Lymph node metastasis in early gastric adenocarcinoma in the United States of America

• Abstract
• Introduction
• Patients and methods
• Overview
• Tumor classification
• Exclusion criteria
• Statistical analysis
• Results
• Analysis cohort
• Univariate associations with lymph node involvement
• Univariate association with low grade early-stage gastric adenocarcinoma
• Univariate association with low grade T1a tumors
• Univariate association with low grade T1b tumors
• Multivariable analysis of lymph node involvement
• Discussion
• References

Abstract

Background and study aims Localized approaches are being increasingly used in the management of early gastric adenocarcinoma; however, there are limited data on lymph node metastasis in the US population. This study examined the incidence and predictors of lymph node involvement for early-stage gastric adenocarcinomas in the USA.

Patients and methods Data were abstracted from the national SEER database from 2004 to 2013. Exclusion criteria included: cases with unknown tumor characteristics, unknown patient characteristics, metastatic disease, neoadjuvant radiation, and lack of surgical resection or lymph node evaluation. Univariate and multivariable analyses were conducted to assess the relationship of tumor stage, grade, and size, and patient sex, race, and age with nodal involvement.

Results 43 769 cases of gastric adenocarcinoma were initially abstracted. After exclusions, 1577 patients remained for analysis. Multivariable analysis revealed that tumor stage (P < 0.001), grade (P = 0.008), and size (P < 0.001) were independent predictors of nodal metastasis. For low grade T1a tumors, nodal metastasis was present in 1.7 %, 1.7 %, 4.5 %, 4.1 %, and 20 % of tumors 0 – 1 cm, 1 – 2 cm, 2 – 3 cm, 3 – 4 cm, and ≥ 4 cm in size, respectively (P < 0.001), and in 8.4 %, 18.0 %, 19.5 %, 22.0 %, and 35.8 % of T1b tumors, respectively (P < 0.001).

Conclusions Low grade T1a tumors < 4 cm in size have low rates of nodal metastasis in the US population and may warrant consideration for local resection. Larger, higher grade T1b tumors have high rates of nodal metastasis in the US population and lymph node dissection may be indicated for patients who are surgical candidates.

Introduction

Gastric cancer is the fourth leading cause of cancer death in the world [1]. This disease has a high incidence in East Asia, South America, and Eastern Europe, and a lower incidence in the USA [2] [3] [4] [5] [6]. Early-stage gastric cancer is defined as gastric cancer limited to the lamina propria or mucosa (T1a) and submucosa (T1b) [7]; it is associated with increased survival [8] compared with all other stages of gastric cancer.

Traditionally, the mainstay of curative treatment for gastric cancer has been total or subtotal gastrectomy ± chemotherapy [9]. Such surgery is associated with significant morbidity and long-term implications for quality of life [9]. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are less invasive, organ-sparing approaches for early gastric cancer, which are standard therapy in Asia and are being increasingly utilized in the USA [10]. Relative to surgical management, endoscopic approaches have lower procedural risks, shorter postoperative hospital stays, and decreased overall postoperative morbidity [11].

Much of the data reported on endoscopic management for proximal gastrointestinal tumors has been gathered in Japan, China, and Korea; however, there have been an increasing number of studies in the USA supporting these approaches for highly selected cases [10] [12] [13] [14].

While causing less morbidity than total gastrectomy, endoscopic approaches do not typically involve lymph node dissection. Therefore, if metastatic disease has been ruled out with imaging, the incidence of lymph node spread must be low for an organ-sparing approach to be preferred. The 2017 National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of EMR/ESD for early gastric cancers that meet the following criteria: ≤ 2 cm in diameter, well or moderately well differentiated, negative margins, limited to the superficial submucosa, and lacking lymphovascular invasion [15]. These NCCN guidelines are based on the Japanese Gastric Cancer guidelines, which are derived from data in Asian populations. The incidence and predictors of lymph node metastasis in early gastric adenocarcinoma in the USA remain unclear. This study assessed the incidence and predictors of lymph node positivity in early-stage gastric adenocarcinoma using a large national US cohort.

