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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2009 August 21; 15(31): 3926-3930

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Prognostic impact of dissected lymph node count on patients with node-negative gastric cancer
 

Chang-Ming Huang, Jian-Xian Lin, Chao-Hui Zheng, Ping Li, Jian-Wei Xie, Bi-Juan Lin, Hui-Shan Lu


Chang-Ming Huang, Jian-Xian Lin, Chao-Hui Zheng, Ping Li, Jian-Wei Xie, Bi-Juan Lin, Hui-Shan Lu, Department of Oncology, Affiliated Union Hospital, Fujian Medical University, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, China

Author contributions: Huang CM and Lin JX conceived of the study, analyzed the data, and drafted the manuscript; Lu HS helped critically revising the manuscript for important intellectual content; Zheng CH, Li P, Xie JW and Lin BJ helped collecting the data and designing the study.

Supported by (in part) The Follow-up Office established by the Department of Oncology, Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian Province, China

Correspondence to: Chang-Ming Huang, Professor, Department of Oncology, Affiliated Union Hospital, Fujian Medical University, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, China. hcmlr253@sohu.com

Telephone: +86-591-83363366  Fax: +86-591-83320319

Received: June 23, 2009           Revised: July 16, 2009

Accepted: July 23, 2009

Published online: August 21, 2009

 

Abstract

AIM: To investigate the long-term effect of the number of resected lymph nodes (LNs) on the prognosis of patients with node-negative gastric cancer.

 

METHODS: Clinical data of 211 patients with gastric cancer, without nodal involvement, were analyzed retrospectively after D2 radical operation. We analyzed the relationship between the number of resected LNs with the 5-year survival, the recurrence rate and the post-operative complication rate.

 

RESULTS: The 5-year survival of the entire cohort was 82.2%. The total number of dissected LNs was one of the independent prognostic factors. Among patients with comparable depth of invasion, the larger the number of resected LNs, the better the survival (P < 0.05). A cut-point analysis provided the possibility to detect a significant survival difference among subgroups. Patients had a better long-term survival outcomes with LN counts 15 for pT1-2, 20 for pT3-4, and 15 for the entire cohort. The overall recurrence rate was 29.4% within 5 years after surgery. There was a statistically significant, negative correlation between the number of resected LNs and the recurrence rate (P < 0.01). The post-operative complication rate was 10.9% and was not significantly correlated with the number of dissected LNs (P > 0.05).

 

CONCLUSION: For node-negative gastric cancer, sufficient number of dissected LNs is recommended during D2 lymphadenectomy, to improve the long-term survival and reduce the recurrence. Suitable increments of the dissected LN count would not increase the post-operative complication rate.

 

© 2009 The WJG Press and Baishideng. All rights reserved.

 

Key words: Stomach neoplasms; Lymph nodes; Gastrectomy; Lymphadenectomy; Prognosis

 

Peer reviewer: Frank I Tovey, OBE, ChM, FRCS, Honorary Research Fellow, Department of Surgery, University College London, London, United Kingdom

 

Huang CM, Lin JX, Zheng CH, Li P, Xie JW, Lin BJ, Lu HS. Prognostic impact of dissected lymph node count on patients with node-negative gastric cancer. World J Gastroenterol 2009; 15(31): 3926-3930  Available from: URL: http://www.wjgnet.com/1007-9327/15/3926.asp  DOI: http://dx.doi.org/10.3748/wjg.15.3926

 

INTRODUCTION

Gastric cancer is a common malignancy worldwide. Despite its declining incidence, mortality of gastric cancer remains high[1]. It is generally accepted that a higher survival rate benefits from a standardized pattern of lymph node dissection[2-4]. Many studies favor an extended lymphadenectomy at the time of potentially curative gastrectomy for node-positive gastric cancer, and the risk of long-term death tends to decrease when the number of resected lymph nodes increases to about 25[5-7]. However, there are few studies on how many nodes should be removed and examined when performing a radical gastrectomy for node-negative gastric cancer. Therefore, the aim of this retrospective study was to evaluate the long-term effect of the number of resected lymph nodes (LNs) on the prognosis of patients with node- negative gastric cancer.

