Lymph node metastasis risk in submucosal invasive gastric cancer based on C-reactive protein gene polymorphism analysis.

We aimed to elucidate clinicopathological variables associated with lymph node metastasis of submucosal invasive gastric cancer. Specimens were surgically resected from 201 patients who had primary submucosal gastric cancer. We studied 39 consecutive patients with lymph node metastasis and 162 patients without lymph node metastasis. We compared the following clinicopathological characteristics of the patients in relation to lymph node metastasis: age, sex, tumor size, histology, extent of submucosal invasion, lymphatic and venous invasion, and ulceration of the tumor. Submucosal invasion was divided subjectively into sm1, sm2, and sm3 (representing invasion of the upper-, middle-, and lower-third of the submucosa, respectively). We also studied the relationship between lymph node metastasis of submucosal gastric cancer and immunohistochemistry for p53, Ki67, vascular endothelial growth factor (VEGF), alpha-fetoprotein, sLe(a), and dendritic cells (DCs). In terms of conventional pathological factors, lymph node metastasis in submucosal gastric cancer was related to tumor size (P = 0.002), depth of submucosal invasion (P = 0.001), lymphatic invasion (P < 0.0001), and venous invasion (P = 0.012). Lymph node metastasis in sm1 gastric cancer was significantly related to VEGF expression (P = 0.047). Also, lymph node metastasis in sm3 gastric cancer was significantly correlated with DC expression (P = 0.016). Multivariate analysis showed that tumor size, tumor invasion depth in the submucosal layer, and lymphatic invasion were independent predictors of nodal metastasis in submucosal gastric cancer. Conventional pathological factors, such as tumor size, depth of submucosal invasion, and lymphatic invasion, have a significant influence on lymph node metastasis. VEGF expression and DC expression may be helpful predictors of lymph node metastasis in patients with sm1 and sm3 gastric cancer, respectively.

AGA Clinical Practice Update on the Utility of Endoscopic Submucosal Dissection in T1b Esophageal Cancer: Expert Review

An accurate assessment of potential lymph node metastasis is important for the appropriate treatment of early gastric cancers. Therefore, this study analyzed predictive factors associated with lymph node metastasis and identified differences between mucosal and submucosal gastric cancers. A total of 518 early gastric cancer patients who underwent radical gastrectomy were reviewed in this study. Clinicopathological features were analyzed to identify predictive factors for lymph node metastasis. The rate of lymph node metastasis in early gastric cancer was 15.3% overall, 3.3% for mucosal cancer, and 23.5% for submucosal cancer. Using univariate analysis, risk factors for lymph node metastasis were identified as tumor location, tumor size, depth of tumor invasion, histological type and lymphovascular invasion. Multivariate analysis revealed that tumor size >2 cm, submucosal invasion, undifferentiated tumors and lymphovascular invasion were independent risk factors for lymph node metastasis. When the carcinomas were confined to the mucosal layer, tumor size showed a significant correlation with lymph node metastasis. On the other hand, histological type and lymphovascular invasion were associated with lymph node metastasis in submucosal carcinomas. Tumor size >2 cm, submucosal tumor, undifferentiated tumor and lymphovascular invasion are predictive factors for lymph node metastasis in early gastric cancer. Risk factors are quite different depending on depth of tumor invasion. Endoscopic treatment might be possible in highly selective cases.

