Clinicopathological Characteristics and Prognosis of Upper Gastric Cancer Patients in China: A 32-Year Single-Center Retrospective Clinical Study

Purpose Upper or proximal gastric cancer occurs in the upper third of the stomach between the cardia and a line connecting the greater and lesser curvatures. As it differs from other gastric cancers in pathology and prognosis, we evaluated patient and disease characteristics that might guide improved treatment and survival of upper gastric cancer. Methods We conducted a retrospective analysis of 649 patients with upper gastric cancer and 1551 patients with lower gastric cancer and R0 radical surgery at our institution between January 1980 and December 2012. Results Survival after radical surgery for upper gastric cancer was 77.8% at 1 year, 49.6% at 3 years, and 41.1% at 5 years. The corresponding rates for lower gastric cancer were 85.9%, 60.0%, and 57.2% (p < 0.001). Upper gastric cancer had a poor prognosis. Sex (p = 0.036), tumor diameter (p = 0.001), macroscopic type (p < 0.001), pTM stage (p < 0.001), tissue differentiation type (p = 0.003), and serosal invasion (p = 0.034) were independently associated with lymph node metastasis. The macroscopic type (p = 0.045), lymphovascular tumor emboli (p = 0.021), and pTNM stage were independently associated with recurrence and metastasis. Survival of 333 patients with D2 total gastrectomy was 81.3% at 1 year, 54.4% at 3 years, and 45.2% at 5 years. The corresponding rates for 316 proximal gastrectomy patients were 75.4%, 44.9%, and 36.7%. Radical total gastrectomy had better survival than radical proximal resection. Conclusions Upper gastric cancers were more aggressive, had a worse prognosis, and were more prone to recurrence and metastasis compared with lower gastric cancers. Survival was better after total gastrectomy than after proximal resection.


Background
Gastric cancer is the sixth most prevalent malignant tumor worldwide and the third leading cause of cancer-related deaths. The International Agency for Research on Cancer estimated that there were about one million new cases of gastric cancer and 782685 deaths from gastric cancer in 2018 [1]. Upper gastric cancer, also known as proximal gastric cancer, occurs below the cardia and above a line connecting the greater and lesser curvatures, and its incidence is increasing [2][3][4][5]. The epidemiology, pathology, surgical treatment, and prognosis of upper gastric cancer differ from those of lower stomach cancer. Its anatomical location makes upper stomach cancer relatively difficult to find, and it lacks specific symptoms at early stages of disease. Diagnosis at a mid or late stage increases the difficulty of treatment and leads to a poor prognosis [4,6,7]. An evaluation of dysphagia may lead to an early diagnosis [8,9]. At present, the choice of surgical treatment has changed from simple anatomy to oncology biology, immunology, and anatomy. The clinical and pathological characteristics of individual upper gastric cancer patients may be of value in choosing surgical options that will improve survival. Radical surgery is currently the most effective treatment, but the extent of lymph node dissection and the optimal surgical procedure may not be easy to determine [10][11][12]. The objective of this retrospective analysis of patient characteristics, surgical treatment, and cancer prognosis was to identify clinical, pathological, and surgical variables that were associated with improved outcomes, prognosis, and survival of those with upper gastric cancer.   Figure 1). Univariate analysis showed that the tumor diameter, macroscopic type, pTNM stage, lymphovascular tumor embolus, serosal invasion, recurrence and metastasis, and postoperative adjuvant chemotherapy were associated with upper gastric cancer prognosis. Survival decreased with pTNM stage local Borrmann type 1 and 2 tumors, smaller tumor diameter, no lymphovascular tumor emboli, no serosal invasion, and no recurrence and/or metastasis. Survival was longer in patients with adjuvant chemotherapy after surgery (Figures 2 and 3). After multivariate analysis, the macroscopic tumor type, recurrence and metastasis, postoperative adjuvant chemotherapy, and pTNM staging were independently associated with upper gastric cancer prognosis ( Table 2). The characteristics of patients with and without lymph node metastasis are shown in Table 3. Metastatic lymph nodes were not found in 231 of the 649 patients with upper gastric cancer (35.6%); 418 (64.4%) had lymph node metastasis. The male : female ratio was 6.7 : 1 in the group without and 3.75 : 1 in the group with lymph node metastasis (p = 0:011). Lymph node metastasis occurred in 72.5% of patients with tumors ≥ 5 cm in diameter and in 52.8% of those with tumors < 5 cm in diameter (p < 0:001); in 68.9% of patients with poorly differentiated tumors and in 58.1%  of patients with well-differentiated tumors (p = 0:005); in 17.0% of early cancers and in 68.1% of advanced cancers (p < 0:001); and in 48.4% of patients with macroscopic local tumors and in 73.3% of infiltrative tumors (p < 0:001). Lymph node metastasis increased significantly with pTNM staging (p < 0:001). The pN rates are shown in Table 3 and ranged from 17.0% for pT1 to 79.5% for pT4b tumors. Lymph node metastasis occurred in 75.8% of patients with serosal invasion and in 56.6% of those with no serosal invasion. Patient sex, age, tissue growth mode, and lymphovascular cancer embolus were not significantly different in patients with or without lymph node metastasis. Multivariate analysis and logistic regression (Table 4) revealed that sex (p = 0:036), tumor diameter (p = 0:001), macroscopic type (p < 0:001), pT stage (p < 0:001), tissue differentiation type (p = 0:003), and serosal invasion (p = 0:034) were independently associated with lymph node metastasis of upper gastric cancer.

