A total 167,747 patients who underwent gastric cancer, 1006 patients (0.6%) were second primary gastric cancer which meet the multiple primary criteria of SEER. Among these 1,006 patients, 93 (9.2%) met the GSC criteria and 282 (28.0%) met the RGC criteria (Fig. 1).
The incidence trend of RGC and GSC were shown in Figures 2 and 3. We can observe that both the RGC and GSC were increased in the following years. The increase was more obvious after 2007 in both groups.
The first primary gastric cancer characteristics of two study patients are described in Table 1. For the group of GSC, 70 (75.3%) were male, while 163 (57.8%) were male in the RGC group (P=0.003). The mean age at diagnosis for the first cancer of GSC group (FGSC) was 60.1 years, and those for the first cancer of RGC group (FRGC) were 65.9 years (P<0.001). In patients with staging, most patients had stage I/II disease, 95.2% for FGSC and 84.1% for FRGC（p＜0.322）. The most location both of two groups were low gastric, include gastric antrum and pylorus, 44（47.3%）in FGSC and 133（47.2%）in FRGC.
The characteristics of second gastric cancer are described in Table 2. The mean age at diagnosis for GSC patients was 73.4 years, and the average latency period was 13.34 years. As for RGC group, the mean age was 70.0 years, and the average interval was 4.24 years（p=0.25）. In GSC with staging, 39（70.9%）were stage I/II disease and 10(13.9%) were stage M1, while 89(65.4%) were stage I/II and 38(13.9%) were stage M1 for RGC（p=0.396）.
On univariate analysis, younger age at diagnosis of primary gastric cancer (p< 0.001), male gender (p =0.003) and difference grade (p=0.039) were significantly associated with the GSC (Table 1, Table2).
Both the median CSS and median OS between the GSC and RGC were not statistically significant (40.0 months vs. 25.0 months, p=0.032 and 20.0 months vs. 16.0 months, p=0.547, respectively) (Fig 4). To evaluated the effective of surgery treatment, we compared both RGC and GSC according to CSS and OS. The results showed that surgery treatment or not, the CSS and OS have statistically significant (64.0 months vs. 10.0 months in median OS, p＜0.001) (Fig. 5). Similarly, in GSC group, the median OS were 33 months by surgery treatment and 13 months in patients not underwent surgery (p=0.014) (Fig. 6).
The definition of gastric stump cancer remains controversial. It was first described and defined in 1922 as ‘‘cancer in the remnant stomach after surgery for benign disease at least 5 years’’. Subsequently, studies suggested that cancer appeared in remnant stomach after surgery for gastric cancer at least 10 years also classified as GSC in 1982. However, the Japanese Gastric Cancer Association suggested that GSC refers to all cancers detected from the remnant stomach after partial gastrectomy, irrespective of the primary disease and interval. In China, it still suggested that the time interval of GSC must at least 10 years after surgery for first gastric cancer . The time interval of GSC was varied in previous studies. Since the rarely morbidity and long-time follow up, the clinicopathology, treatment and the definition of GSC following resection of gastric cancer lacks of a large sample study.
Previous studies often focus on compare the clinicopathology of GSC between gastric cancer and benign disease or compare the prognosis of GSC and primary gastric cancer (PGC). Most studies have reported that the prognosis between GSC and PGC have no significant difference[6, 12, 13] and revealed that the 5-year survival rates were 41.7 % vs. 45.2 % .
With increasing number of partial gastrectomy for gastric cancer and the number of patients with long-term survival after gastrectomy, the number of patients with GSC following resection of gastric cancer has increased[2, 14]. The present study also approved this trend. This raises two practical questions: 1) Should the interval of GSC following the first resection for malignant disease be at least 10 years? 2) How to treatment base on TMN stage after the normal anatomic structure has been destroyed?
In order to answer the first question, we compared the clinicopathology between GSC and RGC, male and younger patients may more likely to develop GSC and there was no statistically significant on others variable. This difference may be explained that younger and early gastric cancer patients may more likely to have long-term survival more than 10 years. On the other hand, the prognosis was not significant difference between GSC and RGC. Thus, we suggest that the definition of GSC should not be limited to 10 years after surgery. However, different to the traditional recurrence of gastric cancer, in the present study, RGC were classified as multiple primary gastric cancer by SEER database, which was defined as the following rules: 1) Tumors diagnosed more than one year apart, and 2) Tumors with ICD-O-3 histology codes that are different at the first (x xxx), second (x xxx) or third (x xxx) number are multiple primaries. 3) These rules are NOT used for tumor(s) described as metastases. Based on the present study outcome and this definition, we suggest the definition of GSC may be based on the following rules: 1）cancer occur in the remnant stomach after surgery for benign disease at least five years and those after surgery for gastric cancer at least 10 years. 2) Or tumors with difference histology between the primary cancer and second cancer after surgery within 10 years. Similarly, many previous study defined GSC as cancer that occurs within 10 years following the initial gastrectomy for gastric cancer and is thought to have developed independently of the initial lesion[2, 15]. With the development of molecular markers, the analysis of molecular genetic characteristics might be expected to improve the specificity of the definition of GSC.
In order to answer the second question, we evaluated the effective of surgery treatment for GSC and RGC. The result showed that surgery still suit for GSC and RGC since the satisfactory prognosis compare to those no underwent surgery. Previous studies considered that although previous gastric resection tends to render surgery for GSC more challenging, due to adhesions and anatomical changes, R0 resection remains as the best treatment for GSC[14-17]. However, due to the anatomical changes for first gastric cancer, the patterns of lymph drainage from lesions in the remnant stomach were also changed. Studies have shown that in most patients with previous cancer, lymph drainage from the remnant stomach was newly developed to the lower mediastinum, to the jejunal mesentery, or to the duodenal side through the anastomotic line made at the initial surgery. The reason was probably due to the surgical ablation of preexisting lymphatics and lymph nodes in the peri-gastric areas at the initial cancer surgery[15, 18, 19]. This situation reveals that the N stage of TNM staging system based on primary gastric cancer is unsuitable for GSC patients. Base on this conclusion, some studies recommended develop a new and more suitable staging systems for GSC[12, 20]. However, a consensus has not been reach on the new N stage. More studies are needed to explore a suitable N stage and appropriate treatment base the new stage. For the surgery treatment, R0 resection should comprise a total gastrectomy and radical lymph node resection, especially the jejunal mesentery of the anastomosis.
Although the present study has revealed some significant clinical information, there were some limitations. The SEER database did not provide information on the type of resection (R0, R1 or R2), lymph node dissected pattern, or pattern of recurrence. Furthermore, for the classification of multiple primary gastric cancer, a second primary versus a recurrence can be complex. There may be some misclassification cases on the study. In addition, the missing variable on the present study may cause bias.