Clinicopathological difference of gastric cancer between lesser and greater curvature

Background: Gastric cancer(GC) is heterogeneous disease, recent years has established a molecular classication and described distribution of molecular subtypes in stomach. However, the clinicopathological difference of gastric cancer between lesser and greater curvature is still unknown. In this study, we investigated the clinicopathological difference of gastric cancer between lesser and greater curvature. Methods: Between January 2010 and August 2014, 1249 consecutive patients with GC located at lesser or greater curvature were treated in our surgery department, the data of demographic, pathological type, differentiation, tumor size, TNM stage, tumor markers, operative methods, complications and follow-up data were analyzed by univariant analysis and Kaplan-Meier analysis retrospectively. Results: We found the tumor size in lesser curvature was larger than in greater curvature (4.95±2.57 vs. 4.43±2.62cm, P=0.034); The patients with gastric cancer in lesser curvature had a higher incidence of total gastrectomy, but a lower incidence of distal gastrectomy than it in greater curvature (60.2% vs. 43.2%, and 34.8% vs. 49.2%, P=0.002); The 5-year survival rate of gastric cancer between the curvatures was not statically signicant (62.6±0.02% vs.66.1±0.06%, P=0.496); The rate of EGFR expression in lesser curvature was 40.55%, which was signicantly higher than that in greater curvature (25.92%(cid:0)P=0.024), and the 5-year survival rate in patients with EGFR positive was 50.8±0.06%, which was signicantly lower than that in patients with EGFR negative (64.8±0.03%(cid:0)P=0.021). Conclusions: Our results suggest that the clinicopathological difference of gastric cancer is signicant between lesser and greater curvature. Emphasizing the difference contribute to improve outcome of treatment.

localized tumor increased, but regional tumor decreased (9). Cristescu demonstrate microsatelliteunstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum, and the tumors have the best overall prognosis and the lowest frequency of recurrence. (10) Lesser curvature near to stomachic angular is the most common location for GC, however, the tumor located in greater curvature is less than 3%. (11) Till now, the clinicopathological difference of gastric cancer between greater and lesser curvature is unclear. Therefore, in this study, we investigated the difference between lesser curvature and larger curvature and aimed to provide powerful evidence for GC treatment.

Results baseline characteristics.
A total of 1249 cases met the inclusion criteria and were analyzed in this cohort study ( Figure. 1), of whom 1124 cases were distributed in lesser curvature of gastric, and other 125 cases were distributed in greater curvature. The comparison of baseline data between the lesser and greater curvature was described in Table 1. There were no signi cant differences between the lesser and greater curvature regarding preoperative variables, such as age, sex, symptoms, positive sign and blood test. The patients with gastric cancer in lesser curvature had a higher rate of family history of neoplasm than that in greater curvature.(9.4% vs. 4%, P = 0.041). (Table 1)  The concentrate of serum markers of cancers, CEA, CA19-9, CA125 and AFP, were not signi cantly different between lesser curvature and greater curvature. And according to cut-off values, the positive rate of these markers were not signi cantly different yet. (Table 3) The measurement data were described as mean ± SD (standard deviation), and were analyzed by Student t-test; Total no. mean the total specimen detected; n(%) denoted positive specimen and rate. Chi-square test and the Fisher's exact test were used to analyze categorical variables.

Comparison of operative data
The patients with gastric cancer in lesser curvature had a higher incidence of total gastrectomy, but a lower incidence of distal gastrectomy than it in greater curvature(60.2% vs. 43.2%, and 34.8% vs. 49.2%, P = 0.002), Also, the incidence of radical resection in lesser curvature was higher than in greater curvature (96.1% vs. 91.7%, P = 0.002). In addition, the incidence of other organ combined resection was higher in lesser curvature than in greater curvature (17.6% vs. 10.1%, P = 0.012). moreover, the amount of operative bleeding in lesser curvature was larger than greater curvature (272.88 ± 262.27 vs. 218.23 ± 196.37 ml, P = 0.041). but, the operation time was similar between two curvatures. (Table 4) there was no hospital death in this study. The incidence rate of total complications in lesser curvature was not statistically different from that in the lager curvature (6.49% vs. 10.4%, P = 0.102) and anastomotic complications wee similar between curvatures(0.71% vs. 0%, P = 0.344). In addition, there were no differences regarding pulmonary complications, wound rupture, duodenum leak,anastomotic leakage and stricture, and severe bleeding according to the univariate analysis (Table 5).
The data were showed by no. Chi-square test was used to analyze complication incidence.
5-year survival rate between gastric cancer in greater and lesser curvature 1108 Cases had complete follow-up data, and average ow-up time was 29.14 ± 17.09 months (ranged from 0.17 to 66.73 months). The difference of 5-year survival rate between greater and lesser curvature were not statically signi cant by Kaplan-Meier analysis (62.6 ± 0.02% and 66.1 ± 0.06%, P = 0.496). ( Fig. 2A and C) The difference of EGFR expression between greater and lesser curvature The positive rate of EGFR expression in lesser curvature was 40.55%, which was signi cantly higher than that in greater curvature (25.92%,P = 0.024). EGFR expression was negatively correlated with 5-year survive, the survival rate in patients with EGFR positive was 50.8 ± 0.06%, which was signi cantly lower than that in patients with EGFR negative by Kaplan-Meier analysis. (64.8 ± 0.03%,P = 0.021). (Fig. 2B and  D). But the difference of HER2, CD44, CD34, S-100 and c-MET expression was not found between the curvatures. (Table 6).