Patients and Methods
The survival analysis of patients with and without lymph node metastasis is shown in Figure 4. The 1-year survival of the 231 patients with no lymph node metastasis was 86.1%, 3-year survival was 69.7%, and 5-year survival was 63%. The corresponding survival rates for the 418 patients with lymph node metastasis were 73.2%, 38.4%, and 28.7% (p = 0:001). When pN stage was included in the analysis, 5-year survival ranged from 63.0% for pN0 to 11.3% for pN3b tumors (p < 0:001) showing that survival decreased with increased pN stage. Five-year survival was ranged from 79% for pT1 to 22.2% for pT4b stage patients without metastatic lymph nodes. Five-year survival of patients with corresponding pT stages and metastatic lymph nodes ranged from 65.6% to 8.6%. (42.7%). Recurrence occurred in 47.4% of patients with tumors ≥ 5 cm in diameter and in 36.0% of those with tumors < 5 cm (p = 0:004). Recurrence and metastasis occurred in 12.8% of early upper gastric cancers and 45.0% of advanced stage cancers (p < 0:001); 28.6% of localized tumors and 49.4% of infiltrating tumors (p < 0:001); 52.3% of patients with lymphovascular cancer emboli and 39.2% who were thrombus-negative (39.2%, p = 0:003); and 50% of patients with serosal invasion compared with 37.7% of those with noninvasive tumors (p = 0:002). As shown in Table 5, recurrence and metastasis increased significantly with pTNM stage, 17.8% at stage I, 27.1% at stage II, and 58.8% at stage III (p < 0:001). Multivariate analysis (   the macroscopic type (p = 0:045), lymphovascular tumor emboli (p = 0:021), and pTNM stage were independently associated with recurrence and metastasis after tumor resection.

Surgical Methods and Prognosis of Upper Gastric Cancer.
D2 total gastrectomy with 1-7, 8a, 9, 10, 11p, or 12a lymph node dissection and Roux-en-Y reconstruction were performed in 333 patients. D2 proximal gastrectomy with esophagogastrostomy was performed in 281 patients, ten with jejunal interposition, and 25 with double-tract reconstruction. The spleen was preserved unless it contained metastatic lymph nodes. Better survival rates were achieved with total gastrectomy than with proximal gastrectomy (p = 0:029, Figure 5). One-year survival of the 333 patients with D2 total gastrectomy was 81.3%, 3-year survival was 54.4%, and 5-year survival was 45.2%. One-year survival of the 316 proximal gastrectomy patients was 75.4%, 3-year survival was 44.9%, and 5-year survival rate was 36.7%. In patients with tumors that had invaded the serosa, survival was better with total than with proximal gastrectomy (p = 0:045, Figure 6(a)). Survival was also better with total than with proximal gastrectomy in patients with infiltrative type upper gastric cancer (p = 0:028, Figure 6(b)). Differences in survival were not associated with other patient characteristics (Table 7). Twenty-one patients with total gastrectomy (6.3%) and 36 with proximal gastrectomy (11.4%) had postoperative complications. Five total gastrectomy patients experienced wound infections, three developed pneumonia, and two experienced fluid esophagitis; and intestinal obstruction, abdominal infection, and pancreatic fistula occurred in one patient each. There were seven occurrences of diarrhea, anemia, pneumothorax, and dumping syndrome. Wound infections and anastomotic leakage each occurred in eight proximal gastrectomy patients, five patients developed pneumonia, and four experienced reflux esophagitis. There were three cases of intestinal obstruction, three of abdominal infection, and two of pancreatic fistula. There were ten reports of diarrhea, anemia, pneumothorax, emphysema, and heart failure.

