The purpose of this study was to determine the immunologic role of lymph node (LN) and stage migration by assessing LN count and metastatic LN count.
A total of 2,117 patients with gastric adenocarcinoma located in the body and antrum who underwent distal/subtotal gastrectomy with D2 LN dissection between January 1, 1998 and December 31, 2008 were enrolled. LN count and number of metastases were determined in the N1 tier (area of D1 dissection) and N2 tier (area of D2 dissection). The lower and upper quartiles of LN counts in the same pN stage were grouped to compare the prognosis and LN positivity according to the LN tier.
Stage migration from N1 tier to N2 tier occurred in 3.2% of cases. The 5-year disease-specific survival rates of the upper and lower LN count groups within the N1 tier were 91.0% and 86.7% (P=0.01), respectively. LN positivity in the N2 tier of the lower LN count group was higher than that of the upper LN count group (14.1% vs. 8.2%, P<0.01). Stage migration in the N2 tier of the lower LN count group was also higher than that of the upper LN count group (4.6% vs. 1.8%, P<0.01).
The lower LN count group had a decreased survival rate compared to that of the upper LN count group, suggesting that perigastric LN has an immunological defense role in weakening the disseminating power of metastatic tumor cells, as indicated by the LN count.
The Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) classifies the N stage of gastric cancer based on the metastatic lymph node (LN) count [
Recently, suspicions have been raised that stage migration is exaggerated in meta-analysis studies, arguing that although there is evidence that fat clearance and methylene blue staining during LN harvest increases LN count [
The purpose of this study was to determine the immunologic role of LN and stage migration by assessing LN count and metastatic LN count.
Among 3,041 patients, 2,841 received radical distal/subtotal gastrectomy with D2 LN dissection between January 1, 1998 and December 31, 2008. Patients with cancer located in the upper third, who received neoadjuvant chemotherapy, and who previously underwent surgery for other intra-abdomen cancer or gastric cancer surgery were excluded from this study. Finally, the remaining 2,117 patients were included in the present study.
The hospital in which the surgeries were performed is a center that specializes in gastric cancer surgery and in which more than 150 surgeries are performed annually. Two specialized surgeons (DHY and CYK) performed the surgeries in the present study. Depending on the location of the primary tumor, one-half or two-thirds of the stomach was eliminated, and
The pN stage was performed according to the UICC/AJCC TNM classifications 7th edition. Japanese Gastric Cancer Association recommendations were followed for each LN station, D1 and D2, for LN dissection. LN stations 1, 3, 4sb, 4d, 5, 6, 7 were included in the D1 area, while both the D1 area and LN stations 8a, 9, 11p, and 12a were included in the D2 area. First, the pN stage was determined based on metastatic LN count in the D1 area. LN positivity changes in LN 8a, 9, 11p, and 12a areas were observed, and finally, changes in stage migration in the D2 area were recorded. The disease-specific five-year survival rate in pN stage within the D1 area was also calculated in order to study the relationship between LN positivity and stage migration.
LN counts were divided into lower and upper groups according to quartile. Because LN count was in proportion to metastatic LN count, as shown in
Differences in LN positivity and stage migration were observed between the lower and upper LN count groups. In order to compare disease-specific 5-year survival rates in the D1 and D2 areas, the lower and upper LN counts were calculated for both areas. The lower and upper LN count groups in D1 area included 570 and 575 patients, respectively. The lower and upper LN count groups in D2 area included 566 and 570 patients, respectively. Differences in clinicopathologic features were assessed between the lower and upper LN count groups for patient age, sex, body mass index (BMI), tumor size, extent of lymphadenectomy, tumor differentiation, Lauren classification, presence of lymphatic invasion, pT stage, pN stage, and TNM stage.
In patients with multiple synchronous gastric cancers, the lesion with the deepest infiltration of the gastric wall was regarded as the main lesion. The clinicopathological characteristics of the main lesion were used for the analysis. Resections were deemed radical when no gross residual disease was evident at the time of operation, with tumor-free resection margins on histological examination.
Not all patients were administered postoperative chemotherapy. Patients with advanced gastric cancer more than TNM stage II were administered 5-fluorouracil-based postoperative chemotherapy starting within three weeks after surgery. No patients were administered postoperative or preoperative radiotherapy.
In general, the follow-up consisted of abdominopelvic computed tomogram every 6 months for 5 years after surgery and esophaggastro-duodenoscopy annually for 5 years after surgery. Follow-up of patients was completed until the cutoff date of 31 December, 2013. The median follow-up interval at the cutoff date was 50 months (range, 0–232 months). At the time of the last follow-up, 334 patients (11.8%) had been lost to follow-up.
