Abstract
Background/Aim: To date, the different clinicopathological characteristics of gastric cancer (GC) in the lesser curvature and greater curvature remain unclear. The aim of this study was to investigate the different features of the tumors in the two sites and provide new strategy for a tailored therapy. Patients and Methods: Between January 2003 and December 2019, 121 patients with GC located in the lesser or greater curvature were surgically treated with curative intent. Data about clinico-pathological features were retrospectively analyzed. In addition, we analyzed the different lymph node patterns according to the lymph node (LN) metastasis between the two groups of patients. Results: No statistically significant differences were found regarding the 5-year overall survival (5y-OS) and 5y disease-free survival (5y-DFS) between patients with GC in the two sites (p=0.94 and p=0.98, respectively). Considering TNM pathological stage, patients with GC in the lesser curvature in stage II and III, showed a worse survival than those with GC in the greater curvature (stage II 5y-OS: 80 vs. 100% and stage III 5y-OS: 18.9 vs. 55.5%). Considering the median value of metastasis LNs, GC in the greater curvature metastasized more often to LN stations no. 8, 10, and 11, whereas GC in the lesser curvature to LN stations no. 8, 9, and 12. Conclusion: GC in the lesser curvature showed a worse prognosis than GC in the greater curvature. Therefore, GC in the lesser curvature could undergo a more aggressive surgery, including an extended lymphadenectomy, and a close follow-up.
Gastric cancer (GC) is the third most common cause of cancer-related death and the fifth most common cancer worldwide (1). Furthermore, GC is a heterogeneous disease and location, histology and molecular characteristics could influence patient survival prognosis as highlighted by The Cancer Genome Atlas project (2). For example, tumors with Epstein-Barr virus-positive and intestinal subtype have been found more frequently in gastric corpus. However, intestinal subtype tumors with TP53 aberrations have been commonly detected in the proximal part of the stomach.
Further, the different distribution of molecular subtypes suggests that there are clinico-pathological differences in the tumor distribution. In fact, tumors with microsatellite instability, occurring in the antrum, showed the best prognosis and the lowest incidence of post-surgical recurrence. In addition, it is well known that the intestinal histotype is more localized in the antral region whereas the diffuse one is often distributed in the upper.
Over time, few studies have been performed to evaluate the different clinico-pathological characteristics between GC localized in the lesser and greater curvature; therefore, these two entities remain unknown (3) and there are no homogeneous data in the literature. The aim of this study was to investigate the different clinico-pathological features and prognosis of GC localized in the lesser and greater curvature.
Patients and Methods
From January 2003 to December 2019, 121 patients affected by GC in the lesser or greater curvature were surgically treated with curative intent in the Surgery Department of “Santa Maria della Misericordia” Hospital of Perugia, Italy.
Data were extracted from a collected database. We included patients who underwent total or subtotal gastrectomy for adenocarcinoma with at least 16 lymph nodes harvested. We excluded patients who underwent surgery for gastrointestinal stromal tumors (GIST), lymphoma or other gastric neoplasia not identified as adenocarcinoma, Sievert I tumor, specimen with micro and macroscopic positive margin, underage patients, those who underwent palliative surgery, and patients with incomplete data.
Patients affected by locally advanced GC underwent neoadjuvant treatment as guidelines recommended (4) and the most used chemotherapy regimens were DOX, FLOT or FOLFOX. No patients with Hereditary Diffuse Gastric Cancer (HDGC) belonged to this series. We dichotomized patients into two groups based on the localization of tumor diagnosed during endoscopy and/or computed tomography (CT). The following clinical and pathological features were retrospectively analyzed using univariate analysis and the Kaplan-Meier method: demographic characteristics, TNM stage, histological type, type of surgery, type of lymphadenectomy, tumor markers, perineurial invasion, lymphovascular invasion and post-operative complications.
Finally, we analyzed the pattern of lymph node metastasis according to the different gastric localization. After surgery, all specimens were examined according to the 8th American Joint Committee on Cancer/International Union Against Cancer system (TNM). All patients were followed-up with physical examination, laboratory tests and imaging every 3-6 months in the first year and then every 6-12 months for at least five years after surgery. All procedures followed were under the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. All the patients signed a written consent to be included.
Statistical analysis. Continuous variables are presented as the mean±standard deviation or median, and categorical variables are presented as frequencies and percentages. The differences among the clinico-pathological characteristics were compared using either Fisher’s exact test or the Chi-square test when applicable. Survival curves and disease survival rates were determined using the Kaplan-Meier method, and differences were compared using the log-rank test. Data management and statistical analyses were performed using SPSS software (Chicago, IL, USA) and Prism 9 Graph PAD software (Boston, MA, USA). A p-value <0.05 was considered statistically significant.