Discussion
The biological behavior of tumors determines the occurrence, development, and pathological features of tumors. It is a sign of the nature and malignancy of tumors. The gastric cancer in different parts has great differences in biological behavior. The macroscopic type, growth pattern, and degree of tissue typing of gastric cancer can correctly reflect the biological behavior of gastric cancer, and it is a sign of malignant accumulation and invasive expansion of gastric cancer.
Diagnosis of early stage disease has been reported in only 4.3% of patients with upper gastric cancer [13], which is significantly less frequent than in patients with lower gastric cancer. In this series, 7.2% of the upper gastric cancers were found at an early stage, which was significantly lower than the 21.4% of early lower gastric cancer diagnoses. The proportion of tumors that were ≥ 5 cm was significantly greater in patients with upper than with lower gastric cancer; more upper than lower gastric cancer tumors were poorly differentiated. The pT stage was significantly more advanced in upper than in lower gastric cancers; infiltration was deeper; and pN stage, proportion of tumors with lymphovascular emboli, and the proportion of tumors with serosal invasion were all higher. Recurrence and metastasis after surgery were also more frequent in patients with upper than with lower gastric cancer.
The study results are consistent with previous findings that survival is worse with upper than with lower gastric cancer. In this series, 5-year survival was 41.1% in upper gastric cancer compared with 57.2% in lower gastric cancer patients (Figure 1), which is comparable to the 40% 5-year survival reported by others [14,15]. Univariate analysis showed that the tumor diameter, macroscopic type, pTNM stage, lymphovascular tumor emboli, serosal invasion, tumor recurrence and metastasis, and postoperative adjuvant chemotherapy all affected the prognosis of upper gastric cancer. Five-year survival was 50.9% when the tumor diameter was <5 cm and 34.1% when it was ≥5 cm; 77.9% for early and 38.0% for advanced disease; 51.4% for local and 34.2% for infiltrative tumors; 44.3% in the absence of and 31.4% in the presence of lymphovascular tumor emboli; 30.3% with and 47.5% without serosal invasion; 7.2% with and 66.2% without recurrence and metastasis; and 52.3% with and 36.0% without adjuvant therapy.
Five-year survival also significantly decreased from 69.8% to 24.0% with the increase of pTNM stage from I to III. Multivariate analysis found that the macroscopic type, recurrence and metastasis, postoperative adjuvant chemotherapy, and pTNM stage were all independently associated with the prognosis of upper gastric cancer.
Most upper gastric cancers are diagnosed at a more advanced stage than lower gastric cancers; few cases of early  disease are detected. The macroscopic type is generally infiltrative, the tumor diameter is large, and the tissue is poorly differentiated and has invaded the serosa. Lymph node metastasis, late pTNM stage, and recurrence and metastasis after surgery are the main contributors to a worse prognosis than that of lower gastric cancer. Adjuvant chemotherapy is known to increase the effectiveness of surgery in advanced gastric cancer [16][17][18][19][20][21][22]. Five-year survival was 52.3% in patients with adjuvant chemotherapy compared with 36.0% in those who did not receive it, which supports a  recommendation for adjuvant chemotherapy in upper gastric cancer patients following resective surgery.
Lymph node metastasis has a poor prognosis in gastric cancer, which makes the removal of a sufficient number of regional lymph nodes an important component of radical surgery. Five-year survival was 28.7% in patients with and 63% in those without lymph node metastasis. The finding of lymph node metastasis in 64.3% of upper gastric cancer patients compared with 58.8% of those with lower gastric cancer is consistent with previous reports [23]. In this study, male sex, tumors ≥ 5 cm, poor tumor differentiation, macroscopic infiltration, and serosal invasion were more frequent in patients with lymph node metastasis. Statistical analysis found that sex, tumor diameter, macroscopic type, pT stage, tissue growth pattern, and serosal invasion were independent risk factors for lymph node metastasis of upper gastric cancer.
