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10.1245/ASO.2003.09.009
Annals of Surgical Oncology 10:783-791 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Accurate Lymph Node Staging is of Greater Prognostic Importance Than Subclassification of the T2 Category for Gastric Adenocarcinoma

Abeezar I. Sarela, MD, Alan D. Turnbull, MD, Daniel G. Coit, MD, David Klimstra, MD, Murray F. Brennan, MD and Martin S. Karpeh, MD

From the Departments of Surgery (AIS, ADT, DGC, MFB, MSK) and Pathology (DK), Memorial Sloan-Kettering Cancer Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Martin S. Karpeh, Jr., MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021; Fax: 212-794-5847; E-mail: karpehm{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Examination of 15 or more lymph nodes is necessary for accurate staging of gastric adenocarcinoma. This study examined whether prognostic discrimination is improved by distinguishing between pT2 tumors limited to the muscularis propria (MP) and those extending to subserosa (SS).

Methods: A single-institution, prospectively maintained database for 1985–2000 was reviewed for patients who had had R0 resection of pT2 gastric carcinoma.

Results: There were 161 patients with MP and 201 patients with SS. The prevalence of nodal metastasis was significantly lower with MP than with SS (47% vs. 66%, respectively; P < .001). As compared with MP, SS was associated with a similar prevalence of pN1 (44% vs. 43%) but a significantly higher prevalence of pN2 or pN3 (3% vs. 23%; P < .001). Five-year survival was significantly greater for patients with MP than with SS (64% vs. 49%; P = .005). On multivariate analyses, however, only the pN category and tumor site were independently significant prognostic factors. With accurate nodal staging, patients with MP or SS had similar survival in association with pN0 (90% vs. 86%) or pN1 (56% vs. 44%). pN2 or pN3 were mainly limited to SS tumors and these patients had poor survival (26% and 0%).

Conclusion: For pT2 gastric adenocarcinoma, the depth of mural invasion was not an independently significant prognostic factor.

Key Words: Gastric neoplasms • Staging • Lymph nodes • T category


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The importance of accurate risk stratification for gastric adenocarcinoma has resurfaced in the debate following recent publication of a phase III trial that concluded that adjuvant 5-fluorouracil plus leucovorin and radiotherapy should be administered to all patients who have had R0 resection of high-risk (any other than pT1pN0) disease.1 Although patients were stratified according to pT and pN categories, stage-specific survival benefit of adjuvant therapy in this trial was not reported. It is of major concern that a substantial proportion of patients had inaccurate assignment of the pN category, consequent to limited lymphadenectomy. It is well established that histopathologic examination of at least 15 regional lymph nodes is necessary to accurately assign the pN category for gastric adenocarcinoma.2 Proper staging is essential for the identification of patients who have truly high-risk disease.

Up to one third of the number of patients in the trial reported by Macdonald et al.1 had pT2 tumors (tumor invades the muscularis propria [MP] or subserosa [SS]). Although such tumors constitute advanced gastric cancer,3 prognosis is significantly better than that associated with pT3 or pT4 tumors.2,4,5 It is also recognized that the pT2 category for gastric cancer comprises two distinct subcategories: tumors limited to the MP and tumors that extend to the SS.3,6 The prognostic significance of distinguishing between these subcategories of pT2 tumors is unclear.

The primary aim of the present study was to determine whether distinguishing between MP tumors and SS tumors provides additional prognostic information when used in conjunction with accurate lymph node staging by examination of 15 or more regional nodes. A secondary aim was to identify a subgroup of patients who have a sufficiently good prognosis following surgery such that the potential benefit of adjuvant therapy would be marginal.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A prospectively maintained database of all patients with gastric cancer admitted to Memorial Hospital at Memorial Sloan-Kettering Cancer Center (MSKCC) between July 1, 1985 and December 31, 2000 was reviewed to identify patients whose primary tumor had been categorized as pT2. A total of 2578 patients were entered into this database and 1188 had R0 resection during this period. Depth of primary tumor invasion within the pT2 category (MP vs. SS) was classified according to the rules of the Japanese Research Society for Gastric Cancer.3 A single pathologist reviewed the data and confirmed depth of invasion. Lymph node metastases were classified according to the 1997 American Joint Committee on Cancer (AJCC)6 staging criteria (pN0, no lymph node metastases; pN1, one to six metastatic lymph nodes; pN2, 7 to 14 metastatic lymph nodes; and pN3, 15 or more metastatic lymph nodes) for all patients. The operating surgeon indicated the extent of lymphadenectomy. Follow-up details were obtained from clinic visits, chart review, or phone calls to patients or their primary physicians.