To evaluate risk factors for lymph node (LN) metastasis in mucosal gastric cancer, particularly the effect of cellular differentiation, and implications for the indication of endoscopic submucosal dissection (ESD). The indication of ESD has been expanded to undifferentiated-type (UD-type) gastric cancer despite risk of LN metastasis. Patients who underwent radical gastrectomy for pT1a stage primary gastric adenocarcinoma between 2008 and 2012 were retrospectively analyzed. We evaluated risk factors of LN metastasis using univariate and multivariate analyses. Pathologic slides of primary tumor and metastatic LNs from LN positive patients were reviewed. A total of 1003 mucosal gastric cancer patients were enrolled, and mean number of retrieved LNs was 35.5. Eighteen (1.8%) among them had LN metastasis: 2 of the 502 differentiated-type (D-type) patients and 16 of the 501 UD-type patients (0.4% vs 3.2%, P < 0.001). Type of cellular differentiation was a significant risk factor for LN metastasis in univariate and multivariate analyses. Of 216 UD-type patients satisfying the expanded indication of ESD, 5 patients (2.3%) showed LN metastasis. Despite more aggressive clinical features such as larger size of tumor and more LN metastasis, the UD-type cancer showed a less invasion into the muscularis mucosae layer than the D-type cancer. Because UD-type cancer is a risk factor for LN metastasis in mucosal gastric cancer, ESD cannot be concluded to be a better option than surgery in all UD-type cancer patients. Redefinition of the expanded indication of ESD is required.

The clinicopathologic features of gastric cancers containing a mixture of differentiated-type and undifferentiated-type components remain uninvestigated. We evaluated the risk of lymph node metastasis and the feasibility of endoscopic submucosal dissection (ESD) for the treatment of mixed-histologic-type gastric cancers. We histologically classified 376 cases of gastric cancer with submucosal invasion into four types (differentiated type, differentiated-type-predominant mixed type, undifferentiated-type-predominant mixed type, and undifferentiated type) and studied the clinicopathologic relations of each type to lymph node metastasis. Lymphatic invasion was evaluated by D2-40 immunostaining. The overall prevalence of lymph node metastasis in gastric cancer with submucosal invasion was 16.5% (62/376). The prevalence of lymph node metastasis was 36.5% (23/63) in undifferentiated-type-predominant mixed type, which was significantly higher than those in the other three types (P < 0.001 vs. differentiated type, P = 0.013 vs. differentiated-type-predominant mixed type, and P = 0.003 vs. undifferentiated type). Lymphatic invasion, a depth of invasion of 500 microm or more from the lower margin of the muscularis mucosae (SM2), tumor size above 30 mm, and undifferentiated-type-predominant mixed histologic type were independent risk factors for lymph node metastasis. Submucosal cancers without these four risk factors were free of lymph node metastasis (0/41; 95 % confidence interval 0%-8.6%). Undifferentiated-type-predominant mixed-type gastric cancer with submucosal invasion carries a high risk of lymph node metastasis. ESD can be indicated for gastric cancer with submucosal invasion provided that the following conditions indicating a low risk of metastasis are met: a depth of invasion of no more than 500 microm or more from the lower margin of the muscularis mucosae (SM1), no lymphatic invasion, a tumor size of no more than 30 mm, and a proportion of undifferentiated components below 50%.

Lymph node metastasis, a crucial factor in the spread of gastric cancer (GC), is strongly associated with a negative prognosis for patients. This study aimed to investigate the association of the mesothelin (MSLN) gene polymorphisms (rs3764247, rs3764246, rs12597489, rs1057147, and rs3765319) with the risk of lymph node metastasis of GC patients in a Chinese Han population. The PCR-LDR genotyping was used to detect the genotypes of MSLN polymorphisms in GC patients with lymph node metastasis (n = 610) or without (n = 356). Our research indicates that certain genetic markers, specifically rs3764247, rs3764246, rs12597489, and rs3765319, do not appear to be linked with an increased risk of lymph node metastasis in GC. However, we did observe that patients with the rs1057147 GA genotype exhibited a higher likelihood of lymph node metastasis in GC when compared to those with the GG genotype (OR = 1.33, 95% CI = 1.01 - 1.76, P= 0.045). Patients with rs1057147 GA + AA genotype were found to have a higher likelihood of lymph node involvement (OR = 1.35, 95% CI = 1.03 - 1.77, P = 0.029) when compared to those with GG genotype in the dominant model. The allelic model revealed that the A allele of rs1057147 exhibited a stronger correlation with lymph node metastasis compared to the G allele (OR = 1.28, 95% CI = 1.02 - 1.60, P = 0.031). In addition, we found that rs1057147 polymorphism revealed a poor prognosis for GC patients with lymph node metastasis. Further stratified analysis revealed that the prognostic effect of rs1057147 was more pronounced in patients with GC who had lymph node metastasis and had a tumor size of 4cm or greater, as well as more than 2 lymph node metastases. Bioinformatics studies showed that the binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147. Our study confirmed the important role of MSLN rs1057147 polymorphism locus in GC lymph node metastases and suggested a potential prognostic factor during GC progression. KEY POINTS: • Rs1057147 GA genotype had an increased risk of lymph node metastasis in gastric cancer. • The A allele of rs1057147 had a stronger association with lymph node metastasis than the G allele. • The binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147.

