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All authors contributed equally to this article. S.H.N, T.S., and W.J.H. were responsible for study conception and design; S.H.N, T.S., J.H.L., Y.M.K., and J.Y.A. were responsible for data acquisition; S.H.N., T.S., W.J.H., and H.-I.K. were responsible for data analysis and interpretation; S.H.N, T.S., and W.J.H. drafted the article; and W.J.H., J.-H.C., and S.H.N. made critical revisions to the article.
The seventh edition of the tumor, lymph node (LN), metastasis (TNM) staging system increased the required number of examined LNs in gastric cancer from 15 to 16. However, the same staging system defines lymph node-negative gastric cancer regardless of the number of examined LNs. In this study, the authors evaluated whether gastric cancer can be staged properly with fewer than 15 examined LNs.
The survival rates of 10,010 patients who underwent curative gastrectomy from 1987 to 2007 were analyzed. The patients were divided into 2 groups according to the number of examined LNs, termed the “insufficient” group (≤15 examined LNs) and the “sufficient” group (≥16 examined LNs). The survival curves of patients from both groups were compared according to the seventh edition of the TNM classification.
Three hundred sixteen patients (3.2%) had ≤15 examined LNs for staging after they underwent standard, curative lymphadenectomy. Patients who had T1 tumor classification, N0 lymph node status, and stage I disease with an insufficient number of examined LNs after curative gastrectomy had a significantly worse prognosis than patients who had ≥16 examined LNs. Moreover, having an insufficient number of examined LNs was an independent prognostic factor for patients who had T1, N0, and stage I disease.
Lymph node (LN) involvement is one of the most important prognostic indicators of gastric cancer.1-4 Since 1997, the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) tumor, LN, metastasis (TNM) staging system has classified lymph node (LN) status according to the absolute number of metastatic LNs.5 Lymph node stage can be determined appropriately when the number of total examined LNs (eLNs) is ≥16 according to the latest TNM staging system.6
However, the recommended minimum number of eLNs required for proper staging remains controversial, because this number varies considerably between institutions and countries.7-16 The seventh edition of the TNM staging system designates LN-negative (N0) disease as any gastric cancer with all eLNs negative, regardless of the total number of eLNs.6 In addition, the latest UICC TNM supplement has stipulated that LN-positive gastric cancer should be staged in the same manner, independent of the number of eLNs.17
A significant portion of patients with early stage gastric cancer have been staged incorrectly because of an insufficient number of eLNs.10 Large population studies from various institutions and countries have demonstrated an association between an adequate number of eLNs and improved overall survival,10, 11, 18-20 thus providing evidence that examination of an insufficient number of LNs may have a detrimental effect on the overall survival of patients with gastric cancer who receive curative treatment.
In this study, we hypothesized that inadequate LN evaluation correlates with worse survival outcomes after curative gastrectomy for gastric cancer. We analyzed the long-term survival of patients with gastric cancer who received curative treatment to investigate staging and the dependence on the number of eLNs.
MATERIALS AND METHODS
Overall Surgical Strategy and Pathologic Examination of Lymph Nodes
In this study, the standard surgery for primary gastric cancer was D2 lymphadenectomy (advanced gastric cancer) and D1 + beta or D2 lymphadenectomy (early gastric cancer). The definition for lymphadenectomy was based on the Japanese Research Society for Gastric Cancer guidelines.21 All surgeons followed the same strategy and extent of lymphadenectomy.
Each resected specimen was carefully prepared for accurate pathologic staging. First, the surgeon carefully separated the dissected soft tissues according to the anatomic location of the LNs before sending them for pathologic examination. Specialized pathologists examined the divided soft tissues and retrieved as many LNs as possible. All LNs were stained with hematoxylin and eosin and were examined by pathologists using light microscopy.
From 1987 to 2007, in total, 11,137 gastrectomies for gastric cancer were performed in the Department of Surgery, Yonsei University College of Medicine. Patients were excluded from this study if they underwent surgery for remnant gastric cancer, received chemotherapy before the operation, or died within 30 days of surgery. After exclusion, in total, 10,010 patients who underwent curative resection (R0) were included. The study only included patients who underwent total and subtotal gastrectomy. All but 199 patients were followed from the date of surgery until December 31, 2009 or death. For the survivors, follow-up survivors ranged from 24 months to 280 months (median, 84 months). The 199 patients who were not followed were censored on the last day of follow-up.
We divided the patients into 2 groups: those with ≤15 eLNs (the “insufficient” group) and those with ≥16 eLNs (the “sufficient” group). Clinicopathologic data, such as age, sex, type of operation, histology, size, location, the number of involved LNs, and survival data, were analyzed and compared between the 2 groups. We also performed the same analyses after classifying the patients according to the seventh edition of the TNM classification. Multivariate analysis of the factors that influenced overall survival after treatment was performed using a Cox proportional hazards model in each classification. This study was approved by the Institutional Review Board of the Severance Hospital, Yonsei University (4-2011-0411).