Statistical Analysis
SPSS version 10.0 (SPSS Inc., Chicago, IL) was used for analysis. {chi}2 test or Mann-Whitney U-test was used for comparison of clinicopathologic characteristics between patients with MP and SS tumor. Follow-up status was recorded as no evidence of disease (187, 52%), alive with disease (15, 4%), dead of recurrent disease (107, 30%), dead of unrelated causes (52, 14%), and lost to follow-up.1 Death from recurrent disease was used as the end point for disease-specific survival analysis by the Kaplan-Meier method and all other outcomes were treated as censored observations. Disease-specific survival was chosen to reflect deaths caused specifically by recurrent disease as compared with death from all causes, including those that were not cancer related. The log rank test was used to compare survival characteristics. Cox regression analysis was used to analyze multiple prognostic indicators. P < .05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinicopathologic Characteristics
A total of 423 patients with pT2 gastric cancer were identified, of whom 362 (86%) had R0 resection. The male-to-female ratio was 2:1 and median age was 67 years (21–95).

Primary tumor location was classified as proximal stomach (gastroesophageal junction, 104, 29%; upper one third of stomach, 66, 18%), distal stomach (body or middle one third of stomach, 82, 22%; antrum or pylorus, 104, 29%), or diffusely involving the stomach.6 In 161 (45%) patients, the tumor was limited to the MP and in the remaining 201 (55%) patients the tumor extended to the SS layer. MP and SS tumors were similar with respect to age and gender of patient, site, and histologic type of the primary tumor (Table 1). SS tumors were significantly larger and more likely to be poorly differentiated (not statistically significant) than MP tumors. Two thirds of SS tumors were associated with nodal metastases (pN1–3) as compared with only one half of MP tumors (P < .001). pN1 disease was detected in similar proportions of patients with MP or SS tumors (44% vs. 43%, respectively). The pN2 and pN3 categories, however, comprised almost one fourth of patients with SS tumors as compared with only 3% of those with MP tumors.


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  		TABLE 1. Comparison of clinicopathologic characteristics of patients with pT2 gastric adenocarcinoma limited to the muscularis propria (MP) or extending to the subserosa (SS)
 
Resections comprised esophagogastrectomy for 123 (34%) patients; proximal gastrectomy for 28 (8%) patients; total gastrectomy for 60 (17%) patients; distal subtotal gastrectomy for 148 (41%) patients; and other procedures for 3 patients. A D2 or greater lymphadenectomy was performed for 282 (78%) patients.

Survival Characteristics
Nine of 362 (2.5%) patients died within 30 days of operation. For the remaining patients, median follow-up was 26 months (range, 1–170 months). For the entire cohort of patients, disease-specific survival was 55% at 5 years and 48% at 10 years, with an estimated median survival of 8.7 years (Fig. 1). A significantly larger proportion of patients with SS tumors died of recurrent disease as compared with those with MP tumors (34% vs. 24%; P = .05). On stratifying patients according to depth of mural invasion, 5-year survival for those with MP tumors was significantly greater than for those with SS tumors (64% vs. 49%, respectively; P = .005), with median survival of 47 months for those with SS tumors (Fig. 2). On stratifying patients according to the N stage, 5-year survival was 83% with pN0 disease, 44% with pN1 disease (median survival, 46 months), 11% with N2 disease (median survival, 33 months), and 0% with N3 disease (median survival, 21 months) (P < .001, log rank test for trend [Fig. 3]). On univariate analyses, pN category, site of primary tumor, depth of mural invasion, and size of the primary tumor were significant prognostic indicators. On multivariate analysis, however, only site and pN category retained independent prognostic significance (Table 2).



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  		FIG. 1. Disease-specific survival for the entire cohort of patients (n = 362) with pT2 gastric cancer.

 


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  		FIG. 2. Disease-specific survival for patients with pT2 gastric cancer limited to the muscularis propria (MP, n = 161) and that extending to the subserosa (SS, n = 201) (P = .005).

 


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  		FIG. 3. Disease-specific survival for patients with pT2 gastric cancer stratified according to pN category as per the 1997 American Joint Committee on Cancer classification (P = .001). MP, muscularis propria; SS, subserosa.