With respect to gastric cancer treatment, improvements in endoscopic techniques and novel therapeutic modalities [such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD)] have been developed. Currently, EMR/ESD procedures are widely accepted treatment modalities for early gastric cancer (EGC). These procedures are most widely accepted in Asia, including in Korea and Japan. In the present era of endoscopic resection, accurate prediction of lymph node (LN) metastasis is a critical component of selecting suitable patients for EMR/ESD. Generally, indications for EMR/ESD are based on large Japanese datasets, which indicate that there is almost no risk of LN metastasis in the subgroup of EGC cases. However, there is some controversy among investigators regarding the validity of these criteria. Further, there are currently no accurate methods to predict LN metastasis in gastric cancer (for example, radiologic methods or methods based on molecular biomarkers). We recommend the use of a 2-step method for the management of early gastric cancer using endoscopic resection. The first step is the selection of suitable patients for endoscopic resection, based on endoscopic and histopathologic findings. After endoscopic resection, additional surgical intervention could be determined on the basis of a comprehensive review of the endoscopic mucosal resection/endoscopic submucosal dissection specimen, including lymphovascular tumor emboli, tumor size, histologic type, and depth of invasion. However, evaluation of clinical application data is essential for validating this recommendation. Moreover, gastroenterologists, surgeons, and pathologists should closely collaborate and communicate during these decision-making processes.

Purpose: Lymph node metastasis is an important prognostic factor in patients with early gastric cancer. Therefore, we analyzed the predictive factors for lymph node metastasis in submucosal gastric cancer and explored the feasibility of minimally invasive surgery. Methods: The clinicopathological features of 317 patients with submucosal gastric cancer, who underwent radical gastrectomy with lymph node dissection at Department of Surgery, Keimyung University School of Medicine from January 2003 to December 2007, were examined retrospectively. The lesions were divided into 3 layers according to the depth of submucosal invasion of the cancer cell (SM1, SM2, and SM3). We analyzed the clinicopathological variables regarding lymph node metastasis. Results: Of the 317 patients, 74 patients (23.3%) had lymph node metastasis. Tumor size, histological type, Lauren classification, depth of invasion, lymphatic invasion, vascular invasion, and perineural invasion showed a positive correlation with lymph node metastasis by univariate analysis. In multivariate analysis, tumor size (≥4 cm vs ＜2 cm, P=0.034 and 2∼4 cm vs ＜2 cm, P=0.043), histological type (P=0.013), and lymphatic invasion (P=0.000) were significantly correlated with lymph node metastasis. Conclusion: Tumor size, histological type, and lymphatic invasion were independent risk factors for lymph node metastasis in submucosal gastric cancer. Minimally invasive surgery, such as endoscopic submucosal dissection may be applied to submucosal gastric cancer with a tumor size less than 2 cm, differentiated histological type, and no lymphatic invasion.