Categorical variables were analyzed with the chi-square test, and continuous variables were analyzed with a 2-sample t test. Kaplan-Meier survival estimation was used for plotting survival curves, and the log-rank test was used to compare differences in survival. A Cox proportional hazards model was used for the multivariate analysis of risk factors for death after curative gastrectomy. For subgroup analyses, the interaction between the number of eLNs and each tumor, LN, and TNM classification was tested at a significance level of .05. Binary logistic regression (Enter method) analyses were performed to identify predictors of an insufficient number of eLNs. P values < .05 were considered statistically significant.
Overall Operative Outcomes
Of all 10,010 patients in the study, 316 patients (3.2%) had ≤15 eLNs in their pathology reports. Of those patients, 5.4% had 1 to 5 eLNs, 17.7% had 6 to 10 eLNs, and 76.9% had 11 to 15 eLNs. In addition, in this “insufficient” group, 257 patients (81%) reportedly had no cancer involvement of LNs (Fig. 1). The mean number of eLNs in the entire study population was 39.6 (median, 38 eLNs).
Comparison of Clinicopathologic Characteristics
In the “insufficient” group, the mean age (±standard deviation [SD]) was 58.9 ± 11.3 years (range, 31-85 years); whereas, for the “sufficient” group, it was 56.2 ± 11.8 years (range, 19-91 years). Patient distribution was 77.8% men in the “insufficient” group and 66.8% men in the “sufficient” group. The type of operation, tumor histology, size, and location differed significantly between the 2 groups (Table 1). There also were significant differences between the 2 groups in the distribution of tumor classification, LN status, the total number of retrieved LNs, and the number of metastatic LNs.
Table 1. Comparison of Clinicopathologic Characteristics
No. of Patients(%)
Insufficient Group: ≤15 eLNs
Sufficient Group: ≥16 eLNs
Abbreviations: eLN, examined lymph nodes; LNs, lymph nodes; SD, standard deviation; UML, upper, middle, and lower stomach.
a Tumor classification (T) and lymph node status (N) were based on the seventh edition of the International Union Against Cancer/American Joint Committee on Cancer TNM staging system.
Total no. of patients
Age: Mean±SD, y
Size: Mean±SD, cm
Total no. of eLNs: Mean±SD
No. of positive LNs: Mean±SD
When overall survival curves were compared, there was no statistically significant difference between the “insufficient” and “sufficient” groups (81.8% vs 75.3% in 5-year survival rates, respectively; log-rank P = .09). When the patients were categorized using the most recent TNM staging classification, the “insufficient” group had significantly worse survival than the “sufficient” group only among those with T1 tumors (P < .001) (Fig. 2A). For LN status, the “insufficient” group had significantly worse survival only among those with N0 status (P = .01) (Fig. 2B). Although worse survival was noted in the “insufficient” group for those with T1 tumors and N0 status, this group included more LN-negative patients and patients with early gastric cancer than the “sufficient” group with T1 tumors and N0 status (93.6% vs 89.2%, respectively, of LN-negative cases [P = .048] and 73.9% vs 66.9%, respectively, of patients with early gastric cancer [P = .018]). A significant difference in survival also was noted between the 2 groups for the stage I subgroup but not for the other subgroups (P < .001) (Fig. 2C).
Multivariate Analyses of Factors Influencing Survival
For all patients analyzed, an insufficient number of eLNs, age ≥60 years, men, higher T classification and LN status, and upper tumor location were identified as significant risk factors for survival (Table 2). Upon further analysis, we determined that, in patients with T1 tumors and N0 status, the examination of ≤15 LNs was a risk factor for poor survival. In patients with stage I disease, an insufficient number of eLNs, age ≥60 years, and men were correlated with a worse prognosis. However, in the other subgroups, having ≤15 eLNs was not a risk factor for poor survival (data not shown).
Before conducting subgroup analyses, interaction tests between the number of examined LNs and each tumor classification, LN status, and TNM stage were performed. Interactions were present between the number of eLNs and T classification and TNM stage, but not LN status. Hence, over interpretation of the results from subgroup analyses for LN status should be avoided.
Multivariate analyses were done for only 9922 patients who had complete information on all variables listed. Twenty-nine patients with unclassifiable histology, 58 patients without information on tumor size, and 1 patient without information on tumor location were excluded from the analyses.
Binary Logistic Regression Analyses of Factors Influencing Inadequate Evaluation of Lymph Nodes
In binary logistic regression analyses to identify predictors of insufficient eLNs, older age (≥60 years vs <60 years), lower LN classification (N0, N1, and N2 vs N3), and differentiated histology (compared with undifferentiated histology) were risk factors for inadequate LN assessment (Table 3).