Discussion
The aim of the present study was to investigate clinicopathological difference of gastric cancer between lesser and greater curvature. We found tumor size, the extent of gastrectomy, postoperative complication and EGFR expression level were signi cantly different between lesser curvature and greater curvature.
In this study, we found gastric cancer were more commonly founded in lesser curvature than in larger curvature. The distributed characteristic of our results was also agreed with the prior studies (11). It has reported H. pylori infection is regard as a de nite environmental risk factor for the development of GC (19),H. pylori infection cause intestinal metaplasia (IM) and atrophy. In addition, mean atrophy and IM scores are higher in lesser curvature of the corpus than in greater curvature (20), moreover, yellowish-white nodules are observed in Helicobacter pylori-associated gastritis, which are frequently observed on lesser curvature of the corpus mucosa in 20%, greater curvature of the corpus mucosa in 0.9%. (21) In addition, Gastric ''crawling-type'' adenocarcinoma (CTAC) is a neoplasm histologically comprising irregularly fused glands with low-grade cellular atypia that tends to spread laterally in the mucosa. CTAC was most frequently located in the lesser curvature of the middle-third of the stomach.(22) Combined with the above studies, our results emphasized the susceptibility of carcinogenesis in lesser curvature of stomach. We found a higher ratio of family history in patients with lesser curvature tumor, this give us sign that gastric cancer in lesser curvature was more frequently correlated with heritage background than in larger curvature.
It has reported that the anatomical location-based classi cation of lymph node metastasis is an important tool for gastric cancer prognosis,(23) and the incidence of lymph nodular metastasis tended to be higher in cases at the lower location than in those at the middle/upper location.(24) Therefore, some authors hypothesize that primary gastric tumors towards the lesser curvature can be treated by a modi ed D2 lymphadenectomy, and for tumors towards the greater curvature, a D1(+) lymphadenectomy always including the no. 7 & 9 lymph node stations complex, might be enough. (25) In this study, we didn't nd the difference of lymph node metastasis between lesser curvature and large curvature. Our result was consistent with the study demonstrated that metastasis of tumors located in greater curvature was similar to lesser curvature (26), but contrast to the study showed the most frequent metastasis were located in the lower third and lesser curvature of the stomach (27).
We investigated the operative mode of gastrectomy in all patients, and found the patients with gastric cancer in lesser curvature had a higher incidence of total gastrectomy, but a lower incidence of distal gastrectomy than it in greater curvature, the incidence of radical resection in lesser curvature was higher than in greater curvature. In addition, the incidence of other organ combined resection was higher in greater curvature than in lesser curvature. Moreover, the amount of operative bleeding in greater curvature was larger than lesser curvature. These results suggest that tumor in greater curvature was more commonly in ltrate adjacent organs such as pancreas and spleen. The incidence rate of total postoperative complications and anastomotic complications were not different between curvatures in this study. Our results were not consistent with the study by Hirota and Kim who report lesser curvature tumor has signi cantly higher frequency of postoperative complications than greater curvature (28), such as prolonged abdominal symptoms, food residue, and perforation. (29) Several studies have reported that the 5-year overall survival rate of gastric cancer were in uenced by tumor size, depth of invasion, lymph node metastasis, and chemotherapy, early detection and radical resection are essential to improve the prognosis of patients gastric cancer (30,31). We found the 5-year survival rate of gastric cancer between greater and lesser curvature was not statically signi cant. Our results were not consistent with the report showed the worse survival at the greater curvature location than lesser curvature of the gastric cancer. (32) In our study, we investigated the expression status of several tumor markers which are closely related with clinicopathologic characteristic and prognosis in GC, and are commonly used in the current clinic. But except for EGFR, none of them were found statically different expression between lesser curvature and larger curvature. We found an increasing expression levels of EGFR in lesser curvature than in lager curvature. This result supplemented for the distribution of EGFR in gastric cancer. In addition, enhancement of EGFR in lesser curvature maybe reveal its new prognostic value in gastric cancer. EGFR is a potential therapeutic target for various cancers including gastric cancer (33). We also found the 5-year survival in EGFR negative group was signi cantly higher than it in EGFR positive group, therefore, our results provided powerful evidence for the therapeutic value of EGFR in gastric cancer.

