Background
Gastric cancer (GC) continues to be a major challenge in the health care community worldwide especially in East Asian countries; such as China, South Korea and Japan [
1,
2]. Despite the advances in medical treatments, gastrectomy with regional lymphadenectomy remains the primary treatment for patients with resectable GC and has a five-year overall survival (OS) rate of approximately 20-30%. The low OS rate is due to the high frequency in the post-surgery recurrence of cancer [
3,
4].
The most reliable indication of the prognosis following surgery can be provided through the assessment of the GC using the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM staging guidelines [
5]. However, it has been noted that many patients that have been determined to have the same UICC/AJCC TNM stage have heterogeneous survival rates. Therefore, there has been an increased focus on determining other prognostic indicators that will aid in the identification of GC patients with a higher risk for the recurrence of their cancer and who may be candidates for other adjuvant therapies.
The major factor contributing to the recurrence of cancer and mortality is thought to be the systemic dissemination of cancer cells. Lymphovascular invasion (LVI), also referred to as blood vessel and/or lymphatic invasion, is the presence of tumor cells within the lumen of the blood and/or lymphatics; the process of which leads to circulating tumor cells. The presence of LVI is a common pathological finding in a variety of human cancers and has been shown to be associated with a high recurrence rate and poor prognosis in patients with breast cancer, colorectal cancer, non-small cell lung cancer and clear cell renal cell carcinoma [
6-
10]. The combination of traditional TNM staging with an assessment for LVI could lead to a more accurate indication of the patient’s prognosis [
11].
Previous studies have investigated the prognostic significance of LVI in relation to GC in small selected cohorts. The results of these studies indicated that the presence of LVI, either in the blood or lymphatics, correlated with tumor recurrence and a low survival rate that appeared to be independent of lymph node status [
8,
12-
18]. The prognostic value of an LVI assessment in GC remains controversial due to the small number of participants in the study. To address this issue, a large retrospective study of GC patients who had undergone surgery in Southern China was designed and carried out to thoroughly investigate the correlation between LVI and cancer-recurrence/ long-term survival.
Discussion
The presence of LVI, a common pathological finding for a variety of different cancer types, has been of considerable interest in the last few decades as a potential biomarker. The effectiveness of LVI as a reliable indicator of cancer recurrence and prognosis has been clearly established for both hepatocellular carcinoma and testicular cancer, supporting its incorporation into the UICC/AJCC TNM staging system [
19,
20]. Previous studies have also shown that the presence of LVI correlated with a poor prognosis. However, due to the lack of large, well-designed and prospective studies, at this time LVI is only recommend to be included in final pathological reports rather than being included in the initial TNM staging system of GC as stated in the NCCN Guidelines for Gastric Cancer of 2013 [
21].
In this large-scale retrospective study, through the use of H & E staining, LVI was determined to be present in resected GC specimens at a fairly high frequency. Its presence was also shown to correlate with a higher chance of cancer recurrence and was shown to be an independent predictor of a poor survival rate in post-surgical GC patients.
The presence of LVI was detected in 35.2% of GC patients by H & E staining in this study. Similarly, del Casar et al. had previously reported that 31.9% of GC patients had presented with LVI as detected using H & E staining complemented by immunostaining with CD34 [
22]. However, a study by Kim et al. had indicated that LVI was detected in 44.3% of GC patients by immunostaining with D2-40 and CD31 [
16]. The differences in the detection rate of LVI could be due to variations in the detection methods. The use of H & E staining, an elastic fiber stain and immunostaining are currently accepted methods in the literature for the detection of LVI. Histological identification of LVI using H & E staining can be subjective, which could lead to the underestimation of the incidence of LVI. However, successful vessel identification using H & E staining has been previously shown to be sufficiently reliable. With quality control measures in place, the prognostic value of LVI as detected by H & E staining was determined for upper urinary tract urothelial carcinoma, breast cancer, colorectal cancer and non-small cell lung cancer [
11,
23-
25]. Additionally, a previous study indicated that both LVI and BVI, as detected by both H & E and IHC staining, significantly correlated with lymph node metastasis [
17]. Consistent with previous findings, our data demonstrates that the presence of LVI, as detected by H & E staining, significantly correlates with DFS and DSS in post-surgical GC patients.
