Background
The incidence of GC (gastric cancer) has decreased worldwide. However, it is still the fifth most common cancer overall and the third most common cause of cancer mortality [
1]. The difference in the tumor biology, tumor stage at presentation, location and differences in treatment are presumed to be reasons for the difference in survival between patients [
2]. The multimodal treatment of GC includes the combination of variable disease-based therapeutic components, including different extents of LND (lymphadenectomy). The recurrence rates after gastric surgery remain high (ranging from 20% to 50%) and LN (lymph node) involvement ought to have the strongest influence on recurrence and prognosis of GC [
3‐
5]. For this reason, an accurate LND represents an essential component of GC surgical treatment.
The Japanese Gastric Cancer Association classification (JGCA) system for GC requires the resection of 20 LN stations plus the 110, 111, and 112 groups. LN stations 1–12 and station 14v are regarded as locoregional gastric lymph nodes, other node stations are, generally, considered as distant metastases. For esophageal invading tumors, station 19, 20, 110 and 111 are also classified as locoregional. In a total gastrectomy, a less extensive D1 LND consists of resection of the peri-gastric LNs; station 1 to 6, and LN station 7; a second-tier LN station. A D2 LND consists of resection of the D1 LN stations and the stations 8a, 9, 11p, 11d and 12a. In a distal gastrectomy a D1 LND consists of resection of the LN stations 1, 3, 4sb, 4d, 5, 6 and 7. In a distal gastrectomy a D2 LND includes the D1 stations and stations: 8a, 9, 11p and 12a [
6]. For cancer of the upper stomach invading the greater curvature, dissection of station 10 is considered a D2 + LND following the 5
th edition of the JGCA guidelines. In previous editions of the JGCA guidelines this was defined as a D2 LND.
A more extensive LND ought to result in lower rates of loco regional recurrence and improved overall survival [
7‐
9]. However, a more extensive D2 LND is accompanied with higher morbidity rates (43%-46% versus 25%-28%) and mortality rates (10%-13% versus 4%-6.5%) in comparison with a less extensive D1 LND [
9,
10]. For selected early gastric tumors, endoscopic resection is feasible.
The Japanese Gastrointestinal Endoscopy Society has established criteria for endoscopic resection for early GC. Tumors confined to the mucosa (T1a), well-differentiated, non-ulcerated and ≤ 2 cm can be curatively treated by endoscopic resection, as the chance of LN metastases is negligible. Expanded criteria were defined for: (1) well-differentiated mucosal cancer without ulceration, greater than 2 cm in diameter; (2) well-differentiated mucosal cancer with ulceration, up to 3 cm in diameter; (3) undifferentiated mucosal cancer without ulceration, up to 2 cm in diameter and (4) differentiated submucosal cancer (SM1, < 500 μm), up to 3 cm in diameter. Tumors that meet the expanded criteria for endoscopic resection carry the risk of LNM. This risk should be balanced with the risk of surgery [
11,
12].
The overall prevalence of LN metastases in T1 tumors is 8%–31%, while the overall prevalence of LN metastases in T2-T4 tumors is considerably higher; 45%–90% [
13‐
15]. This difference in metastases rates suggest the necessity for a more tailored approach based on the gastric T-stage. The Japanese Guidelines advocate a D1 LND for T1a tumors and well-differentiated, < 1.5 cm T1b tumors that do not meet the criteria for endoscopic resection. While a D1 LND is accompanied with less morbidity and mortality, the question remains whether a D1 LND is adequate for early, T1-stage gastric carcinomas.
The objective of this systematic review is to investigate and compare the prevalence of nodal metastases in the individual LN stations between different T-stages.
Methods
Design
Data reporting and structure of this systematic review follows the PRISMA checklist [
16].
Literature search
The Medline/Pubmed database was thoroughly searched by two independent observers on June 1st 2022. If consensus could not be reached a third observer was consulted. The search included the following Mesh terms: “Stomach Neoplasms”, “Lymphatic Metastasis” and “Lymph Node Excision”. Besides Mesh terms the search included synonyms for these terms through appending “[tiab] words”. In Table
1 the search strategy is outlined in detail.
("Stomach Neoplasms"[Mesh] OR gastric cancer[tiab] OR stomach carcinoma*[tiab]) AND ("Lymphatic Metastasis"[Mesh] OR Lymphatic Metastas*[tiab]) AND (pattern*[tiab] OR distribution*[tiab]) AND ("Lymph Node Excision"[Mesh] OR Lymph Node Excision*[tiab] OR Lymph Node dissection*[tiab] OR lymphadenectom*[tiab]) AND english[Language] | 175 |
Study selection and inclusion criteria
Studies reporting the prevalence of nodal metastases for the individual LN stations per T-stage, were included. Initially, articles were screened on eligibility based on title or abstract. Then the full-text article was retrieved and selected for inclusion if they met the following criteria: (1) randomized controlled trials, cohort studies, (2) patients who underwent gastric surgery including a LND, (3) patients with operable GC (4) studies reporting the prevalence of nodal metastases for the individual LN stations separately for the different T-stage. Systematic reviews, narrative reviews and case series and studies which do not distinguish between gastric and esophageal tumors were excluded. If the two observers had divergent ideas on any data, a third observer was asked to constitute and reach consensus.
