Prediction of lymphatic invasion for patients with early gastric cancer: a review

Introduction

The long-term results of the prospective randomized controlled study (RCT) Sentinel Node ORIented Tailored Approach (SENORITA) trial have recently been published (1). This study compared laparoscopic sentinel node navigation surgery (SNNS) vs. laparoscopic gastrectomy with lymph node (LN) dissection for early gastric cancer (EGC). The short-term results of the SENORITA trial showed no differences according to postoperative complications but benefits for quality of life and nutrition for the group with SNNS (2). In order to better rate the results, we have attempted to present the current status of curative treatment of EGC with special consideration of regional differences.

Gastric cancer in East and West

Gastric cancer is one of the most common cancers and is characterized by a poor prognosis (3). In 2020 worldwide 1,089,103 new cases of gastric cancer were registered, and 768,793 new cases of death caused by gastric cancer occurred (3). But there are relevant differences between Eastern Asian countries, including Japan, South Korea and China compared to Western industrial regions like Europe or North America (3,4). Nearly for all countries in the world the incidence rate of non-cardia gastric cancer declined during the last 50 years (3). The main difference between Eastern Asian and Western industrial countries is the level of the incidence rates. The age standardized incidence rates (ASRs) in 2020 for gastric cancer in males was 32.5 and in females 12.5 per 100,000 inhabitants in Eastern Asia while it was in males 8.2 and in females 3.8 per 100,000 inhabitants in Western Europe (3).

The different frequency of this type of tumor between East and West also influences the treatment concepts in the different regions. Due to the high incidence rates of gastric cancer in East Asia, screening programs have been introduced in some countries. This led to an increased detection of early tumor stages, with the consequence of a significantly improved survival rate after adequate therapy, i.e., complete removal of the tumor. Surgical treatment involves the loss of a significant portion of the stomach, mandating changes in the dietary habits of patients. According to the literature, it is well established that the Health-Related Quality of Life (HRQoL) is substantially adversely affected by the panacea of different symptoms patients experience after surgical procedures like gastrectomy (5). However, these patients are usually still young and therefore have the chance to live longer, but with the sequela of the therapy, like weight loss, disturbed nutrition etc. In a recent published study, it could be shown that EGC-patients had a reduced life expectancy compared to the age- and gender-adapted population (6). Especially younger patients (<60 years) showed high rate of years of life lost. Therefore, in addition to the radical removal of the tumor, the aim of all therapeutic measures is to cause as little damage as possible to the organs involved. In Japan, for example, endoscopic procedures such as endoscopic mucosal resection (EMR) for tumors confined to the mucosa or endoscopic submucosal resection (ESD) for small tumors of the submucosa were introduced very early on. With all these local resection procedures, it remains unclear whether the tumor has not already spread to the LNs. Sentinel lymph node (SN) biopsy is one possibility to propose LN invasion. The SN is regarded as the first LN to receive lymphatic drainage from the primary tumor and metastasis from the primary lesion (7). If this theory is correct and the SN is free of tumor, all regional LN can be predicted to be negative for metastasis. There are different methods to evaluate SN distribution. To date, several studies have been conducted to prove the feasibility of the SN concept in gastric cancer (8). We want to discuss the possibilities to optimize the therapeutic decision according to side effects of the therapy and to the accuracy of the prediction of lymph node metastasis (LNM) for patients with early cancer of the stomach.

EGC

For the term “Early Gastric Cancer” several definitions exist. According to the Japanese Classification of Gastric Cancer, EGC is defined as clinical stage I which include cT1 (mucosa and submucosa)/cT2 (muscularis propria), cN0, M0 tumors (9). In Western countries the definitions of the extent of the primary tumor and metastasis is based on the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) TNM criteria (10). Since January 1, 2017, the 8^th edition has been used in Europe (10). Hereby, EGC means UICC stage IA (cT1a or 1b, N0, M0) or IB (cT1, N1, M0 or cT2, N0, M0).

At first glance, the two classifications differ only marginally. While the Japanese classification for early carcinoma only includes cN0 tumors—i.e., without LNMs—in the UICC classification, a tumor that is limited to the mucosa and only has one or two LNMs—cN1—is also an early carcinoma. In any case, the assignment to the clinical assessment of the LN status is problematic. The definition based on imaging techniques such as computer tomography, magnetic resonance imaging (MRI) or endoscopic ultrasound (EUS) is not valid due to insufficient sensitivity and specificity (11). The main difference between the two definitions arises from the treatment decision. In Asian countries, EGC is treated endoscopically according to precise criteria. These procedures have been continuously improved in recent decades. Even though these methods have also been adopted in western industrialized nations, the data from Western is more often based on surgically treated patients. It follows that clinical T, N is mixed with pathologic T and N category.