Table 3. Binary Logistic Regression Analyses of Factors That Influenced Inadequate Evaluation of Lymph Nodes
In this study, we observed that the majority of patients who had ≤15 eLNs for staging had T1 tumors (64.2%) or N0 (81.3%) LN status. Moreover, we observed that these same patients and the patients with stage I disease had a significantly worse prognosis after they underwent standard curative lymphadenectomy compared with patients who had ≥16 eLNs. In multivariate analyses, having ≤15 examined LNs was an independent prognostic factor that was correlated with a worse prognosis. Subgroup analyses also demonstrated that an insufficient number of eLNs indicated a poor prognosis for patients with stage I disease who had T1 tumors and N0 status.
The prognostic impact of the number of eLNs has been suggested primarily in patients with advanced gastric cancer. For these patients, having a greater number of eLNs has been correlated with a better prognosis.11, 15 Our previous study on the number of eLNs in patients with locally advanced gastric cancer revealed a significant impact in survival rates when a more LNs were examined.15 Few studies have focused on the influence of an insufficient number of eLNs; however, it is known that, for staging tumors, a low number of eLNs correlates with poor survival.10, 15, 18, 22 These data suggest that inappropriate staging may lead to inaccurate diagnoses in patients with potentially curative disease and loss of opportunity for adjuvant treatment,23 usually in patients with LN-negative disease or early gastric cancer.10, 18, 19 In a Surveillance, Epidemiology, and End Results database study of earlier stage tumors, the survival rate reportedly increased when patients had an adequate number of eLNs.10, 19 The results from our current study also demonstrate that, in patients who have ≤15 eLNs, there is a lower survival rate among those with T1 tumors, N0 LN status, and stage I disease. To our knowledge, these studies, including ours, are the largest studies in patients with gastric cancer to date that correlate the number of eLNs with the survival rate, although the proportion of adequately assessed patients and the median number of eLNs among the studies differed.
The main reasons for examination of an insufficient number of LNs after curative gastrectomy are inaccurate LN dissection or retrieval.8, 24-32 These inaccuracies most likely are determined by a low operation volume of surgeons and decreased diligence of pathologists.18, 23, 33, 34 In addition, they may be closely related to host factors, such as patient clinicopathologic status and immunologic response.20, 35, 36 In the current study, older age, differentiated histology, and lower LN status were predictors of inadequate LN assessment. In addition, patient's comorbidities, the intrinsic number of LNs, lymphovascular invasion status, and preoperative endoscopic procedures may play a role in inadequate LN dissection and assessment.
In a randomized Dutch Gastric Cancer Group trial, it was suggested that LN retrieval from the specimen, rather than the extent of lymphadenectomy, was responsible for differences in the number of eLNs.8 In addition, pathologists can be affected by the suggested minimum number of LNs required for examination.10 Presumably, a preoperative diagnosis of early cancer or a less aggressive tumor can lead physicians to make biased decisions. Accordingly, these factors may make surgeons and pathologists reluctant to perform strict lymphadenectomy and retrieval. It is less likely that smaller metastatic or nonmetastatic LNs may result in the failure to examine an adequate number of LNs.27 In addition, smaller LNs reportedly were correlated with decreased immune response in gastrointestinal cancer37-40; and older age, men, and differentiated histology reportedly triggered weaker immune responses. Our current results indicate that these host factors were more likely to be observed in patients who had ≤15 eLNs.
In the TNM staging system, there have been no validation studies to justify the published and suggested number of LNs that should be examined for proper staging in LN-negative gastric cancer. Ours is the first comprehensive study with large number of patients who underwent curative gastrectomy with extended LN dissection. Because of the high volume of surgery for gastric cancer, surgeons and pathologists removed and examined much greater numbers of LNs with consistent results.
Our study, however, has some limitations. First, the survival of patients with advanced gastric cancer could not be properly evaluated. Thus, we cannot suggest a proper staging strategy for patients with LN-positive tumors who have ≤15 eLNs, because our sample size was too small. Second, our results are based on retrospective analyses in a single institution over a long duration (1987 to 2007). Third, we also could not analyze cancer-specific survival rates to determine the relation between the number of eLNs and cancer recurrence after standard treatment. Finally, these results may not be directly applicable to Western institutions, in which >50% of patients with nonmetastatic gastric cancer undergo inadequate LN assessment.
On the basis of our results, the definition of LN-negative gastric cancer should be re-evaluated to take into account the number of eLNs. Our results suggest that examination of ≤15 LNs may cause inaccurate staging and treatment, thus affecting survival rates. Thus, if the number of eLNs is inadequate after standard curative resection of gastric cancer, then a more thorough reassessment, such as fat clearance, should be performed. Otherwise, these patients should be considered a high-risk group for stage migration and worse survival compared with those who have adequate LN evaluation. In conclusion, future studies should further evaluate the effects of examining insufficient numbers of LNs to clarify the minimally required and optimal number that will contribute to proper TNM staging and patient survival.