Several small-scale studies have previously noted the prognostic value of LVI on DSS and DFS in GC patients. The presence of LVI was shown to be significantly associated with a poorer OS in 77 patients with primary gastric adenocarcinoma [
22]. The three-year OS and three-year DFS of 149 GC patients were found to be significantly higher in GC patients without LVI as compared to those with LVI [
16]. A retrospective analysis indicated that the OS of the LVI-positive patients, out of 436 stage II GC patients, was shown to be worse than that of the LVI-negative patients [
26]. Similarly, we confirmed the negative impact of LVI on DSS and DFS in a large cohort of 1148 patients with gastric adenocarcinoma who underwent gastrectomy. Additionally, a stage-stratified survival analysis determined that the presence of LVI in GC patients correlated with a poorer prognostic outcome. Notably, our study identified LVI as an independent prognostic factor through the use of multivariate analysis. Our findings are in agreement with the results of previously published studies [
18,
26]. However, it is of note to point out that LVI was not identified as an independent prognostic factor in GC patients in all of the previous studies identified. Kim et al. had reported that the presence of LVI was shown to have a significant impact on patient survival; however, it was not determined to be an independent prognostic factor in GC. A close relationship between the presence of LVI and tumor progression was speculated to be the basis for this negative result [
16].
This study, along with previous reports, supports the view that the presence of LVI in GC is a promising indicator of tumor aggressiveness; providing additional information regarding the risk of cancer recurrence and mortality. The addition of LVI assessment to the current UICC/AJCC TNM staging system may lead to a more accurate risk stratification of affected patients and may lead to more appropriate clinical decision-making. Interestingly, randomized controlled trials have recently demonstrated treatment benefits from adjuvant therapy given to GC patients who have undergone surgery [
4,
27,
28]. This supports the idea that GC patients with LVI may be good candidates for further adjuvant therapies that may improve their chances at survival.
The status of nodal metastasis was not evaluated as a statistically significant prognostic factor in multivariate analysis in the present study. However, nodal metastasis was found to be closely correlated with a poor prognosis in our univariate analysis on patient survival. Lymph node status, TNM stage and LVI were included in our multivariate analyses for DSS and DFS. It is known that the status of nodal metastasis is included in TNM staging for GC and there is a strong association between nodal metastasis status and TNM stage. Meanwhile, in agreement with previously published studies, our data indicate that the status of nodal metastasis significantly correlated with the presence of LVI in GC [
12,
22]. Therefore, the effect of covariate mainly contributes to this negative result.
Consistent with previous studies, the 5-year DSS rate in this study was determined to be approximately 51.0% for all stages, 70.5% for stage I-II and 36.1% for stage III-IV [
29,
30]. However, the published SEER data indicated that in the United States, the 5-year relative survival for GC was 28.3% for all stages, 64.1% for a localized stage, 28.8% for a regional stage. In fact, it has been suggested that patients with GC have a more favorable prognosis in Asia as compared to those in Europe and the US; a variety of potential reasons have been proposed to explain this. First, the survival advantage of the Asian ethnicity continues to play a role even after being controlled for using other well-known prognostic factors [
31,
32]. Additionally, the higher surgical quality may contribute to the increased survival rate in Asia; gastrectomy with D2 lymphadenectomy is the standard treatment for GC patients in China. Several clinical trials also have also confirmed the survival benefit for D2 lymph node dissection [
33]. Meanwhile, the high incidence of GC in China has subsequently resulted in highly experienced surgeons due to the vast number of times they perform that particular surgery.
Several limitations that could affect the interpretation of our results exist due to the retrospective nature of the study. Potential bias was minimized through the use of strict inclusion and exclusion criteria for patient selection as well as duplicate reviews for each pathologic evaluation carried out according to the commonly used unified international criteria. Further validation of our results will require subsequent large-scale prospective studies.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MYC is responsible for the study design. PL performed the experiments and drafted the manuscript. HQH carried out the data analysis and interpretation. CMZ, YHL, WMH, XKZ, RZL, JPY and DX participated in the data collection.YFL provided the patients’ clinical data. All authors read and approved the final manuscipt.