Therefore, it is difficult to compare the incidence rates for EGC between the different countries. Park et al. described an increasing percentage of Korean patients with EGC from 28.6% in 1995 to 63.6% in 2019 (12). In contrast, the rate of EGC in Germany is about 20% of all gastric cancers without changes in the last years. (13).

LNMs in EGC

The existence of LNM influence the therapeutic decisions and probably the prognosis of the patient (14). The knowledge about the lymphatic drainage of gastric tumors is of great importance.

In addition to the different frequency of EGC between Eastern Asian and Western industrial countries the invasiveness of the tumor seems to vary. Hölscher et al. compared the frequency of LNM in patients with pT1 gastric cancer from Asian and European countries. The rate of LNM in mucosal carcinomas was 6.5% and for submucosal carcinomas 23.9% in European countries compared to 2.7% or 22.9% in Asian countries (15). Similar results were published from other authors (16,17). Vos et al. (16) described about 22.1% LNM in patients with submucosal gastric cancer from Asian regions compared to 27.3% from Western countries.

There are many reasons for these differences in the frequency of LNM in EGC between East and West. First of all, it is noticeable that the introduction of screening programs for gastric carcinoma in Asian countries were followed by more early lesions. This means that the tumors infiltrating only the first third (m1) or second third (m2) of the mucosa are found more frequently in mucosal carcinomas in the Asian results than in the comparable results from Western countries. Patients with EGC infiltrating only the first two thirds of the mucosa showed no LNM (15).

Another striking feature is the different localization of EGC between East and West (2,18,19). The randomized controlled SENORITA trial from Korea showed about 6% of 518 tumors located in the upper third of the stomach (2). Zelong et al. (18) used data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute in the USA and found that of 5,440 surgically treated patients with EGC between 1988 and 2015, 24.4% were diagnosed in the proximal third of the stomach. Akiyama et al. (19) used data from the Japan Clinical Oncology Group study (JCOG0912) to investigate the influence of tumor location. Of 815 pT1 tumors, 506 (62.1%) were in the middle third and 309 (37.9%) in the lower third. No correlation between tumor location and the existence of LNM was found in either analysis. The answer remains open, as adenocarcinomas in the upper third of the stomach are classified and treated differently depending on the actual location of the tumor—as esophageal, cardia or gastric carcinoma.

Further reasons for the different incidence rates in the mentioned regions are discussed. Helicobacter pylori (H. pylori) infection increases the risk of gastric carcinoma by three to six times (20). There is a large variation of H. pylori prevalence, with the high prevalence like Asia (66.6%) and the low reported in Western Europe (34.3%) and Northern America (37.1%) (21). This may be one explanation for the higher incidence of gastric cancer in the East compared to West industrial countries.

Lifestyle factors such as increased salt consumption in Asian countries influence the risk of gastric cancer. In combination with an H. pylori infection, the risk increases further. Controversy results are published metabolic syndrome and overweight (22,23). Molecular factors that are discussed for the development of a tumor in the stomach are found with different frequencies in tumors in the East and West (24).

Therapeutic options for patients with EGC

Treatment options for EGC range from endoscopic procedures like EMR and ESD to different surgical options like laparoscopic or open distal gastric resection to gastrectomy with radical LN dissection. Guidelines from Eastern and Western countries suggested that the standard procedures for EGC are ESD or gastrectomy with regional LN dissection (9,13,25).

A prerequisite for the use of an endoscopic procedure for the safe removal of a tumor are the criteria defined in the Japanese guidelines—absolutely indicated and expanded criteria (9). The results from Japan and Korea confirm the practicably of the endoscopic procedures for the treatment of patients with these indications (26-28). The question remains whether these good results can also be transferred to the western regions (29-31). Benites-Goñi et al. (30) examined this in a meta-analysis. They included 1,875 patients from 14, 11 and 2 studies from Europe, South America and North America. Curative resection was possible in 75% of adenocarcinomas and complications were reported as 5% bleeding and 2% perforation. The low number of patients in most of these studies is striking. Newland et al. (31) used the data from the National Cancer Database/USA from 2010 to 2016 and was able to identify gastric carcinoma patients with local excision, which he divided into eCura high (n=1,167) and low (n=13,905). In the absolute indication group (high), 30-day mortality was 0%, readmission at 2.3%, and the rate of R0 resection 93% compared to the eCura low group at 2.8%, 7.8%, and 27.1%, respectively. The authors conclude that the right patient selection determines success.