 

MATERIALS AND METHODS

Materials

Between January, 1995 and March, 2004, 211 patients diagnosed with primary gastric cancer were treated with curative resection at the Department of Oncology, Affiliated Union Hospital of Fujian Medical University, Fuzhou, China. The surgical procedure was defined as curative when no grossly visible tumor tissue (metastasis or LN involvement) remained after resection and when the resection margins were histologically normal. There were 164 males and 47 females whose age ranged from 29 to 84 years (57.4 ± 11.3 years). All patients received a D2 dissection according to the Japanese Classification of Gastric Carcinoma[8]. Lymph nodes were meticulously dissected from the en bloc specimens, and the classification of the dissected LNs was determined by specialist surgeons who reviewed the excised specimens after surgery, based on the Japanese Classification of Gastric Carcinoma[8]. All resected lymph nodes were proven to be without nodal involvement. The tumors’ size was 4.2 ± 2.1 cm. Patients were divided according to the primary site of gastric cancer: 75 upper third (U) tumors; 40 middle third (M) tumors; and 96 lower third (L) tumors. Based on the Japanese Classification of Gastric Carcinoma[8], there were 69 at stage pT1, 58 at stage pT2, 62 at pT3 and 22 at pT4. As far as the histological grades were concerned, there were 55 differentiated and 156 undifferentiated cases. Total gastrectomy, proximal subtotal gastrectomy and distal subtotal gastrectomy were carried out in 99, 15 and 97 cases, respectively. A total of 4649 LNs were taken for histological examination, and the median number of LN per patient was 22 (range, 6-48; mean 22.7 ± 7.0). Routine follow-up consisted of physical examination, laboratory tests (including measurement of carcinoembryonic antigen, CA19-9 and CEA levels), chest radiography, and abdominopelvic ultrasonography or computed tomography (CT). At the early stage (pT1), patients were followed every 6 mo during the first 2 years, and then yearly beyond the third year; at more advanced stages (pT2 or greater), follow-up was every 3 mo during the first year, every 6 mo or yearly beyond the second year, for a total of 5 years. Endoscopy was performed every 6 mo or yearly. All surviving patients were followed for more than five years. The survival time was the time from diagnosis until the last contact, the date of death, or the date that the survival information was collected. The rate of follow-up visits was 92.9%, with 196 cases involved.

 

Methods

Patients were stratified into five groups, based on the total number of LNs removed, as follows: < 15 LNs (18 cases), 15-19 LNs (49 cases), 20-24 LNs (63 cases), 25-29 LNs (44 cases) and 30 LNs (37 cases). The statistical analysis was performed with the Statistical Package for Social Science (SPSS), version 13.0 for Windows. Actuarial survival was determined via the Kaplan-Meier method, with univariate comparisons between groups through the log-rank test. Cox regression was used for multivariate analysis, with a backward elimination model for all covariates. Spearman rank correlation coefficient was used to analyze the relationship between the number of dissected LNs and recurrence rate. The correlation between the number of resected LNs and post-operative complication rate was analyzed with logistic regression model. Significance of differences was assumed at P < 0.05.

 

RESULTS

Univariate survival analysis

The five-year overall survival rate of the entire cohort was 82.2%. The clinicopathological variables tested in the univariate analysis are shown in Table 1. Factors influencing the 5-year survival rate were tumor size (P = 0.033), depth of invasion (P < 0.001) and number of resected LNs (P < 0.001). The covariates age (P = 0.431), gender (P = 0.170), tumor location (P = 0.432), pathological types (P = 0.645) and type of gastrectomy (P = 0.640) had no significant influence on the survival.

 

Multivariate survival analysis

Multiple survival analysis was calculated by the Cox’s proportional hazard regression model. The prognostic factors considered at univariate analysis were analyzed first by stepwise regression, including tumor size, depth of invasion and number of resected LNs. As a result, there were two independent, statistically significant prognostic parameters: depth of invasion (P = 0.032) and number of resected LNs (P < 0.001). The risk ratios and their 95% confident interval were listed in Table 2.

 

Impact of total LN counts by univariate survival analysis

The five-year survival, based on T category, showed considerable variations with increasing counts of resected LNs. An obvious trend toward better survival was observed for higher numbers of resected LN (Table 3).

 

Cut-point survival analysis

A cut-point analysis was performed to determine the numeric LN value that determines the greatest actuarial survival difference between pT1-2 and pT3-4 subgroups. We selected the ability to detect differences between groups based on the magnitude of the log-rank test c2 statistic. Results for all relevant cut points and stage subgroups are listed in Table 4. The cut-point analysis yielded the greatest survival difference at the levels of 15 (pT1-2), 20 (pT3-4) and 15 (entire cohort).