Patients and methods

Overview

Data were abstracted from the Surveillance, Epidemiology, and End Results (SEER) database, a national sample of population-based cancer data put forth by the National Cancer Institute. The study was reviewed by the Emory University Institutional Review Board and was found to be exempt because of the use of public, deidentified data. All cases of gastric adenocarcinoma were abstracted from the SEER database covering the years 2004 to 2013. Data prior to 2004 lack detailed information concerning the depth of invasion and were excluded.

Tumors were staged using the criteria of the American Joint Committee on Cancer (AJCC) Staging Manual, 7th edn. [16]. Abstracted variables included: metastatic disease at diagnosis, surgical resection, method of histologic confirmation, histologic features, results and method of lymph node evaluation, depth of invasion, radiation, tumor site in stomach, tumor grade, patient age, patient race, and patient sex.

Tumor classification

Tumor stage was assigned by matching the depth of invasion to the AJCC Staging Manual [16]. Tis disease was defined as tumors confined to the epithelium, T1a disease was defined as tumors limited to the lamina propria or mucosa, and T1b disease was defined as tumors that involved and were restricted to the submucosal layer of the stomach wall [16]. Tumor grade was classified into four categories: well differentiated (grade 1), moderately differentiated (grade 2), poorly differentiated (grade 3), and undifferentiated/anaplastic (grade 4). Low grade was defined as well or moderately differentiated. High grade was defined as poorly differentiated or undifferentiated/anaplastic. Tumor size was classified into five groups: < 1 cm, 1 – 2 cm, 2 – 3 cm, 3 – 4 cm, and ≥ 4 cm.

Exclusion criteria

Exclusion criteria included: age < 18 at diagnosis, advanced or metastatic disease, no surgical resection or microscopic evaluation of lymph nodes, not meeting AJCC staging criteria, unknown tumor grade, unknown tumor size, unknown depth of tumor invasion, unknown patient race, unknown patient age, unknown patient sex, and neoadjuvant radiation. Tumors located in the cardia with esophageal involvement or recoded as esophageal cancer were also excluded as gastric adenocarcinomas of the cardia are believed to behave more similarly to esophageal cancers than to gastric adenocarcinomas in other areas of the stomach. Tumors with mixed-type adenocarcinoma, diffuse-type adenocarcinoma, signet-ring cell, carcinoid, and neuroendocrine features on histology were also excluded. T1 NOS tumors were excluded to enable characterization of the relationship between early tumor stages and lymph node metastasis. Early-stage disease was defined as Tis, T1a, and T1b.

Statistical analysis

Data were abstracted from the SEER Program of the National Cancer Institute using SEER*Stat data retrieval software, version 8.3.2 (available from: https://seer.cancer.gov/seerstat/). The data were imported into Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA) for reorganization. Lymph node involvement, tumor grade, and tumor size were recoded for analysis. Well and moderately well differentiated tumors were coded as low grade, while poorly differentiated and anaplastic/undifferentiated tumors were coded as high grade. Tumors were grouped according to size (< 1 cm, 1 – 2 cm, 2 – 3 cm, 3 – 4 cm, and ≥ 4 cm).

Data were subsequently analyzed using IBM SPSS 23.0 (IBM Corporation, Armonk, New York, USA). Univariate analysis of early-stage gastric adenocarcinoma was performed using chi-squared analyses to evaluate the association between covariates and lymph node involvement. Univariate analysis was additionally performed for low grade early-stage gastric adenocarcinomas and subdivided into T1a and T1b groups. Multivariable analysis of early-stage gastric adenocarcinoma was performed using binomial logistic regression to identify independent predictors of nodal metastasis. All potentially relevant variables available in the SEER data set (T stage, tumor grade, tumor size, anatomic site, sex, race, and age) were included in the multivariable analysis. An alpha of 0.05 was considered significant for the univariate and multivariable analyses.