Outcome
The primary outcome was the highest prevalence of nodal metastases per T-stage, defined as the highest number of patients with pathological positive LNs in an individual LN station separately reported for the different gastric T-stages. The secondary outcome was the prevalence of nodal metastases in every individual LN station between different T-stages, defined as the number of patients with pathological positive LNs per LN station separately reported for the different gastric T-stages. The T-stage classification following the 7
th edition of the AJCC Cancer Staging Manual was used [
17]. As the included articles were performed between 1989 and 2014, the 7th rather than the 8th edition of the AJCC Cancer Staging Manual was used. The classification of the nodal stations was used following the Japanese classification of gastric carcinoma [
6,
18].
Quality assessment
Two researchers (M.J. and W.D.) independently assessed the methodological quality of the included studies with the use of the CASP-checklist [Critical Appraisal Skills Program (2017)]. If consensus could not be reached a third observer (M.B.H) was consulted. This checklist contains questions regarding the methodological quality of the studies. Points were given dependent on the various answers. The articles were scored on their quality, ranged from 0 (low quality) to 12 (high quality). Articles scoring between 0 and 5 points were defined as “low quality”, between 6 and 8 points as “moderate quality” and between 9 and 12 points as “high quality”.
The following information about the study design characteristics was extracted: first author, year of publication, journal of publication and study design. The following data about the patient characteristics and the surgery was extracted: number of patients, number of patients with positive LN metastases, tumor location, type of LND, what T-stage the study addressed and the outcome as mentioned above.
Discussion
This systematic review investigated the prevalence of nodal metastases for the individual LN stations between different T-stages. The results show a correlation of the prevalence of nodal metastases between the different LN stations and different T-stages, with an overall low prevalence in early, T1 gastric carcinomas and an overall high prevalence in the more advanced, T3 and T4 gastric carcinomas.
No previous systematic review reported the prevalence of nodal metastases in the individual LN stations. To determine the adequate extent of LND, it is critical to understand which LN stations are generally affected for a specific gastric T-stage. In addition, this is crucial to determine whether a D1 LND is justified for early, T1-stage GC and whether a D2 LND is justified for more advanced gastric carcinomas.
This review is consistent with previous literature studies reporting the metastases rate for the different T-stages [
12,
24,
25]. These studies similarly show an overall low metastases rate in the early carcinomas and an overall high prevalence in the more advanced carcinomas. However, these studies do not report the prevalence of nodal metastases in the individual LN stations.
There are limited studies reporting the prevalence of nodal metastases for the individual LNs per T-stage. As a result, only five articles could be included. There was a considerable heterogeneity between studies; not every article reported the metastases rate in every individual LN station for every T-stage. No recently performed studies were eligible for inclusion. The 7th rather than the 8th edition of the AJCC Cancer Staging Manual was used because all included articles were performed between 1989 and 2014.
In addition to gastric T-stage, tumor location plays a significant role in the LN metastases pattern and extent of LND [
26]. Furthermore, histological and immunohistochemical characteristics and molecular profiling affect the prognosis [
27,
28]. As a result of the considerable heterogeneity between studies; including considerable differences in distribution of tumor location, differences in histology and molecular profiling could not be processed in this systematic review. The combination of T-stage and tumor location could, however, provide a further understanding of the extent of LND for a more personalized approach.
All included studies were conducted in Asia. The results of this study endorse a more tailored approach based on gastric T-stage. However, these results cannot directly be extrapolated to a Western population as tumor biology and neoadjuvant chemotherapy regimens differ. Studies that investigate the distribution of LN metastases in a Western GC population are needed.
While preoperative staging is essential for deciding on the treatment strategy, the accuracy of GC staging is known to be limited. It remains unclear which preoperative imaging modality for GC should be regarded as optimal [
29]. Current multidetector computerized tomography in combination with endoscopic ultrasonography has increased the accuracy of clinical gastric tumor staging [
30]. However, detecting peritoneal and nodal metastases remains uncertain [
31,
32]. Using a multimodality strategy, accuracy for clinical lymph node staging ranges between 50 and 90% [
33]. Even with an increased accuracy of clinical tumor staging, a significant deviation between the clinical and the pathological T-stage remains [
34]. With important consequences for the clinical applicability.
Neoadjuvant chemotherapy is considered a standard treatment for locally advanced gastric cancer. While still debated in some Eastern countries [
35,
36], neoadjuvant chemotherapy has been widely used in the treatment of patients with locally advanced GC [
37,
38]. However, neoadjuvant chemotherapy influences the tumor and potentially downstages the N-stage and T-stage. As a result, the deviation between clinical and pathological T-stage will increase. Previous studies showed a considerable downstaging of tumor stage after neoadjuvant chemotherapy together with poor accuracy of preoperative staging [
39,
40]. The included studies in this review do not report whether neoadjuvant chemotherapy was administrated. Studies focusing on the optimalisation of imaging modalities in GC are awaited.
This systematic review showed an overall high prevalence of nodal metastases in the more advanced gastric carcinoma suggesting that a D2 LND should be considered for T2-4 tumors. Furthermore, it showed an overall low prevalence of nodal metastases in the early gastric carcinomas, especially in the individual LN station 8–12, suggesting that possibly a D1 LND could be adequate for T1 tumors who are not suitable for endoscopic resection.
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