All statistical analyses were performed using SPSS 15.0 (SPSS, Inc., Chicago, IL, USA). Categorical variables were compared by chi-square tests. Correlation analysis was performed with two-tailed test, and Pearson coefficients were calculated. Disease-specific survival rates were determined using the Kaplan-Meier method and compared using log-rank tests. For all analyses, P-values of < 0.05 were considered statistically significant.
All information was obtained with appropriate Institutional Review Board waivers, and data were collected without revealing any personal information. The study was approved by the Ethical Review Board at the Chonbuk National University, Jeonju, Korea (2012-01-003).
The mean age of patients was 59 years (median, 60; standard deviation [SD], 11.3; range, 22–91 years), with a male-to-female ratio of 2.1:1. The clinicopathologic characteristics of the lower and upper LN count groups in the D1 and D2 areas are shown in
There were 677 patients with D2 LN dissection (32.5%), and 1,430 patients were diagnosed with over D2 LN dissection (67.5%). The TNM stage for the patient group was as follows: Ia, 1,465 (55.2%); Ib, 221 (10.4%); IIa, 161 (7.6%); IIb, 178 (8.4%); IIIa, 109 (5.1%); IIIb, 141 (6.7%); and IIIc, 139 (6.6%). The median LN count for the total patient group was 45 (mean, 48.0; SD, 20.2; range, 6–168). The median LN count for the D1 area was 25 (mean, 26.6; SD, 12.6; range, 2–112). The median for the LN 8a, 9, 11p, and 12a areas were 17 (mean, 18.2; SD, 8.9; range, 0–72). The median LN count for the D2 area was 42 (mean, 44.8; SD, 17.4; range, 6–149).
The median positive LN count in the D1 area was 4.0 (mean, 5.8; SD, 7.5; range, 1–43) and 639 patients (30.2%) showed LN positivity. The median positive LN count for the LN 8a, 9, 11p, and 12a areas was 2.0 (mean, 2.9; SD, 4.4; range, 1–33), with 223 patients (10.5%) showing LN positivity. Two hundred and twelve patients showed LN positivity in both areas. Only 11 patients (0.5%) showed negative results in the D1 area but positive in the D2 area. The median positive LN count in the D2 area was 4.0 (mean, 6.7; SD, 9.7; range, 1–73) and 650 patients (30.7%) showed LN positivity in the LN 8a, 9, 11p, and 12a area, which included 11 patients with LN positivity.
Sixty-eight patients (3.2%) showed stage migration between the D1 and D2 areas. Subdividing according to pN stage within the D1 area in order to observe the changes in LN positivity and stage migration in the LN 8a, 9, 11p, and 12a areas revealed LN positivity and stage migration of 0.7% and 0.7%, respectively, for pN0; 13.7% and 7.7%, respectively, for pN1; 26.5% and 10.5%, respectively, for pN2; 48.4% and 14.3%, respectively, for pN3a; pN3b had an LN positivity of 83.5%, showing an increase with increased pN stage (
One minus the cumulative 10-year disease-specific survival rates for pN stage within the D1 area were 0.8%, 15.8%, 17.3%, 46.7%, and 81.0% for pN0, pN1, pN2, pN3a, and pN3b, respectively, which were similar to the LN positivity rates of 0.7%, 13.7%, 26.5%, 48.4%, and 83.5% for pN0, pN1, pN2, pN3a, and pN3b, respectively (
Analysis of the differences in LN positivity within the LN 8a, 9, 11p, and 12a areas in the lower and upper LN count groups within the D1 area revealed that the total positivity rate in the lower group was 14.0% compared to 8.2% in the upper group and was also higher for each pN stage (P= 0.01) (
The disease-specific five-year survival rates in the lower and upper LN count groups for the D1 area were 86.7% and 91.0%, respectively (P= 0.01) (
The important initial event by which solid tumors spread occurs through the lymphatic system. Since metastatic regional LN is considered a prognostic indicator, it is important to avoid missing positive LNs. To obtain sufficient LN count is not only by the range of LN dissection but the motivation of the pathologist as well. While the national guidelines suggest harvesting more than 15 LNs, up to three times this number is required to approach the Japanese standard. Therefore, there is an increased risk for stage migration with inappropriate LN dissection or when the pathologist is passive at finding LNs [
The role of LNs in cancer progression is still not fully understood. Multiple steps are necessary to successfully seed from tumor cells passing the lymphatic vessel to the draining LN that causes lymphatic metastasis, which is different from previous hypotheses. Therefore, successful LN metastasis requires that both tumor and host factors be fulfilled. The presence of a few LN metastases in solid tumors suggests that other clones from metastatic cells from the primary cancer site have escaped in large numbers. However, before the LN count can increase throughout the body, the LN count of the host may act as an immunologic defense barrier. There is no doubt that the immune system has an important role in patient prognosis. For example, tumor-infiltrating lymphocytes are linked to a favorable prognosis, in which the immune system plays an important role. However, to the authors’ knowledge, few reports have shown a direct relationship between LN count and immunologic response. Kim et al. [
While LN count and metastatic LN count are in proportion, the reason for differences between individuals and the direct parameter for immunologic response is unknown. Previous reports suggest that younger patients have higher LN counts, that Asians and non-Hispanic blacks have an increased frequency of higher LN count compared to that of non-Hispanic whites, and that patients diagnosed with higher stage and operated on have a higher LN count. The significant factors in our study included age under 60 years, low BMI, tumor size > 3 cm, poorly-differentiated adenocarcinoma, diffuse-type Lauren classification, more extensive lymphadenectomy, and advanced pT and pN stage.