Results

Analysis cohort

A total of 43 769 cases of gastric adenocarcinoma were abstracted from the SEER database. After excluding cases with age < 19, lack of microscopic confirmation, T0 /TX and advanced tumor stage, known metastatic disease, lack of surgical resection, lack of microscopic evaluation of lymph nodes, and exposure to neoadjuvant radiation, 2989 cases remained ([Fig. 1]). Tumors with T1 NOS stage, unknown grade, unknown size, unknown patient race, not meeting the criteria for AJCC staging, and with a location designated as cardia, “Stomach NOS,” or recoded as “Esophagus” were removed.

In total, there were 1577 cases of early-stage gastric adenocarcinoma that met the inclusion criteria and were included in the analysis cohort. These 1577 cases consisted of 0 Tis, 545 T1a, and 1032 T1b tumors ([Table 1]; [Fig. 1]).

Univariate associations with lymph node involvement

The overall incidence of nodal metastasis in patients with early-stage gastric adenocarcinoma (n = 1577) was 18.0 %. Tumor stage (P < 0.001), tumor grade (P < 0.001), and tumor size (P < 0.001) were all significantly associated with lymph node metastasis in our US cohort. Of patients with T1a tumors, 6.4 % had nodal metastasis, compared with 24.1 % of patients with T1b tumors. Lymph node involvement was present in 15.0 % of patients with low grade tumors and 23.5 % of patients with high grade tumors. Positive lymph node involvement was recorded in 4.7 % of cases for tumors < 1 cm, 12.6 % for tumors of 1 – 2 cm, 18.3 % for tumors of 2 – 3 cm, 22.0 % for tumors of 3 – 4 cm, and 34.2 % for tumors ≥ 4 cm.

Univariate association with low grade early-stage gastric adenocarcinoma

The incidence of nodal metastasis in patients with low grade early-stage gastric adenocarcinoma was also significantly associated with stage, tumor grade, and tumor size. Of patients with T1a tumors, 4.6 % had metastasis to lymph nodes, compared with 21.5 % of patients with T1b tumors (P < 0.001). Nodal metastasis was present in 5.5 % of patients with well differentiated tumors and 18.7 % of patients with moderately well differentiated tumors (P < 0.001). Nodal metastasis was present in 4.5 % of cases for tumors < 1 cm, 11.1 % for tumors of 1 – 2 cm, 14.8 % for tumors of 2 – 3 cm, 16.1 % for tumors of 3 – 4 cm, and 31.8 % for tumors ≥ 4 cm in size (P < 0.001) ([Table2]).

Univariate association with low grade T1a tumors

Tumor grade and size were also identified as predictors of nodal metastasis in patients with low grade T1a gastric adenocarcinoma. Patients with well differentiated T1a tumors had a 1.4 % rate of lymph node positivity, while patients with moderately well differentiated T1a tumors had a 6.4 % rate of lymph node positivity (P = 0.02) ([Table 2]). For T1a tumors, nodal spread was present in 1.7 % of tumors < 1 cm in size, 1.7 % of tumors 1 – 2 cm in size, 4.5 % of tumors 2 – 3 cm in size, 4.1 % of tumors 3 – 4 cm in size, and 20.0 % of tumors ≥ 4 cm in size (P < 0.001) ([Table 2]; [Fig. 2]).

Univariate association with low grade T1b tumors

Similarly, univariate analysis indicated that tumor grade and size were significantly associated with nodal spread in patients with low grade T1b tumors. Patients with well differentiated T1b tumors had a 10.1 % rate of lymph node positivity, while patients with moderately well differentiated T1b tumors had a 25.1 % rate of positivity (P < 0.001). For T1b tumors, nodal metastasis was present in 8.4 % of tumors < 1 cm in size, 18.0 % of tumors 1 – 2 cm in size, 19.5 % of tumors 2 – 3 cm in size, 22.0 % of tumors 3 – 4 cm in size, and 35.8 % of tumors ≥ 4 cm in size (P < 0.001) ([Table 2]; [Fig. 2]).