Conclusion
Our results suggest there exist clinicopathological difference of gastric cancer between lesser and greater curvature. EGFR expression level were also signi cantly different between lesser curvature and greater curvature. These ndings supplement for the distributing characteristics of gastric cancer and contribute to make reasonable treatment.

Consent for publication
All participants gave written consent for their personal or clinical details along with any identifying images to be published in this study.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable requesturrent study are available from the corresponding author on reasonable request

Competing interests
All authors of this study declare no competing interests.

Funding
There was no funding con ict in this study Authors' contributions GCL conceiving and designing the study, and writing the manuscript HWZ and QCZ: providing critical revisions; PY: analyzing and interpreting the data; FNP, LLX and XAW: collecting the data; All authors approved the nal version of the manuscript.
analysis of the comparability of the groups. The concentrate of serum markers of cancers, CEA(Carcinoembryonic antigen), carbohydrate antigen (CA)19 − 9,AFP(Alpha fetoprotein) and CA125,were also detected by radioimmune method in our hospital, and putting 5 ng/ml, 7 ng/ml, 27 U/ml and 35 U/ml as cut-off values respectively, we classi ed the expression level of markers as positive and negative expression.

Perioperative observations
Postoperative data included pathological type, Borrman type, grade of differentiation and tumor size. The histological subtype and pathological stage were determined using the Union for International Cancer Control and TNM classi cation for gastric cancer. Several tumor markers has been con rmed to be closely related with clinicopathologic characteristic and prognosis of GC, and are commonly used in the current clinic, including EGFR(Epidermal growth factor receptor),HER-2(human epidermal growth factor receptor-2) (12-14),S-100(s-100 calcium-binding protein) (15), CD44(16), CD34(17), c-MET(Receptor tyrosine kinase MET) (18). These markers were stained postoperatively by immunohistochemistry and were judged as positive or negative staining by two pathologists.
Patients were performed radical gastrectomy with D2 lymphadenectomy by the method of laparotomy or laparoscopic. The extent of resection of stomach were determined by tumor size, location, in ltration of organ and pathological type, which included total, proximal and distal gastrectomy. And when tumor in ltration with surrounding organ, an enlarged gastrectomy combined with organ resection were performed, but when tumor metastasis profoundly, the explosive or palliative operation was performed. The anastomoses including esophagogastrostomy, gastroduodenostomy and esophagojejunostomy, were performed with 28 mm diameter circular stapler. Operative bleeding and operation time were counted by anesthesia doctor.
Postoperative complications, including anastomotic complication, wound infection, wound rupture, lung infection, bleeding, reoperation, duodenal leak and intestinal obstruction were evaluated. Anastomotic complication assessment was performed using a water-soluble radiological contrast enema at 6-8 days post-operatively. A clinical leak was de ned by extravasation of the contrast medium detected on radiography.

Follow-up Data
All patients were followed for ve years from the beginning of operation. And at the end of follow-up, the status of patients were recorded, which included survival, death, and lost follow-up.
Statistical analysis.
Statistical analysis was performed using SPSS 17 software (SPSS Inc., Chicago, IL, USA). Differences among groups consisted of measurement data were analyzed by students' t test; Differences in expression rate among groups were analyzed by Pearson's Chi-squared (χ2 ) test. The Fisher's exact test was used to assess the difference of positive rate when the number of total cases was less than 40. P value < 0.05 was considered statistically signi cant. Survival analysis were used by Kaplan-Meier. Figure 1 Page 20/20 ow diagraph of data enrollment. Figure 2 the survival difference between lesser curvature and larger curvature in patients with gastric cancer. A).

Figures
the difference of 5-survival rate between lesser curvature and larger curvature. B) the difference of 5survival rate between EGFR-positive group and EGFR-negative group. * denoted there was a statistically difference between the two groups, P value <0.05. C) 5-year survival curve of patients with gastric cancer located in lesser curvature and larger curvature. D) 5-year survival curve of patients with EGFR-positive or with EGFR-negative.