With low motivation during LN harvest along with inappropriate LN dissection, the possibility of stage migration due to missing positive LN does not disappear. In other cases, LN count does not need to be reflected in the patient’s survival as an immunologic indicator [
In conclusion, LN positivity and stage migration in the D1 and D2 LN dissection areas showed a trend for increasing pN stage; however, the overall trend was not statistically significant. The lower LN count group had a worse survival rate compared to that of the upper LN count group, suggesting that perigastric LN has an immunological defense role in weakening the disseminating power of metastatic tumor cells, as indicated by the LN count.
This study has some limitations. First, our long-term retrospective study design in a single Eastern institution could cause selection bias. Second, there may be treatment biases due to the progression of surgical skill, including LN dissection, and chemotherapy. Third, while cancer-related survival was the study end-point, the reported cause of death report was not always accurate.
No potential conflict of interest relevant to this article was reported.
Lymph node counts (LNCs) were divided into lower and upper groups according to quartile. (A) LNC increased in proportion to metastatic LNC (Pearson coefficient=0.30, P<0.01). In order to eliminate selection error, we marked the upper and lower LNC group through making a quartile for each number of the metastatic lymph node (LN). (B) LNCs within the LN 8a, 9, 11p, and 12a were proportionate with LNC within the D1 area, having a Pearson coefficient of 0.27 (P<0.01).
The pN stage and stage migration. Subdividing according to pN stage within the D1 area shows the ratio between the lymph node (LN) positivity in the LN 8a, 9, 11p, 12a area and the pN stage within the D1 area shows the frequency of stage migration in the D2 area. LN positivity and stage migration increased with pN stage.
The 10-year disease-specific survival rate for pN stage within D1 are 1– the cumulative 10-year disease-specific survival rate similar to the lymph node (LN) positivity rate in LN 8a, 9, 11p, 12a area.
The lymph node (LN) positivity and stage migration. (A) The ratio of LN positivity within LN 8a, 9, 11p, 12a area is shown through pN stage within the D1 area. While LN positivity increases with pN stage, there was more in the lower group of lymph node count (LNC) than the upper group (P=0.01). (B) pN stage within the D1 area shows the frequency of stage migration in the D2 area. While the stage migration increases with pN stage, there was a higher frequency in group of LNC (P=0.01).
The 5-year disease-specific survival rate. (A) Five-year disease-specific survival rates in the upper and lower lymph node count (LNC) group for the D1 dissection area was 91.0% and 86.7% (P=0.01) while the 5-year disease-specific survival rates for the LNC group for the D2 dissection area was 91.5% and 88.5% (P=0.04). (B–F) Five-year disease-specific survival rate of pN0 through pN3b is shown as well as the survival rate for the D1 and D2 dissection areas were calculated. There was not a large difference in the pN0 5-year disease-specific survival rates from pN1 through pN3 were low in the lower LNX group.
