Similar to other subtypes, SRC was found mostly in the lower third of the stomach. In terms of Lauren's classification, most SRC (96.4%) were classified as diffuse-type, and most cases of WMD (94.8%) were classified as intestinal-type. In cases of PD, 61.1% were classified as diffuse-type, whereas 27.8% were intestinal-type.
The median length of follow up was 63.9 months. KM curves according to pathologic classification are shown in Figure 2. SRC had significantly better OS than non-SRC (10 year OS: 80% vs 70%; P < 0.001; Fig. 2A). Intriguingly, when all patients were divided into early gastric cancer (EGC) and advanced gastric cancer (AGC) groups, SRC displayed significantly better survival than non-SRC in EGC (10 yr OS: 95% vs 85%; P < 0.001; Fig. 2B); however, the survival was overturned in AGC (10 yr OS: 53% vs 54%; P = 0.049; Fig. 2C).
We then compared the OS of SRC with that of non-SRC after dividing the latter into WMD and PD groups (Figs. 2E–I). By peforming a pair-wise comparison, we found that SRC showed a significantly better OS than both WMD and PD in EGC (10 yr OS: SRC: 95%; WMD: 84%; PD 89%; SRC vs WMD and PD: P < 0.001; Fig. 2E). Interestingly, the OS of PD was significantly longer than WMD (KM P < 0.001). On the other hand, SRC and PD demonstrated significantly worse OS than WMD in AGC (10 yr OS: SRC: 53%; WMD: 58%; PD: 52%; WMD vs SRC and PD: P < 0.001; Fig. 2F). However, the OS of SRC and PD were not significantly different on pair-wise comparison analysis.
Regarding to individual stages, SRC showed the best survival outcome, followed by PD and WMD in stage I (10 yr OS: SRC: 96%; PD: 89%; WMD 83%; SRC vs WMD and PD: P < 0.001; Fig. 2G). Meanwhile, in stage II, no statistically significant differences were observed among the three groups. In stage III, the worst survival was observed for SRC, followed by PD and WMD (10 yr OS: SRC: 32%; PD: 37%; WMD 40%; SRC vs WMD: P < 0.001; SRC vs PD: P = 0.086; Fig. 2G). These survival trends were also applied to the RFS of respective groups, as shown in Supplementary Figure 1 http://links.lww.com/SLA/B27.
Predictors of Recurrence and Mortality
The unadjusted bivariate analysis results of the RFS and OS of all patients are shown in Supplementary Table 1, http://links.lww.com/SLA/B27. In all patients, SRC (vs non-SRC) was the factor associated with reduced recurrence and mortality. However, when compared with WMD, SRC was not associated with recurrence and mortality.
Thereafter, we performed an unadjusted analysis for RFS and OS divided by EGC and AGC (Table 4). In EGC, SRC was associated with reduced recurrence and mortality, comparing both with non-SRC and WMD. Meanwhile, in AGC, SRC (vs WMD) was associated with increased recurrence and mortality, and SRC (vs non-SRC) displayed a borderline significance in increased recurrence and mortality in AGC (RFS: Cox hazard ratio, (HR) 1.15; 95% confidence interval (CI) 0.99 to 1.34; P = 0.066; OS: Cox HR 1.15; 95% CI 1.00 to 1.33; P = 0.050).
Multivariable analysis results for EGC and AGC using Cox's proportional hazard model after adjustments for age, sex, and stage are listed in Table 5 and Supplementary Table 2, http://links.lww.com/SLA/B27. SRC (vs WMD) was an independent favorable predictor of recurrence and mortality in EGC (RFS: Cox HR 0.37; 95% CI 0.19 to 0.71; P = 0.003; OS: Cox HR 0.66; 95% CI 0.44 to 0.98; P = 0.041). On the other hand, in AGC, SRC (vs WMD) was an unfavorable predictor of RFS and OS (RFS: Cox HR 1.22; 95% CI 1.02 to 1.46; P = 0.033; OS: Cox HR 1.45; 95% CI 1.22 to 1.71; P < 0.001). In the case of SRC (vs non-SRC), whereas it was an independent favorable predictor of recurrence and mortality in EGC (RFS: Cox HR 0.40; 95% CI 0.21 to 0.76; P = 0.005; OS: Cox HR 0.66; 95% CI 0.45 to 0.99; P = 0.043), it had no significant value in predicting recurrence in AGC (RFS: Cox HR 1.11; 95% CI 0.96 to 1.30; P = 0.170).
