A nomogram for predicting the likelihood of lymph node metastasis in early gastric patients

Gastric cancer is currently among the most common cancer worldwide and the second most common cause of cancer-related death [1‐3]. Early gastric cancer (EGC) is defined as a lesion confined to the mucosa or submucosa, regardless of the size or the presence of regional lymph node metastasis [4‐7]. Treatment options for EGC include endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), wedge resection, laparoscopically assisted gastrectomy and open gastrectomy [8, 9]. Currently, although gastrectomy plus lymph node dissection is still the gold standard of treatment for EGCs, endoscopic surgical techniques have been widely accepted as an alternate treatment for EGC patients with the appropriate criteria to maintain the quality of life for a subgroup of EGC patients [7, 10‐12]. Technically, endoscopic surgery is used to dissect the mucosal or the submucosal layer, with regional lymph nodes left untreated. Thus, identifying patients with a high risk of lymph node metastasis is crucially important for the application of endoscopic surgery.

The likelihood of lymph node metastasis is one of the most important factors to consider when determining the most appropriate treatment. The absence of lymph node metastasis is a prerequisite for EMR/ESD [12], which preserves gastric function and maintains quality of life by avoiding a radical gastrectomy. Endoscopic resection for EGC is currently the established choice of treatment in Korea and Japan because it is both minimally invasive and effective in the curative management of EGC [13, 14]. Endoscopic resection with curative intent is indicated only in tumors that fulfill the endoscopic resection criteria because these tumors rarely metastasize to lymph nodes [15]. Recently, based on a large-scale case series, expanded indications for endoscopic resection have been proposed because those tumors meeting the expanded criteria had no risk of lymph node metastasis [16]. Previous studies have suggested that the definite indications of endoscopic resection include differentiated adenocarcinoma, intramucosal cancer, a tumor size up to 20 mm and the absence of ulceration [17‐19]. In the era of endoscopic resection, the accurate prediction of the risk of lymph node metastasis in EGC is crucial to select patients suitable for this procedure.

Nomograms have been developed to quantify risk factors of lymph node metastasis in several carcinomas [20, 21]. However, there is no predictive nomogram for the risk of lymph node metastasis in EGC, especially in the Eastern population, which has a high incidence of gastric cancer [22]. The aim of the present study was to identify risk factors for lymph node metastasis and construct a nomogram for patients with EGC to guide treatment.

Most surgeons consider D2 lymphadenectomy (dissection of all group I and group II lymph nodes) to be the standard and optimal surgical procedure for patients with EGC within the past ten years [28, 29]. The lymph node metastasis incidence of EGC is reported to be approximately 11 % to 18 %, and approximately 70 % to 80 % of patients will undergo overtreatment with D2 lymphadenectomy [29‐32]. Recently, less invasive treatments have been performed for EGC, including endoscopic mucosal resection and endoscopic submucosal dissection [33, 34]. Because of recent advances in surgical instrumentation and techniques, laparoscopic procedures have also been suggested as an alternative minimally invasive treatment for EGC [35, 36]. For this purpose, we retrospectively analyzed 597 EGC patients based on clinical and routinely definitive pathological characteristics to investigate the evidence used for making medical decisions. Many cancer clinicians are increasingly becoming attracted to simple tools such as Nomograms to improve cancer treatment. In the present study, we have developed a nomogram that could predict the incidence of lymph node metastasis in EGC patients.

The lymph node metastasis incidence of all EGC patients was 9.7 % in the current study, 51.7 % in cancers with lymphovascular invasion, 20.8 % in cancers with an ulcer, 14.0 % in cancers with an undifferentiated histology, 18.3 % in submucosal cancers, 13.1 % in larger sized tumors (≥2.0 cm), 17.9 % in macroscopic type III/mixed, and 15.0 % in younger patients (<50 years old), which are similar to or lower than previous results [32, 38, 39]. In the multivariate analysis, the patients’ age at diagnosis, differentiation status, the presence of an ulcer, lymphovascular invasion and depth of invasion were independent factors for lymph node metastasis, and the presence of lymphovascular invasion was considered the most important predictor. Previous surveys have clarified the pathological characteristics of EGC with or without nodal metastases. Histologic ulceration of the tumor, larger size (≥20 mm) and submucosal penetration were independent risk factors for regional lymph node metastasis [39, 40]. Lymphovascular involvement and mixed histological type tumors have previously been reported as risk factors for nodal metastases [41, 42]. In general, the depth of tumor invasion reflects the progression of a tumor originating from the mucosal layer and is significantly associated with the presence of regional lymph node metastasis in EGC [18]. Our results were consistent with the above studies. Based on the previous studies and our results, the tumor size, macroscopic type and histology were considered to have significant clinical meaning among the risk factors of lymph node metastasis in EGC. Therefore, we chose these characteristic features in our nomogram for predicting the incidence of lymph node metastasis in EGC. This figure could generate estimates of the likelihood of metastatic lymph node involvement. Our nomogram appears to be simple and practical with a relatively high area under the ROC curve of 0.860, thus exhibiting a good performance related to a mean error that never exceeded 5 %. These findings support our selection of variables for determining suitable treatment.

The gold standard in the curative treatment of gastric cancer is a radical operation generally associated with D2 lymphadenectomy which has a high success incidence in early cases [43]. However, some complications and mortality are associated with this procedure that are not always necessary [44]. Certain groups of patients with EGC have a lower possibility of lymph node metastases, allowing less invasive treatment strategies to be adopted for these situations [38]. Endoscopic resection with curative intent is indicated only in tumors that fulfill the endoscopic resection criteria because these tumors rarely metastasize to lymph nodes [16]. These treatments preserve bodily functions and maintain quality of life. Our investigation has provided a good and helpful method to address this issue. For example, an undifferentiated submucosal gastric cancer patient with an ulcer and lymphovascular invasion, who is younger than 50 years of age, has more than an 80 % possibility of lymph node metastasis without considering other factors. This patient is suitable for a radical operation with lymphadenectomy or laparoscopic lymph node dissection following endoscopic dissection. In contrast, a patient with opposite characteristics, such as differentiated mucosal cancer, without an ulcer or lymphovascular invasion, and older than 50 years old, has almost no risk of lymph node metastasis with respect to other patients (less than 5 %), and should receive less invasive treatments. Therefore, we believe our nomogram will assist surgeons in selecting the appropriate treatment for patients with EGC with regard to the probability of lymph node metastasis.

To our knowledge, this is the first study providing a nomogram to predict the incidence of lymph node metastasis for EGC. The potential limitations of this study include the small cohort, and we should expand the sample size to improve the nomogram. Additionally, this is a single center retrospective study that needs further external validation with different populations. In this study, we did not use specific cutoff values of lymph node metastasis for different treatments with EGC. Despite these limitations, this nomogram offers an effective tool to predict the incidence of lymph node metastasis for EGC patients, with which we could select the appropriate treatments for patients.

In conclusion, the present study constructed a nomogram to predict the probability of lymph node metastasis in EGC patients based on lymphovascular invasion, depth of invasion, differentiation, age, macroscopic type, size, and histology. This tool can assist clinicians and patients in quantifying the potential lymph node metastasis incidence to make surgical decisions. Certain patients are suitable for a radical operation or endoscopic dissection plus D2 lymphadenectomy, and some patients can be selected for only endoscopic dissection (ESD, EMR). For future studies, we should expand the sample size, add additional centers to prove this nomogram, and determine the cutoff value of the lymph node metastasis incidence for different treatments.