Clinicopathologic characteristic of the lower and upper quartile group of lymph node count in the D1 and D2 dissection area
Characteristic | LNC quartile of D1 dissection area | LNC quartile of D2 dissection area | ||||
---|---|---|---|---|---|---|
|
| |||||
Lower (n= 570) | Upper (n= 575) | P-value | Lower (n= 566) | Upper (n= 570) | P-value | |
Sex | 0.23 | 0.89 | ||||
Male | 396 (69.5) | 380 (66.1) | 393 (69.4) | 398 (69.8) | ||
Female | 174 (30.5) | 195 (33.9) | 173 (30.6) | 172 (30.2) | ||
| ||||||
Age (yr) | < 0.01 | 0.01 | ||||
< 60 | 256 (44.9) | 324 (56.3) | 262 (46.3) | 322 (56.5) | ||
≥ 60 | 314 (55.1) | 251 (43.7) | 304 (53.7) | 248 (43.5) | ||
| ||||||
BMI (kg/m2) | < 0.01 | < 0.01 | ||||
< 20 | 73 (12.8) | 122 (21.3) | 66 (11.7) | 133 (23.4) | ||
20–25 | 289 (50.7) | 297 (58.0) | 279 (49.4) | 335 (58.9) | ||
> 25 | 208 (36.5) | 110 (20.7) | 220 (38.9) | 101 (17.7) | ||
| ||||||
Tumor size (cm) | 0.04 | < 0.01 | ||||
≤ 3 | 348 (61.7) | 315 (55.7) | 353 (62.9) | 287 (51.2) | ||
> 3 | 216 (38.3) | 251 (44.3) | 208 (37.1) | 274 (48.8) | ||
| ||||||
Extent of lymphadenectomy | 0.85 | < 0.01 | ||||
D2 | 184 (32.3) | 189 (32.9) | 229 (40.5) | 157 (27.5) | ||
Over D2 | 386 (67.7) | 386 (67.1) | 337 (59.5) | 413 (72.5) | ||
| ||||||
Differentiated | 0.01 | 0.01 | ||||
Well | 325 (57.0) | 287 (49.9) | 330 (58.3) | 295 (51.8) | ||
Poorly | 245 (43.0) | 288 (50.1) | 236 (41.7) | 275 (48.2) | ||
| ||||||
Lauren | 0.02 | 0.04 | ||||
Intestinal | 265 (60.0) | 228 (52.2) | 276 (61.6) | 227 (54.8) | ||
Diffuse | 177 (40.0) | 209 (47.8) | 172 (38.4) | 187 (45.2) | ||
| ||||||
Lymphatic invasion | 0.15 | 0.29 | ||||
Negative | 287 (69.2) | 327 (73.6) | 286 (67.5) | 293 (70.9) | ||
Positive | 128 (30.8) | 117 (26.4) | 138 (32.5) | 120 (29.1) | ||
| ||||||
pT stage | 0.44 | 0.01 | ||||
pT1 | 352 (61.8) | 326 (56.7) | 356 (64.5) | 301 (52.8) | ||
pT2 | 67 (11.8) | 72 (12.5) | 65 (11.5) | 82 (14.4) | ||
pT3 | 65 (11.4) | 72 (12.5) | 59 (10.4) | 70 (12.3) | ||
pT4 | 86 (15.0) | 92 (16.0) | 77 (13.6) | 117 (20.5) | ||
| ||||||
pN stage |
0.58 | 0.51 | ||||
pN0 | 382 (67.0) | 395 (68.7) | 384 (67.8) | 378 (66.3) | ||
pN1 | 63 (11.1) | 59 (10.3) | 63 (11.1) | 57 (10.0) | ||
pN2 | 49 (8.6) | 56 (9.7) | 49 (8.7) | 65 (11.4) | ||
pN3a | 35 (6.1) | 36 (6.3) | 34 (6.0) | 39 (6.8) | ||
pN3b | 41 (7.2) | 29 (5.0) | 36 (6.4) | 31 (5.4) | ||
| ||||||
TNM stage |
0.83 | 0.12 | ||||
Ia | 313 (54.9) | 300 (52.2) | 323 (57.1) | 277 (48.6) | ||
Ib | 58 (10.2) | 62 (10.8) | 56 (9.9) | 62 (10.9) | ||
IIa | 38 (6.7) | 45 (7.8) | 39 (6.9) | 49 (8.6) | ||
IIb | 46 (8.1) | 51 (8.9) | 44 (7.8) | 55 (9.6) | ||
IIIa | 37 (6.5) | 29 (5.0) | 34 (6.0) | 33 (5.8) | ||
IIIb | 39 (6.8) | 43 (7.5) | 33 (5.8) | 40 (7.0) | ||
IIIc | 39 (6.8) | 45 (7.8) | 37 (6.5) | 54 (9.5) |
Values are presented as number (%).
LNC, lymph node count; BMI, body mass index.
Final stage including D2 and over D2 lymph node dissection patients.