In the treatment of even these early tumors, the main thing is the complete removal of the malignant cells. Therefore, surgical resection of the primary tumor together with possible metastases in the corresponding lymphatic drainage area is still recommended. The extent of the stomach resection varies with the size and location of the tumor. A gastrectomy with a corresponding D1(+) or D2 lymphadenectomy best fulfills the requirements for radicality. For tumors in the lower third, a subtotal gastric resection with a sufficient safety margin after oral and aboral resection may be indicated. Various studies showed the disadvantages of these procedures compared to endoscopic removal of the tumor: the total hospitalization days, operation time, postoperative fluid intake time, hospitalization expenses, and proportion of antibiotic use rate in the ESD/EMR group were lesser than those in other groups (P<0.05) (32). Several meta-analyses have examined the advantages and disadvantages between endoscopic and surgical procedures for the treatment of EGC with extended indication criteria. Sun et al. (33) searched for relevant studies published until the end of 2022 and included 3,308 ESD patients and 4,534 surgically treated patients. Significantly fewer wound infections occurred in the group of ESD patients [odds ratio (OR) =0.45; 95% confidence interval (CI): 0.34–0.65; P<0.001] compared to gastrectomy patients. A further meta-analysis including six studies confirmed the lower rate of adverse events for patients with expanded indication in the ESD group (26).

Recently, laparoscopic approaches for gastrectomy were introduced to improve the quality of life for patients with EGC (34). The results of this large RCT showed lower rate of wound infection in the laparoscopic group (3.1%) compared to open procedures (7.7%). The major intra-abdominal complication (7.6% vs. 10.3%, P=0.095) and mortality rates (0.6% vs. 0.3%, P=0.687) were similar between the two groups. Both laparoscopic subtotal resection for distal gastric carcinomas and laparoscopic gastrectomy can now be performed safely and with few complications. In a recent literature review (35) of a total of 15 RCTs with 5,576 patients (laparoscopic 2,793 vs. open 2,756), there were no significant differences in terms of feasibility, intraoperative outcome and oncological quality (R0 status and LN yield). Surgical morbidity and mortality were comparable. Patients after laparoscopic surgery showed a significantly faster early postoperative recovery with a lower overall morbidity. In contrast, operative time was significantly prolonged by an average of 45 min compared to the open technique. Comparing ESD with laparoscopic distal radical surgery for tumors in lower third the HRQoL measured after 6 months with 36-term short form was significantly better compared to the surgical group (P<0.001) (36).

The advantage of surgical procedures is complete tumor removal, which is accompanied by an increased rate of undesirable side effects compared to endoscopic resection. The introduction of robot-assisted surgery attempts to optimize procedures and thus compensate for human inadequacies (37). However, a learning phase must also be taken into account here. For EMR and ESD, there is an increased risk of incomplete tumor removal regarding both the primary tumor and LNM. There are various approaches to improving the methods. Robot-assisted applications are also being tested in endoscopy (38,39). Kim et al. were able to show that robot-assisted gastric endoscopic submucosal dissection significantly improves procedure time at challenging locations (39). Endoscopic procedures are combined with laparoscopic lymphadenectomy with the aim to combine the benefits of the two procedures (38,40).

Independently of the kind of resection of the primary tumor, D1(+) or D2 lymphadenectomy is recommended for putative nodal metastasis. Results after these resections for pT1b gastric carcinoma indicated that more than 70% of the patients had no metastasis in the regional LNs. Therefore, several ideas were developed to reduce the invasiveness of the therapeutic procedure with the aim to improve the HRQoL for those patients.

Diagnosis and prediction of LNM in gastric cancer

The presence of LNM is one of the most important prognostic factors in patients with gastric carcinoma. All therapeutic decisions depend on the knowledge about lymphatic invasion of the tumor. Therefore, many ideas and clinical studies were available based on clinical diagnosis to predict the existence of LNM.