 

Impact of the number of resected LNs on recurrence rate

Within 5 years after surgery, a recurrence was confirmed by clinical, radiological examination or reoperation in 62 patients, with an overall recurrence rate of 29.4%. The number of patients with peritoneal and lymph nodes recurrence were 28 and 13 respectively. The most common site of haematogenous recurrence was the liver, occurring in 12 patients. Other patterns of recurrence were bone recurrence in 5 patients and lung recurrence in 4 patients. The relationship between the number of resected LNs and recurrence rate was analyzed by Spearman rank correlation coefficient (Table 5). For either pT1-2 or pT3-4 subgroups, there was a statistically significant, negative correlation between the number of dissected LNs and the recurrence rate (P < 0.01).

 

Correlation between number of resected LNs and post-operative complication rate

Twenty-three of the 211 patients (10.9%) experienced postoperative complications. These included pancreatitis (4 cases), anastomotic leakage (3), intra-abdominal abscess (4), postoperative ileus (1), stenosis (3), countercurrent esophagus (2), pancreatic leakage (2) and pneumonia (4). Logistic regression analysis revealed that the number of dissected LNs was not significantly correlated with the post-operative complication rate (P = 0.214).

 

DISCUSSION

It is commonly regarded that lymph node metastases is one of the most important prognostic factors in patients with gastric cancer after curative operation[9,10]. Bruno et al [11] pointed out that patients with node-negative gastric cancers have clinicopathological features similar to those with early gastric cancer and they showed also how those patients have a better prognosis than those with node-positive gastric carcinoma. The 5-year survival rate of patients with node-negative gastric carcinoma was 89.5%, based on the work by Wu et al [12], whereas, based on our present data, this rate is 82.2%. The only potentially curative treatment for this disease is complete surgical resection, with an en bloc LN dissection. D2 lymph node dissection can increase the long-term survival of gastric cancer patients with lymph node metastases and it has become a standard surgical procedure for curative treatment in Korea and Japan[13]. D2 lymph node dissection requires not only a specific anatomical extension (i.e. it must include both perigastric and suprapancreatic nodes), but also a certain number of resected LNs (at least 15). The number of dissected LNs is closely related to the postoperative pathologic staging and the prognostic assessment. Bouvier et al[14] investigated 749 cases with gastric cancer, and the results showed that the risk of misclassification became significant, with an error rate of 47.1% in the pathology reports, when fewer than 10 lymph nodes were examined. They concluded that, in the latter cases, staging is not reliable. Karpeh et al[15] reviewed 1038 patients with gastric cancer who had undergone gastrectomy with curative intent. They found that removal of 15 LNs appears to provide a considerable survival advantage, in comparison with the removal of < 15 LNs. In an attempt to improve staging accuracy, it was recommended that a minimum of 15 lymph nodes be examined. Based on our data, the median number of total LNs examined was 22 (mean 22.7 ± 7.0) per patient. In addition, the number of LNs dissected emerges as one of the most important prognostic indicators. Our present study shows that, with comparable depth of invasion, patients with a larger number of dissected LNs have a better survival rate (P < 0.05), consistent with the results of Smith et al[16]. The contribution of negative LN counts to the prognosis of patients is partly due to LN micrometastases. In patients without LN metastases identified by HE staining, about 20% had LN micrometastases[17]. Thus, it can be concluded that an extended lymphadenectomy contributes to decrease the number of residual tumor cells, leading to better prognosis. However, it is unclear how many LNs need to be removed in a D2 dissection in patients with node-negative gastric cancer. Giuliani et al[18] suggested that patients with node-negative gastric cancer should undergo adequate lymphadenectomy to permit examination of 23 LNs, which would allow accurate identification of prognostic variables. From the cut-point analysis, we suggest that, to be adequate, the resection, at the time of a D2 radical dissection, should involve 15 LNs for pT1-2 and 20 LNs for pT3-4, and this based on an accurate survival estimates in patients with node-negative gastric cancer.