Results
We evaluated the clinico-pathological features between the two groups of patients with GC, as shown in Table I. Median age was 73 years old (range=37-87 years). Male to female ratio was 1.69; males represented 62.8% of the entire population and females the remnant 37.2%. After dichotomization of patients into two groups according to the location of tumor, 86 patients (71%) had a tumor localized in the lesser curvature, and 35 patients (29%) in the greater curvature. We evaluated pre-operative serum tumor markers, such as carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA 19-9) and alpha-fetoprotein, and we observed that CEA was positive in 71.1% of patients, Ca 19-9 in 24.8% of patients and alpha-fetoprotein in 17.4% of patients. In patients with positive tumor markers, there was no statistically significant difference in survival between patients with GC in the lesser curvature and those in the greater curvature.
Clinico-pathological characteristics.
The median overall survival (OS) of the whole population was 49 months and the 5-year OS (5y-OS) was 60.6%. The median disease-free survival (DFS) of the entire population was 30 months and the 5y-DFS was 62.4%. In particular, no statistically significant differences were found in 5y-OS and 5y-DFS between patients with GC in the greater and lesser curvature (Figure 1A and B, p=0.94 and p=0.98, respectively). In fact, the 5y-OS of patients affected by GC in the lesser curvature was 59.2%, whereas the 5y-OS of patients with tumor in the greater curvature was 62.7%. Instead, the 5y-DFS was 61.3% vs. 65.1%, respectively.
Kaplan-Meier curves showing five-year overall survival (A) and disease-free survival (B) of patients with gastric cancer of the lesser and greater curvature. No statistically significant differences were found between patients with gastric cancer in the greater and lesser curvature.
By dichotomizing patients according to TNM pathological stage, we observed differences in survival (Figure 2). Specifically, patients with GC in the lesser curvature at stages II and III showed a worse survival than those with GC in the greater curvature (stage II 5y-OS: 84.5% vs. 100% and stage III 5y-OS: 28.9% vs. 48.8%).
Kaplan-Meier curves of five-year overall survival for stage II (A) and stage III (B) gastric cancer of the lesser and greater curvature according to TNM stage.
Intestinal, diffuse, and mixed subtypes had a similar incidence in the lesser and greater curvature (61.6% vs. 60%, 31.4% vs. 31.4%, 7% vs. 8.6%, respectively). By dichotomizing patients according to different histotype, we showed a better prognosis in patients with the intestinal subtype, both in the greater curvature and in the lesser curvature (70% and 67.7%, respectively); however, the 5y-OS of patients with diffuse histotype was 39% for the lesser curvature and 49.7% for the greater curvature.
Considering the type of surgery, we found a similar incidence of total and distal gastrectomies in patients with tumors located in the two sites (total gastrectomy: 41.9% in the lesser curvature and 34.3% in the greater curvature; subtotal gastrectomy: 58.1% in the lesser curvature and 65.7% in the greater curvature).
Patients affected by GC of the greater curvature who underwent total gastrectomy had a better 5y-OS than those who underwent total gastrectomy for a tumor of the lesser curvature (58.3% vs. 49%, respectively). However, the 5y-OS of patients who underwent distal gastrectomy was similar in both locations of the tumor (62.5% vs. 62%, respectively).
By analyzing the type of lymphadenectomy, an extended lymphadenectomy was performed in 11.6% of patients with GC in the lesser curvature and in 14.3% of those with a tumor in the greater curvature. We observed neural invasion in 92 patients (67 tumors of the lesser curvature and 25 of the greater curvature), whereas lymphatic invasion was demonstrated in 93 patients (68 tumors of the lesser curvature and 25 of the greater one). Tumor location was not a risk factor for prognosis of GC (Table II, p>0.05).
Univariate analysis.
Incidence of post-operative complications was comparable between patients with tumors located in the lesser and greater curvature (type 1: 15.11% vs. 20%; type 2: 35.22% vs. 14.28; type 3a: 4.65% vs. 2.85%; type 3b: 1.16% vs. 0%; type 4: 3.48% vs. 2.85; type 5: 3.48% vs. 2.85, respectively).
Furthermore, we investigated the different patterns of lymph node metastasis according to the different localizations. Lymph node metastasis was found in 64 patients (52.9%). Considering the median value of metastatic lymph nodes, GC in the greater curvature metastasized more frequently to LN stations no. 8, 10, 11, whereas tumor in the lesser curvature metastasized more frequently to LN stations no. 8, 9 and 12. In particular, tumor located in the lesser curvature with diffuse subtype metastasized more often in posterior lymph node stations (Figure 3).