Endoscopy mostly combined with EUS is one of the standard diagnostic methods for gastric cancer. Therefore, it could be possible to detect suspected regional LNs by this method. The results of a meta-analysis including 22 EUS-studies for cancer in the upper gastrointestinal tract showed a sensitivity of 62% and specificity of 80% (11). The explanation for the low accuracy of EUS is the fact that the size of LNM may be very small. In a study a total of 1,253 LNs from 31 patients with gastric cancer were examined (41). Eighty percent of the tumor-free LN were smaller than 5 mm and whereas 182 (55%) nodes containing metastases were less than 5 mm in diameter. It is obvious that EUS cannot detect such phenomena as nodal micrometastasis or extra nodal lymphatic infiltration. The performance of conventional EUS in diagnosing LNM for gastric cancer could be improved, with the assistance of EUS-guided fine needle aspiration (EUS-FNA), EUS elastography (EUS-E) and contrast-enhanced EUS (CE-EUS). Lisotti et al. (42) included four studies with 336 patients in their meta-analysis and the results showed an improved sensitivity and specificity using CE-EUS of 82.1% and 90.7%, respectively.

Radiologic based methods have comparable problems with the detection and differentiation between tumor-free and infiltrated small LNs. Therefore, radiomic features are more and more used for the prediction of LNM. These methods used the characteristics of tissue and lesions like heterogeneity and shape. In combination with information about patient’s demographics, type of histology, genomic or proteomic data the medical problems could be easier be solved (43). In an actual study You et al. (44) looked for detection of LNM in advanced gastric cancer. They found that radiomics features or combined traditional features have high diagnostic performance in determining the nature of each LN with a short-axis diameter of ≥6 mm in advanced GAC.

A more invasive method is the SN biopsy. The technique is based on the concept that the tumor-bearing status of the SN, which is defined as an LN that directly drains a specific cancer, reflects the tumor status of the remaining nodes. In a Japanese multicenter trial, the feasibility and accuracy of diagnosis using SN biopsy in T1 gastric cancer was evaluated. The proportion of false negatives was much higher than expected (45). A large meta-analysis including 38 studies and more than 2,000 patients with EGC showed a SN detection rate of 94% and an accuracy for LNM detection of 92% (46).

The lymphatic drainage pathways are highly diverse in gastric cancer (47). Skip metastases are more often found in gastric cancer than in other tumors like melanoma or breast cancer. Lee et al. found such skip metastases in patients with EGC, that means that drainage LNs are difficult to predict based on the primary tumor location (48). The results show on the one hand how important it is to have a reliable prediction of possible LNM preoperatively and or intraoperatively and on the other hand explain the different approaches of the research groups to solve the problem. Kinami et al. (49) defined five independent lymphatic basins per feeding artery surrounding the stomach to classify lymphatic pathways. Then, the efficacy of SN biopsy was investigated on a lymphatic basin. Thus, even though LN metastasis was detected in non-SN, LN metastasis can be eradicated in SN biopsy as long as non-SN with metastasis is included in the same lymphatic basin as SN (48). The classification of SN basin area is slightly different between Japan and South Korea. In Japan, gastric lymphatic basins are classified into five directions along the main gastric feeding arteries (49), and in South Korea into 10 nodal stations (50). The application of SNNS for gastric cancer has been inconclusive due to the complexity of the lymphatic networks in the stomach. In South Korea, the SENORITA trial was conducted to investigate the efficacy of SN navigation surgery for gastric cancer (2). This RCT evaluated the application of SNNS combined with different version of laparoscopic SNNS (LSNNS) in comparison to laparoscopic standard gastrectomy (LSG) with LN dissection. The SENORITA study did not show the non-inferiority of LSNNS to conventional LSG in terms of 3-year disease-free survival (DFS), which was the primary endpoint of this RCT. The rate of postoperative complications did not differ between both groups. However, LSNNS showed benefits in terms of quality of life and nutrition relative to LSG.

The actual study evaluated the results of the SENORITA trial after 5 years of follow-up (1). The 5-year DFS was not significantly different between the LSG and LSNNS groups (P=0.0561). Nevertheless, during the 5-year follow-up, gastric cancer-related events, such as metachronous cancer, were more frequent in the LSNNS group than in the LSG group.

To assess the value of this very careful performed study, various aspects must be considered. The aim of both study arms was complete tumor removal regarding the primary tumor and possible LNM. For patients for whom there is no indication for endoscopic resection, surgical therapy is the adequate treatment option. In the SENORITA trial, the laparoscopic approach was chosen due to its lower invasiveness compared to the open approach. In the LSNNS arm, an attempt was made to keep the extent of the surgical procedure as low as possible by using a complex examination technique in order to minimize complications. The goal was not achieved, as there was no difference in postoperative complications between the two groups. Furthermore, the LSNNS group had more tumor-related incidents than the standard group. For patients in regions where these procedures are commonly used, this procedure is nevertheless a treatment option to be discussed, as the quality of life was better in the following years and the 5-year survival time was not significantly affected. However, the use of this option in countries with low rates of EGC does not seem particularly promising, as experience in its use will be difficult to achieve. Thus, the search for a less invasive method to determine possible LNM in EGC and thus a therapy that is less injurious and HRQoL-impairing remains an exciting field of work.