Early gastric cancer that meets the expanded criteria for endoscopic resection (ER) is expected to be associated with a negligible risk for lymph node metastasis (LNM); however, recent studies have reported LNM in submucosal gastric cancer patients who met the existing criteria. In this study, we develop the revised criteria for ER of submucosal gastric cancer with the aim of minimizing LNM. We analyzed the clinicopathological data of 2461 patients diagnosed with differentiated, submucosal gastric cancer who underwent surgery at three tertiary hospitals between March 2001 and December 2012, and re-analyzed the pathological slides of all patients. The depth of submucosal invasion was measured histopathologically in two different ways (the classic and alternative methods) to obtain accurate data. Of the enrolled subjects, 306 (17.0%) had LNM. The width of submucosal invasion correlated well with the LNM. We defined the depth and width of submucosal infiltration associated with the lowest incidence of LNM. None of the 254 subjects developed LNM when the following criteria were met: tumor diameter ≤ 3cm, submucosal invasion depth < 1000μm (as measured using the alternative method), submucosal invasion width < 4mm, no lymphovascular invasion, and no perineural invasion; however, LNM was observed in 2.7% of subjects (6/218) who met the existing criteria. We revised the criteria for ER by adopting the alternative method to measure the depth of submucosal invasion and adding the width of such invasion. Our criteria better predicted LNM than the current criteria used to select ER to treat submucosal gastric cancer.

OBJECTIVE To identify clinicopathological characteristics as predictive factors for lymph node metastasis in submucosal gastric cancer, and in addition to establish objective criteria as indications for endoscopic submucosal dissection (ESD). METHODS Data from 130 patients with submucosal gastric cancer were collected, and the relationship between their clinicopathological characteris -tics and the presence of lymph node metastasis was retrospectively analyzed by multivariate analysis. RESULTS In the multivariate logistic regression model, a tumor size of 2 cm or more and an undifferentiated histologic type were found to be inde -pendent risk clinicopathological characteristics for lymph node metastasis. Among 130 patients with submucosal carcinoma, no lymph node metastases were observed in 17 patients who showed neither of the two risk clinicopathological characteristics. Lymph node metastasis occurred in 61.1% (22/36) of the patients who had both risk clinicopathological characteristics. CONCLUSION A tumor size of 2 cm or more and an undifferentiated histologic type were significantly and independently related to lymph node metastasis in submucosal gastric cancer. It is rational for the paitients with neither of these two independent risk clinicopathological characteristics to undergo an ESD.

Endoscopic submucosal dissection (ESD) enables en-bloc resection of large lesions more than 20 mm in size. Therefore, the use of ESD has gained broader acceptance for clinical applications globally. Previous reports on long-term outcomes after ESD, when followed by additional surgery, have also reported favorable results, positioning ESD as a crucial tool in providing minimally invasive treatment for T1 colorectal cancer (CRC). However, a lack of clear evidence regarding optimal surveillance strategies for T1 CRC following endoscopic treatments such as ESD remains. In some cases of T1 CRC, the need for additional surgery to address the risk of lymph node metastasis (LNM) remains a significant concern in daily practice. This narrative review aimed to examine the evidence on surveillance and additional surgery following the endoscopic treatment of T1 CRC by evaluating the criteria for intervention and associated risk factors. In cases where there are no unfavorable pathological features or risk factors for LNM, the risk of LNM is extremely low, and endoscopic techniques alone are typically sufficient in achieving curative resection for these patients. However, when risk factors for LNM are present, additional surgery should be considered. Several current guidelines recommend determining whether to pursue additional surgery or surveillance based on these risk factors, which must be carefully assessed according to individual patient conditions. Further studies are required to clarify the long-term prognosis, risk of lymph node or distant metastasis, and appropriate surveillance strategies, which may include salvage treatment such as additional surgery.