 

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  		TABLE 2. Univariate and multivariate analyses of prognostic markers for pT2 gastric adenocarcinoma
 
Lymph Node Staging and Survival Characteristics
The median number of lymph nodes identified at gross pathologic examination of the specimens was 23 (range, 0–72). Fifteen or more lymph nodes were identified in 277 (77%) cases, and these patients were deemed to have been accurately staged.6 Distribution of pN categories for these 277 patients is shown in Table 3. For the 84 patients whose disease was staged with examination of less than 15 lymph nodes, distribution of pN categories was pN0 (43, 51%), pN1 (38, 45%), and pN2 (3, 4%). Patients with accurately staged pN0 disease had a significantly better survival rate than those with inaccurately staged (fewer than 15 lymph nodes examined) pN0 disease (P = .03 [Fig. 4]). Similarly, patients with accurately staged pN1 disease had notably better survival than those with inaccurately staged pN1 disease, although the difference in survival was not statistically significant (P = .1 [Fig. 5]). For patients with accurately staged pN0 disease, survival characteristics were similar for MP and SS tumors, with 5-year survival rates of 90% and 86%, respectively (Fig. 6). Similarly, for patients with adequately staged pN1 disease, survival was not significantly different for those with MP and SS tumors (56% vs. 44%, respectively, [Fig. 7]). Comparisons for pN2 and pN3 disease could not be conducted because only three patients had MP-pN2 disease and none had MP-pN3 disease. Similarly, comparisons between MP and SS survival characteristics with examination of fewer than 15 lymph nodes were not conducted because of limited numbers.


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  		TABLE 3. Distribution of pN categories with examination of at least 15 lymph nodes (n = 277 patients)
 


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  		FIG. 4. Disease-specific survival for patients with pT2pN0 gastric cancer stratified according to whether at least 15 lymph nodes (LN) (>=15 LN, n = 108 patients) or fewer than 15 lymph nodes (<15 LN, n = 42 patients) were examined (P = .03). MP, muscularis propria; SS, subserosa.

 


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  		FIG. 5. Disease-specific survival for patients with pT2pN1 gastric cancer stratified according to whether at least 15 lymph nodes (LN) (>=15 LN, n = 117 patients) or fewer than 15 lymph nodes (<15 LN, n = 35 patients) were examined (P = .1). MP, muscularis propria; SS, subserosa.

 


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  		FIG. 6. Disease-specific survival for patients with pT2pN0 gastric cancer and examination of at least 15 lymph nodes stratified according to muscularis propria (MP, n = 57) or subserosa (SS, n = 51) depth of invasion (P = .8)

 


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  		FIG. 7. Disease-specific survival for patients with pT2pN1 gastric cancer and examination of at least 15 lymph nodes stratified according to muscularis propria (MP, n = 52) or subserosa (SS, n = 65) depth of invasion (P = .3)

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study was composed of 362 patients who had had R0 resection of gastric adenocarcinoma, with the primary tumor categorized pT2. The tumor was limited to the MP in 45% and extended to the SS in 55% of patients. Previous studies have also reported approximately equal proportions of the MP and SS subgroups within the pT2 category.7–9 A prominent difference in pathologic characteristics of the two subgroups was in the associated pN categories: 47% of MP tumors were associated with nodal metastases in comparison with 66% of SS tumors, with a significantly lower prevalence of pN2 and pN3 disease for MP tumors than SS tumors (23% vs. 3%, respectively). This observation was not entirely unexpected, given the well-documented correlation between incremental increase in the pT category and prevalence of a higher pN category, using the 1997 AJCC system.2,10,11

For early (pT1) gastric cancer, a definite correlation between depth of submucosal invasion and frequency of lymph node metastases has been demonstrated.12 For the pT2 category of gastric cancer, nodal metastasis (at any stage) has previously been reported with 34% to 37% of MP tumors as opposed to 44% to 60% of SS tumors.7,8 Thus, greater frequency of nodal disease in association with SS tumors than with MP tumors is apparent from earlier studies; the present data additionally demonstrate that more advanced categories of nodal disease were associated with SS tumors than with MP tumors. In addition to observed incidence and extent of nodal disease, SS tumors were larger and more likely to be poorly differentiated compared with MP tumors. Poor differentiation is recognized to be significantly more frequent with advancing depth of the primary gastric tumor and 41% of MP tumors compared with 54% of SS tumors were previously reported as poorly differentiated.13 Based on the above findings, it is apparent that SS tumors are associated with notably adverse pathologic prognostic indices as compared with MP tumors.