Traditionally, gastric cancer has been classified by two morphological differences: intestinal type and diffuse type. In males, intestinal type is more common, and the incidence rises faster with age, whereas diffuse type affects younger people—frequently females. The recent decline in the overall incidence of gastric cancer in Asia stems from the decrease in intestinal type and has been correlated with the corresponding decrease in Helicobacter infestation.9 However, diffuse type, which is uniformly distributed worldwide and continues to increase, is worrisome given that it is thought by Western researchers to have a worse prognosis. Asian researchers have asserted that SRC is not necessarily prognostically worse than non-SRC. However, many of the studies have included only small-sized heterogenous patients including unresected or noncuratively resected cases, early-stage disease, and even metastatic disease. In addition, most studies compared SRC with heterogeneous non-SRC tumors after merging them into a single group. Thus, to the best of our knowledge, this study currently has the largest dataset for SRC analysis in Asia in which we enrolled only patients who were guaranteed to have had D2 dissection and R0 disease, believing that a more clarified natural course of SRC can be obtained from a more homogenous dataset. Furthermore, tubular AC, which comprises the largest portion of gastric cancer, was redivided according to the differentiation, which enables the correction of internal heterogeneity within the group.
We reaffirmed that SRC in an Asian population has distinct features from those of tubular AC. First, the stage distribution at diagnosis was skewed to early-stage, and 60% of SRC cases were EGC. This finding did not align with a previous study that reported a more frequent presentation in late-stage.7 This finding may be largely because of the nationally sponsored screening program. The second feature was the transition of prognosis as disease progressed. Although SRC in EGC had better survival than non-SRC, this was reversed in AGC, with SRC showing a worse prognosis than non-SRC and particularly WMD. These results might suggest that driver mutations controlling the metastatic potential of SRC can occur late in the course of disease. The third feature was early-age onset and a higher female ratio, which was in accordance with previous studies. We observed an onset that was about 7 years earlier in SRC patients than in tubular AC patients, and over half of the patients were female, despite the fact that gastric cancer is widely known to be a male-dominant cancer. All of these findings strengthen the idea that SRC is a form of disease distinct from tubular AC.10–12
The characteristics and prognosis of SRC mentioned above are similar to those suggested in hereditary diffuse gastric cancer (HDGC). HDGC is a disease inherited by autosomal dominant patterns and is characterized by the early-age onset of SRC. SRC in HDGC has the unique characteristic of being indolent in the mucosal layer for a prolonged period at early stages, although eventually displaying aggressive phenotypes, and such traits of HDGC are similar to those shown by SRC in this study. The E-cadherin (CDH1) gene was reported to be relevant to HDGC; however, the germ-line mutation of the CDH1 gene comprised only 1% to 3% of gastric cancer.13,14 However, recently published studies have revealed that somatic mutations of the CDH1 gene are also relevant to diffuse-type gastric cancer.15,16 Therefore, further study is warranted to provide clues regarding the genetic alterations of SRC and its drastic prognosis change.
We believe that stage-adjusted analysis is important in clarifying the prognosis of SRC, which may explain why Western countries that have low EGC prevalence have reported that SRC has a poor prognosis. However, Asian countries that have a widely accepted early detection program, a standardized surgical procedure, and prevailing adjuvant therapy have recently criticized this idea. They have tried to compare the prognosis between SRC and non-SRC; however, the small sample size has been a limitation.6,17,18 A recent American study utilizing Surveillance, Epidemiology, and End Results data adopted stage adjustment to overcome these limitations and demonstrated that SRC is not a negative prognostic indicator.7 However, a large proportion of the patients did not undergo surgical resection, meaning that concerns exist with respect to the reliability of stage and the application of the exact definition of SRC. In addition, it compared SRC with non-SRC after merging non-SRC tumors into a single group for outcome comparison, which is an oversimplification of this heterogeneous disease. This study also demonstrated that SRC confers worse prognosis than WMD in AGC. However, this difference in prognosis was not observed when SRC was compared with non-SRC tumors in terms of recurrence, as PD that has a similar prognosis to that of SRC in AGC was included in the non-SRC group. In this aspect, our study was in line with the report by Bamboat et al,8 which, despite its small sample size, suggested that the prognosis of SRC could be stage-dependent.
Another point of this study was the fact that long-term survival data was used, including recurrence status (collected from a close follow-up program); however, this data also limited our study because of the retrospective nature of its collection. In addition, this study only included patients with surgically resected cancer and did not involve patients with metastatic disease, limiting our knowledge of the full spectrum of SRC. However, as patients with stage IV disease are treated with palliation-aimed chemotherapy, they may show different prognoses; thus, another study that analyzes this particular cohort of patients is needed. Another limitation of the current study was the differences in gastric cancer biology between Eastern and Western countries. Because this study was performed only with Asians, the presented data cannot represent the characteristics of western gastric cancer, where cancers of esophagogastric junction and upper stomach were predominant. Therefore, further stage-adjusted studies for western SRC gastric cancer are required to confirm the findings of the current study.
This study suggests that early-stage SRC could be indolent, demonstrating that more than half of SRC cases are presented as EGC. In addition, SRC in EGC confers a more favorable prognosis after curative resection than WMD. On the other hand, SRC in AGC bestows a worse prognosis than WMD. Therefore, the context-dependent nature of SRC must be considered when predicting its prognostic impact.
The authors deeply appreciate the great help provided by the Gastric Cancer Center Team, the clinical research coordinator, and the pathology team in Yonsei Cancer Center.
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Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
gastric cancer; prognostic factor; signet ring cell carcinoma