    Despite improved prognosis, as a result of early diagnosis, radical operations and the development of adjuvant therapy[9,19,20], death from gastric cancer is still almost entirely due to recurrent disease. About 5% of patients with early gastric cancer and 50% of patients with advanced gastric cancer die with recurrent disease, as reported by Böhner et al[21]. In a large set of follow-up data from Japan, among 14000 patients with recurrent gastric cancer, the rate of loco-regional recurrence following potentially curative resection was 25.6%[22]. This may be due to the insufficient anatomical extension of the dissection at the time of the first surgery, including an insufficient gastrectomy or insufficient lymphadenectomy. The randomized Dutch gastric carcinoma study compared D1 and D2 lymphadenectomy and appeared to observe a significant reduction of the loco-regional recurrence rate after a more extended lymphadenectomy: following D1 lymphadenectomy, 36% of patients died with local recurrence, compared with 27% when a D2 lymphadenectomy was performed (P < 0.05)[23]. Our present study shows that the overall recurrence rate is 29.4% within 5 years after surgery. The Spearman rank correlation coefficient analysis revealed that there was a statistically significant, negative correlation between the number of dissected LNs and the recurrence rate (P < 0.01). A lower recurrence rate was observed in cases with higher total LNs, indicating that a sufficient lymphadenectomy contributed to reduce the number of residual tumor cells. While correlating the number of dissected LNs with the post-operative complication rate, Zilberstein et al [24] did not find any difference between the average number of dissected LNs in patients with and without complications. These authors suggested that the higher morbidity and mortality rates were not due to the extended lymphadenectomy. Those rates may be more likely correlated with the level of experience in gastroesophageal surgery, with the presence of an appropriate learning curve for radical gastrectomy and with the experience in the management of postoperative complications. The post-operative complication rate in our study was 10.9% and the logistic regression analysis showed that the number of dissected LNs did not correlate with the post-operative complication rate (P > 0.05). According to our results, it appears that a suitable increment of the number of dissected LN would not increase the post-operative complication rate if the surgery is performed by a trained surgical team.

 

COMMENTS

Background

Many studies have favored an extended lymphadenectomy at the time of a potentially curative gastrectomy for node-positive gastric cancer, and the risk of long-term death tends to decrease when the number of resected lymph nodes increases to about 25. However, few studies have assessed the relative contribution of the number of total resected lymph nodes to the outcome in patients with node-negative gastric cancers.

Research frontiers

It is generally accepted that a higher survival rate benefits from a standardized pattern of D2 radical dissection, which requires the removal of Group 1 and Group 2 lymph nodes (LNs). The number of dissected LNs is strongly correlated with patients’ survival.

Innovations and breakthroughs

The authors retrospectively reviewed 211 patients with node-negative gastric cancer, who were treated with D2 radical resection at a hospital in Fujian between 1995 and 2004, to assess how the number of dissected LNs may affect their survival rate.

Applications

The authors suggest that importance should be attached to removing a sufficient number of LNs in order to improve the long-term survival and reduce the recurrence rate of patients with node-negative gastric cancer. Moreover, suitable increments of the number of dissected LNs would not increase the post-operative complication rate.

Peer review

The authors are to be congratulated on this paper, recording the effect of the number of lymph nodes resected in a large number of patients (211) with node negative gastric cancer and a remarkable survival rate of 82.2% at 5 years. The number of lymph nodes resected influenced the prognosis of the patients with node negative gastric cancer. This finding has important information for gastrointestinal surgeons.

 

REFERENCES

1      Roviello F, Marrelli D, Morgagni P, de Manzoni G, Di Leo A, Vindigni C, Saragoni L, Tomezzoli A, Kurihara H. Survival benefit of extended D2 lymphadenectomy in gastric cancer with involvement of second level lymph nodes: a longitudinal multicenter study. Ann Surg Oncol 2002; 9: 894-900   PubMed    DOI

2      Kim JP, Lee JH, Kim SJ, Yu HJ, Yang HK. Clinicopathologic characteristics and prognostic factors in 10 783 patients with gastric cancer. Gastric Cancer 1998; 1: 125-133   PubMed    DOI

3      Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, Sydes M, Fayers P. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer 1999; 79: 1522-1530   PubMed    DOI

4      Kasakura Y, Mochizuki F, Wakabayashi K, Kochi M, Fujii M, Takayama T. An evaluation of the effectiveness of extended lymph node dissection in patients with gastric cancer: a retrospective study of 1403 cases at a single institution. J Surg Res 2002; 103: 252-259   PubMed    DOI

5      Marubini E, Bozzetti F, Miceli R, Bonfanti G, Gennari L. Lymphadenectomy in gastric cancer: prognostic role and therapeutic implications. Eur J Surg Oncol 2002; 28: 406-412   PubMed    DOI

6      Siewert JR, Böttcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 1998; 228: 449-461   PubMed

7      Schwarz RE, Smith DD. Clinical impact of lymphadene­ctomy extent in resectable gastric cancer of advanced stage. Ann Surg Oncol 2007; 14: 317-328   PubMed    DOI