Artificial intelligence (AI) for the detection of LNM in EGC

The diagnosis of gastric carcinoma should be made at an early stage. Then, patients have the prospect of a good prognosis. A prerequisite for achieving this goal is the complete removal of the tumor at an early stage. Complete removal, that means the resection of the primary tumor and possible tumor spread into the regional lymphatic vessels and nodes. The stomach has very branched lymphatic pathways, which makes it difficult to detect metastases of the tumor in the lymphatic vessels. Many attempts to predict LNM are well-known and sometimes very time-consuming. The question arises as to whether we are not able to make the prediction of LNM so accurate by specifically entering patient- and tumor-specific parameters with the help of AI that the time-consuming and stressful procedures for the patient could be avoided.

AI refers to the ability of machines to perform tasks that normally require human intelligence. This includes things like learning, problem solving, speech recognition and decision making. AI systems can analyze data, recognize patterns and even learn on their own to improve their performance. AI includes different techniques such as machine learning (ML), deep learning (DL), and natural language processing (NLP). ML is a subset of AI that involves systems that can learn by themselves. DL is a subset of ML that uses models built on deep neural networks to detect patterns with minimal human involvement (51). Artificial neural networks (ANNs) are a class of nonlinear mathematical models that are characterized by a complex structure of interconnected computational elements, the neurons. These computational elements aggregate a series of inputs (factors that influence the development of LNM) by using a summation operation and produce an output, such as the probability that an LN is infiltrated by tumor.

One of the first attempt in using such computer assistance was the Maruyama computer program for the evaluation of LNM in gastric cancer. For this purpose, the authors used data from 4,302 primary gastric cancers treated at the National Cancer Center Hospital in Tokyo between 1969 and 1989 (52). The validity of this program for European patients was evaluated by several authors (53,54). The Maruyama computer program showed good predictive ability for LN metastases in most of the 16 LN stations. The predictive values could be improved using an ANN for the prediction of LN’s (55).

During the last few years several applications of AI in gastric cancer have been published. A systematic review showed that in addition to the prediction and detections of LNM, topics like analysis of endoscopic or radiologic findings for better and quicker diagnosis have gained more and more attention (56).

Table 1 shows examples of AI applications for the prediction of LNs in EGC (55,57-63). Different parameters were included and varying methods for the prediction were used. It is not surprising that most of the studies come from Asia. There are large number of patients and consequently the experience of an optimal treatment for this diagnosis is available. As discussed above, the transferability of these approaches is therefore limited to the Western patient cohorts.

Of course, there are still obstacles to the further and meaningful application of AI in medicine. First of all, large and, above all, valid data sets must be created for training and validation. AI algorithms are usually a black box whose function is not well understood by users. A natural mistrust is therefore predictable. Conversely, blind trust can also cause damage. As a consequence, there is still a lot to consider, especially around data security, in order to be able to use such systems sensibly.

In our vision for the future, we are able to combine the knowledge about the patient variability from East and West using the optimal diagnostic tools for the prediction of LNM. Computers today are powerful enough to process such a large amount of data, as is the knowledge of doctors and computer scientists about the correct application. If we had such a tool, then we could offer many patients a specific therapy that is less aggressive and therefore minimizes side effects.

Conclusions

If a carcinoma of the stomach is diagnosed at an early stage, the chances of cure are very high. All therapeutic measures aim to total remove the tumor without causing too much harm to the patient. Various ideas such as the reduction of surgical trauma through the introduction of minimally invasive surgical procedures or endoscopic methods to remove the primary tumor have shown success. The question of the optimal extent of LN removal is the subject of current research. The different frequency of EGC between East and West must be considered here. The transfer of experience may be facilitated in the future using AI.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-33/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-33/coif). P.S.P. reports receiving the Theodor Billroth-Award 2021 and prize money from the German General and Visceral Surgical Society for the best habilitation, the Julius-Springer-Award 2022 from the journal Die Chirurgie, and personal honoraria for lecture from Berlin-Brandenburger Darmtag (Ernst von Bergmann Klinikum Potsdam) in 2024. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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