Gastric cancer recurs in situ or with lymph node, peritoneal, or liver metastasis or with hematogenous spread outside the liver with metastasis to other locations. Postoperative recurrence and metastasis may be related to tumor characteristics such as size, tissue type, differentiation, growth mode, pTNM staging, the extent of radical surgery, lymph node dissection, and intraoperative spread of cancer cells [24,25]. Gastric cancer prognosis includes a high risk of recurrence and metastasis after radical gastrectomy [26]. Recurrence after radical gastrectomy is estimated to occur in approximately 50% [27], to more than 70% of patients with lymph node metastasis at diagnosis [28]. In this study, recurrence and metastasis occurred in 42.7% of upper gastric cancers and in 33.9% of lower gastric cancers. Recurrence and metastasis in patients with upper gastric cancer and preoperative lymph node metastasis were 54.3%, which is lower than previously reported. One-year survival of patients with postoperative recurrence and metastasis was 70.0%; the 3-year survival was 20.2%; and the 5-year survival was 7.2%, all of which were lower than the 83.6%, 71.5%, and 66.2% survival of patients without recurrence and metastasis, respectively. Recurrence and metastasis were more frequent in patients with tumors ≥ 5 cm, macroscopic infiltration, lymphovascular tumor emboli, serosal invasion, and increased pTNM stage. The macroscopic type, lymphovascular tumor emboli, and pTNM stage were independently associated with recurrence and metastasis.
Radical surgery is recommended by the Japanese Gastric Cancer Association Classification of Gastric Carcinoma fifteenth edition. D2 radical lymph node dissection is recommended, but differences of surgical procedures result in differences of the number of lymph nodes collected. It is still not clear whether total gastrectomy or proximal gastrectomy is preferred [29]. Total gastrectomy achieves sufficient resection and a wide range of lymph node dissection. Proximal gastrectomy preserves part of the stomach, allowing reconstruction of the digestive tract and better physiological recovery [30]. In upper gastric cancer surgery, dissection of lymph nodes 10 and 11b in the second station involves consideration of the spleen and possibly pancreatic body resection. However, two European randomized trials found that D2 surgery with spleen resection did not provide a survival benefit but rather increased the incidence of postoperative complications and mortality [11,31]. A study by the Japan Clinical Oncology Group (JCOG0110) that compared splenectomy and spleen-preserving surgery did not find a significant difference in the 5-year survival in a group of over 500 gastric cancer patients (75.1% vs. 76.4%). The incidence of postoperative complications was higher in the splenectomy group (30.3%) than in the spleen-preserving group (6.7%, p < 0:05). Splenectomy should be avoided in patients with total gastrectomy for upper gastric cancer that does not involve the greater curvature and is without splenic lymph node metastasis. In such patients, splenectomy increases the occurrence of complications without increasing survival [32]. Neither the Japanese gastric treatment guidelines nor the National Comprehensive Cancer Network recommends prophylactic splenectomy [33]. The JCOG9501 study, which included patients who were at high risk, found an 8.4% incidence of No. 10 lymph node metastasis [34]. Whether splenectomy can improve survival in patients at risk of lymph node 10 metastasis because of the extent of local invasion, invasion of the greater curvature, or clinical suspicion of lymph node 10 metastasis deserves study.

Study Strengths and Limitations.
The strengths include a relatively large sample size, which increased the statistical power. The retrospective design is a limitation, as the data may lack variables that could affect the results.

Conclusion
Upper and lower gastric cancer patients differed in sex, age, tumor diameter, tissue type, growth pattern, macroscopic type, infiltration depth, degree of lymph node metastasis, lymphovascular tumor emboli, and postoperative tumor recurrence and metastasis. Upper gastric cancers were more aggressive, had a worse prognosis, and were more prone to recurrence and metastasis after radical gastrectomy than lower gastric cancers. Surgical treatment of upper gastric cancer by radical total gastrectomy achieved better survival radical proximal resection.

Data Availability
This study data is from the "Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang (110001), China," and from patients with gastric cancer who underwent R0 resection for gastric cancer at The First Affiliated Hospital of China Medical University from January 1980 to December 2012. Raw data cannot be provided for personal and commercial purposes.

Ethical Approval
The study was approved by institutional review board of China Medical University.

Consent
Every patient provided written informed consent before enrollment.