Lymph node (LN) metastasis in gastric cancer of the greater (A) and lesser (B) curvature. Gastric cancer in the greater curvature metastasized more frequently to LN stations no. 8, 10, 11, whereas gastric cancer in the lesser curvature metastasized more frequently to LN stations no. 8, 9, and 12.
Discussion
Based on GLOBOCAN evaluation, GC represents the fifth most common diagnosed malignancy and the third leading cause of cancer-related death worldwide (1). To date, GC still has poor prognosis although there have been improvements in chemotherapy.
GC is a very heterogeneous disease that shows different architectural, cytological, morphological and molecular profiles. These issues in addition to the different localization of GC seem to be important for the prognosis of patients. However, little is known about the features of gastric cancer located in the lesser and greater curvature and literature is very limited regarding this issue. Therefore, this study aimed to investigate the different clinical and pathological features of these two different gastric tumors and the survival outcomes.
Feng et al. studied the characteristics of GC located in the lesser and greater curvature and they didn’t find a significant difference in OS between patients with GC in the two sites (5). In our cohort of patients, GC in the lesser curvature was more common than that in the greater curvature. Also, Li et al., showed that GC commonly developed in the lesser curvature (3). Moreover, they demonstrated that patients with positive EGFR had a worse prognosis than those with negative EGFR; in particular, they found that GC in the lesser curvature had higher levels of EGFR expression than GC in the greater curvature and patients with high expression of EGFR had a worst prognosis.
As previously demonstrated by Hayashi et al. (6), lymphoid follicles associated to Helicobacter pylori infection and chronic gastritis are more frequent in the lesser curvature (20%) than in the greater curvature (0.9%). In particular, nodular gastritis in the lesser curvature frequently develops for the major presence of nodular lymphoid follicles. Moreover, patients with Helicobacter pylori infection could develop an invasive gastric adenocarcinoma as Kim described in his study (7). After Helicobacter pylori eradication, most of the nodular lymphoid follicles become smaller and whiter, almost unidentified. In particular they are no longer identified in 74% of cases, decrease in size in 23%, and do not change in 3% of patients with the development of tumor. This is also related to an increased incidence of intestinal subtype of GC in the lesser curvature. Our results emphasized the worst prognosis of patients with GC in the lesser curvature in stages II and III, maybe because of a different pattern of lymph node metastasis and an important trophism for posterior lymph node stations. In addition, GC in the lesser curvature showed more aggressiveness due to a major lymphatic and neuronal invasion.
Lee et al. investigated the pattern of lymphatic drainage in GC in order to predict sentinel node placement according to the tumor location (8). He found that tumors located in the lower third and in the lesser curvature of the stomach presented more often atypical lymph node metastasis (29% for skip metastasis and 18% for transversal metastasis). In fact, he showed that lesser curvature tumor was an independent risk factor for skip metastasis, and tumor located circumferentially in the lesser curvature or longitudinally in the lower third of the stomach was an independent risk factor for transversal metastasis.
Also, Griniatsos et al. (9) analyzed the lymphatic spread according to the tumor location in the stomach. Tumors of the lower and middle third of the stomach were equally drained both to the level I and II lymph node stations. However, tumors located in the lesser curvature were mostly drained in the level II lymph node stations, while tumors in the greater curvature were drained in the level I lymph node stations. This different lymphatic drainage could explain the worst prognosis of GC of the lesser curvature and the need for a tailored therapy.
Another fundamental parameter that could stratify patients with GC in the lesser curvature is the lymph node ratio (LNR). In fact, Oiyama et al. (10) showed the importance of LNR as a survival prognostic factor, in particular in patients with a more advanced N that could occur in the lesser curvature’s tumors.
Our study has some limitations due to the retrospective nature and the small sample.
In conclusion, our results suggest an evident clinicopathological difference between GC in the lesser and greater curvature. These findings support a different prognosis of patients with tumor in the two sites and the need to develop an appropriate therapy.
Footnotes
Authors’ Contributions
Study concepts: N.N., L.G., A.D.; Study design: N.N., L.G.; Data acquisition: N.N.; Quality control of data and algorithms: N.N., L.G., A.D.; Data analysis and interpretation: N.N, L.G, A.D.; Statistical analysis: N.N.; Manuscript preparation: N.N, L.G.; Manuscript editing: N.N., L.G.; Manuscript review: L.G., A.D.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received February 28, 2024.
- Revision received April 26, 2024.
- Accepted April 29, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
