surgery at the end of the millennium. J Thorac Cardiovasc Surg 1998;116:1–20. 9. Lin CS, Chang SC, Wei YH, et al. Prognostic variables in thoracic esophageal squamous cell carcinoma. Ann Thorac Surg 2009;87:1056–65. 10. Bollschweiler E, Baldus SE, Schroder W, et al. Staging of esophageal carcinoma: length of tumor and number of involved regional lymph nodes. Are these independent prognostic factors? J Surg Oncol 2006;94:355–63. 11. Kawahara K, Maekawa T, Okabayashi K, et al. The number of lymph node metastases influences survival in esophageal cancer. J Surg Oncol 1998;67:160–3. 12. Nishimaki T, Suzuki T, Kanda T, et al. Extended radical esophagectomy for superficially invasive carcinoma of the esophagus. Surgery 1999;125:142–7. 13. Wilson M, Rosato EL, Chojnacki KA, et al. Prognostic significance of lymph node metastases and ratio in esophageal cancer. J Surg Res 2008;146:11–5. 14. Hofstetter W, Correa AM, Bekele N, et al. Proposed modification of nodal status in AJCC esophageal cancer staging system. Ann Thorac Surg 2007;84:365–75. 15. Holscher AH, Bollschweiler E, Bumm R, et al. Prognostic factors of resected adenocarcinoma of the esophagus. Surgery 1995;118:845–55. 16. Clark GW, Peters JH, Ireland AP, et al. Nodal metastasis and sites of recurrence after en bloc esophagectomy for adenocarcinoma. Ann Thorac Surg 1994;58:646–54. 17. Nakagawa S, Kanda T, Kosugi S, et al. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg 2004;198:205–11. 18. Berger AC, Sigurdson ER, LeVoyer T, et al. Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. J Clin Oncol 2005;23:8706–12. 19. Alidina A, Gaffar A, Hussain F, et al. Survival data and prognostic factors seen in Pakistani patients with esophageal cancer. Ann Oncol 2004;15:118–22. 20. Iizuka T, Onoda T. TNM classification of carcinoma of the esophagus. Gan To Kagaku Ryoho 1997;24:893–901.