We thank Dr. Fatourou and Roukos for their interest and remarks in response to our article regarding endoscopic resection for undifferentiated early gastric cancer [1]. Since 1999, a national cancer screening program has recommended upper gastrointestinal endoscopy to the normal population older than 40 years for early detection of gastric cancer in Korea. The proportion of early gastric cancer indicated for endoscopic resection has increased. Although conventional endoscopic resection was limited to complete resection only for large or deep tumors confined to the mucosa without the risk of lymph node metastasis, newly developed endoscopic submucosal dissection has enabled complete resection of larger and deeper tumor without any technical barrier. With the progress of technical advances, Japan has proposed expanding the indications for endoscopic resection of early gastric cancer [2]. Although tumor of undifferentiated histology has the risk of much larger size and deeper invasion than expected, some portion of an early lesion could possibility be indicated for complete endoscopic resection as a minimally invasive treatment. In a retrospective study with postoperative pathologic review, undifferentiated early gastric cancer smaller than 2.5 cm and confined to the mucosa did not show any lymph node metastasis in a large series [3]. As expected, the complete resection rate for undifferentiated early gastric cancer was significantly lower than for differentiated histology, which explains the possibility of diffuse infiltration of tumor with undifferentiated histology and the risk of lymph node metastasis. Although endoscopic submucosal dissection has improved the complete resection of early gastric cancer more than conventional mucosal resection, expanding the indication to tumor of undifferentiated histology has the risk of incomplete resection or lymph node metastasis and should be accompanied by long-term follow-up evaluation. We think the indication for endoscopic resection of undifferentiated gastric cancer should be limited to small tumors confined to the mucosa.

Lymph node metastasis in multiple synchronous early gastric cancer

TO THE EDITOR: The article by Gunderson et al provides powerful evidence to support the revised staging system in the seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual for colon cancer. The case numbers of national-based survival data are large enough to explore significant subtle staging factors. However, an interesting point about Tis colon cancers is worthy of deeper discussion, which was not mentioned in the article. We found the contents both in Table 1 and Table 2 in this article showed that a proportion of Tis colon cancers had lymph node metastasis, with a very low incidence. A total of 5,939 patients had Tis colon cancer, and 95 patients (1.6%) had N1 disease and 19 patients (0.32%) had N2 disease. This finding challenges our previous general rule that colon cancer confined to the mucosa has no chance of metastasis and thus no further treatment is needed. According to the previous AJCC consensus in 2000, colon tumors invading the lamina propria up to and including the muscularis mucosae have no associated risk of regional lymph node metastasis. However, recent data using immunohistochemical marker D2-40 have shown the presence of lymphatic channels extending to the colonic mucosa in neoplastic and inflammatory conditions. Literature on the subject of metastatic risk in intramucosal colorectal carcinoma is extremely limited. Only one patient with poorly differentiated intramucosal rectal cancer had recurrence after surgical resection. We reviewed the patient group in our hospital. In total, there were 3,196 patients with colorectal cancer who received treatment at our hospital during 1999 to 2005. Among the 118 patients receiving regional resection for Tis tumors, no lymph node metastasis was found, except in one patient with a polypoid lesion. The pathology slides of this patient were reviewed carefully, and the tumor was actually a T2 lesion that invaded the superficial muscle layer. In fact, certain types of intramucosal cancer can have lymph node metastasis in gastric cancer. In colorectal cancer, data are still lacking regarding lymph node metastasis in intramucosal tumors. We suggest that all pathologic slides of these intramucosal colon cancers with lymph node metastasis in this article should be reviewed carefully, if possible, to certify the actual invasion depth of the tumor. If it is true that lymph node metastasis could occur in intramucosal colon cancer, it will provide us with a new point of view concerning the treatment of this type of tumor. As a result of recent advances for endoscopic procedures, such as endoscopic mucosal resection or endoscopic submucosal dissection, local treatment for early colorectal cancers is generally accepted and widely applied. If intramucosal colon cancers could have risk of metastasis, additional investigation is warranted to define the high-risk group before applying local treatment for these patients.

Expansion of lymph node metastasis in mixed-type submucosal invasive gastric cancer