8      Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma - 2nd English Edition. Gastric Cancer 1998; 1: 10-24   PubMed    DOI

9      Saito H, Fukumoto Y, Osaki T, Fukuda K, Tatebe S, Tsujitani S, Ikeguchi M. Prognostic significance of level and number of lymph node metastases in patients with gastric cancer. Ann Surg Oncol 2007; 14: 1688-1693   PubMed    DOI

10    Mishima Y, Hirayama R. The role of lymph node surgery in gastric cancer. World J Surg 1987; 11: 406-411   PubMed    DOI

11    Bruno L, Nesi G, Montinaro F, Carassale G, Boddi V, Bechi P, Cortesini C. Clinicopathologic characteristics and outcome indicators in node-negative gastric cancer. J Surg Oncol 2000; 74: 30-32   PubMed    DOI

12    Wu CW, Hsieh MC, Lo SS, Tsay SH, Lui WY, P'eng FK. Relation of number of positive lymph nodes to the prognosis of patients with primary gastric adenocarcinoma. Gut 1996; 38: 525-527   PubMed    DOI

13    Degiuli M, Sasako M, Ponti A, Calvo F. Survival results of a multicentre phase II study to evaluate D2 gastrectomy for gastric cancer. Br J Cancer 2004; 90: 1727-1732   PubMed    DOI

14    Bouvier AM, Haas O, Piard F, Roignot P, Bonithon-Kopp C, Faivre J. How many nodes must be examined to accurately stage gastric carcinomas? Results from a population based study. Cancer 2002; 94: 2862-2866   PubMed    DOI

15    Karpeh MS, Leon L, Klimstra D, Brennan MF. Lymph node staging in gastric cancer: is location more important than Number? An analysis of 1,038 patients. Ann Surg 2000; 232: 362-371   PubMed    DOI

16    Smith DD, Schwarz RR, Schwarz RE. Impact of total lymph node count on staging and survival after gastrectomy for gastric cancer: data from a large US-population database. J Clin Oncol 2005; 23: 7114-7124   PubMed    DOI

17    Wu ZY, Li JH, Zhan WH, He YL, Wan J. Effect of lymph node micrometastases on prognosis of gastric carcinoma. World J Gastroenterol 2007; 13: 4122-4125   PubMed

18    Giuliani A, Caporale A, Corona M, Di Bari M, Demoro M, Ricciardulli T, Gozzo P, Galati G, Tocchi A. Lymphadenectomy in gastric cancer: influence on prognosis of lymph node count. J Exp Clin Cancer Res 2004; 23: 215-224   PubMed

19    Katai H, Yoshimura K, Maruyama K, Sasako M, Sano T. Evaluation of the New International Union Against Cancer TNM staging for gastric carcinoma. Cancer 2000; 88: 1796-1800   PubMed    DOI

20    Li C, Kim S, Lai JF, Oh SJ, Hyung WJ, Choi WH, Choi SH, Noh SH. Solitary lymph node metastasis in gastric cancer. J Gastrointest Surg 2008; 12: 550-554   PubMed    DOI

21    Böhner H, Zimmer T, Hopfenmüller W, Berger G, Buhr HJ. Detection and prognosis of recurrent gastric cancer--is routine follow-up after gastrectomy worthwhile? Hepatogastroenterology 2000; 47: 1489-1494   PubMed

22    Yonemura Y, Nojima N, Kawamura T, Kim BS, Fujita H, Nozaki S. Mechanisms of the formation of peritoneal dissemination. In: Yonemura Y, ed. Peritoneal dissemination. Japan Kanazawa Maeda Shoten Co. Ltd., 1998: 1-46

23    Lehnert T, Rudek B, Buhl K, Golling M. Surgical therapy for loco-regional recurrence and distant metastasis of gastric cancer. Eur J Surg Oncol 2002; 28: 455-461   PubMed    DOI

24    Zilberstein B, da Costa Martins B, Jacob CE, Bresciani C, Lopasso FP, de Cleva R, Pinto Junior PE, Junior UR, Perez RO, Gama-Rodrigues J. Complications of gastrectomy with lymphadenectomy in gastric cancer. Gastric Cancer 2004; 7: 254-259   PubMed    DOI

 

   S- Editor  Li LF    L- Editor  Negro F    E- Editor  Lin YP

 

 

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