In this study, MP tumors were associated with significantly better survival characteristics than SS tumors (actuarial 5-year survival, 64% vs. 49%, respectively). On multivariate analyses, however, depth of mural invasion was not an independent prognostic variable; the pN category and site of the primary tumor were the only independently significant factors predictive of death caused by recurrent disease. The pN category (1997 AJCC classification) is established as the most critical prognostic factor following R0 resection for gastric cancer.2,5,14 The adverse prognostic impact of proximal gastric tumors is also well recognized.2,14,15 Other investigators have also reported significantly different prognoses for patients with MP and SS tumors on univariate analysis but not independently from nodal disease on multivariate analysis.7,8 The significantly higher prevalence of advanced category nodal disease (pN2 and pN3) in association with SS tumors than with MP tumors appears to be the critical determinant, rather than any inherent function of the depth of mural invasion, of the overall difference in survival for the two subcategories.

Detailed evaluation of regional lymph node metastases in gastric cancer has demonstrated that assignment of the pN category is critically dependent on the number of lymph nodes that are pathologically examined.16 Examination of a greater number of lymph nodes results in a "stage-migration" phenomenon17 wherein patients can be reassigned to a higher pN category because of detection of more metastatic lymph nodes with examination of a bigger sample. Such stage migration results in improved survival characteristics for each pN category of gastric cancer.2,5,15 The current AJCC manual requires that a minimum of 15 lymph nodes should be examined for accurate nodal staging with optimal prognostic discrimination.6 In the present study, disease for 77% of the entire cohort was staged by examination of 15 or more lymph nodes. For the pN0 category, such accurately staged disease had significantly better survival characteristics for patients than those who had been assigned to the pN0 category by examination of fewer than 15 nodes. Importantly, the survival benefits do not become apparent until after 2 years of follow-up. Consequently, any study with inaccurate staging can falsely represent the true outcome and not be identified until after 2 years. The present data are also notable because a previous study from the authors’ institution showed that when patients with pT2N0 disease are grouped together with pT1N1 disease as stage IB gastric cancer, examination of fewer than 15 nodes or 15 or more nodes does not result in any significant difference in survival characteristics (5-year disease-specific survival, 83% vs. 85%, respectively).2 Similarly, the German Gastric Cancer study reported no difference in survival characteristics of stage IB patients when fewer than 25 nodes or 25 or more nodes were examined (5-year survival, 69% vs. 68%).5 For the pN1 category, survival of patients with accurately staged disease was superior to others, although the difference did not reach statistical significance, perhaps because of inadequate statistical power. These data are consistent with previous reports that for stage II gastric cancer (pT1N2, pT2N1, pT3N0), examination of more than 15 nodes2 or more than 25 nodes5 results in stage migration with significant improvement in survival characteristics. For patients with accurately staged pN0 disease, both MP and SS tumors were associated with similar survival characteristics and an excellent 5-year disease-specific survival rate of approximately 90%. Others have also recently reported equally good survival following R0 resection and D2 lymphadenectomy with accurately staged pT2N0 gastric cancer.18 Survival characteristics of patients with accurately staged pN1 were also not significantly different for MP and SS subcategories. pN2 or pN3 disease, however, was almost exclusive to SS tumors and was associated with a dismal prognosis that contributed to the overall worse outcome of the SS subgroup.

In conclusion, SS tumors are associated with significantly worse prognosis than MP tumors, but this is a function of the significantly higher prevalence of pN2 and pN3 disease with SS tumors and not depth of mural invasion per se. With accurate lymph node staging (examination of 15 or more regional lymph nodes), patients with MP and SS tumors have similar survival characteristics within pN0 and pN1 categories. Consequently, substratification of the current pT2 category for gastric cancer is not indicated when accurate lymph node staging is performed. The staging advantage with examination of 15 or more regional lymph nodes for assignment of the pN category, specifically in association with the pT2 category, is confirmed by this study. Patients with pT2 tumors and accurately staged pN0 disease have an excellent prognosis and are unlikely to benefit from adjuvant chemoradiation. Furthermore, in protocols administering neoadjuvant therapy great caution should be exercised before including tumors that have been clinically staged as T2, especially those that are limited to the muscularis propria.


   FOOTNOTES
 
pT2 gastric adenocarcinoma may be limited to the muscularis propria or extend to the subserosa. Subserosal tumors were associated with a significantly higher prevalence and greater extent of nodal metastasis but depth of invasion was not an independently significant prognostic indicator.

Received for publication September 11, 2002. Accepted for publication May 6, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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