Multivariable analysis of lymph node involvement

Binomial logistic regression was used to identify independent predictors of lymph node metastasis in patients with early-stage gastric adenocarcinoma. Modeled covariates included: tumor stage, tumor grade, tumor size, tumor location, and patient age, sex, and race. Tumor stage (P < 0.001), grade (P = 0.008), and size (P < 0.001) were significant independent predictors of nodal spread, while patient sex (P = 0.89), race (P = 0.78), and age (P = 0.77), and tumor location in the stomach (P = 0.84) were not significantly associated with nodal positivity ([Table 3]).

Patients with T1a gastric adenocarcinoma were less likely than patients with T1b disease to have nodal metastasis (odds ratio [OR] 0.267, 95 % confidence interval [CI] 0.182 – 0.392; P < 0.001). Patients with low grade tumors were less likely than patients with high grade tumors to have nodal metastasis (OR 0.685, 95 %CI 0.517 – 0.907; P = 0.008). Patients with smaller tumors (< 1 cm) were less likely than those with larger tumors (≥ 4 cm) to have nodal metastasis (OR 0.130, 95 %CI 0.068 – 0.248; P < 0.001) ([Table 3]).

Discussion

Organ-sparing approaches to early gastric cancer are being increasingly utilized in the USA [17]. Endoscopic resection of early gastric cancer has been shown to be non-inferior to gastrectomy with regards to overall survival [18]. There is inconsistent reporting of rates of complications when these therapies are compared; however, shorter lengths of stay have been demonstrated with endoscopic resection [18] [19]. National US guidelines now incorporate endoscopic approaches into algorithms for treatment allocation in early gastric cancer [15]. Prior to surgical or endoscopic resection, cross-sectional imaging is used to evaluate for distant metastases.

To forego lymph node dissection with endoscopic resection, the rate of nodal spread must be low. While these rates have been studied in Asian populations where gastric cancer is highly prevalent [20] [21] [22], the risk of spread in US populations has not been well established, particularly for the highly selected subset of patients who would be considered for endoscopic management. This study generated estimates for the incidence of lymph node spread in very early gastric adenocarcinomas, stratified by predictors of increased risk. For early tumors, T stage, size, and grade were all independently associated with the risk of nodal spread. Low grade T1a tumors less than 4 cm in size had low rates of nodal metastasis (< 5 %) and would represent the best subset for endoscopic management.

In patients with early-stage gastric adenocarcinoma, T stage, size, and grade can be used to estimate the rate of nodal involvement and to inform a discussion of the risks with differing treatment modalities. In patients with advanced age and multiple comorbidities, lesions with higher rates of spread might be considered for endoscopic management given the increased risk of surgical resection in these subgroups. Hybrid strategies may also warrant consideration and have been studied in small subsets [23] [24] [25]. An organ-sparing resection of the primary lesion plus a laparoscopic lymph node dissection provides a lower risk intervention and nodal assessment [25], which may represent an approach for additional study in patients with early gastric cancer.

In our data, patients with low grade T1b tumors had higher rates of lymph node involvement. For example, small (< 1 cm) low grade T1b lesions had an 8.4 % rate of lymph node metastasis. If endoscopic resection is performed, this group should be followed closely for evidence of spread. For patients with low grade T1b gastric adenocarcinoma who are good surgical candidates, it may be beneficial to consider lymph node dissection. Endoscopic resection does not preclude or negatively impact a patient’s subsequent candidacy for gastrectomy if needed.

There are several limitations to be acknowledged. Features such as tumor ulceration [7] [20] [21] [22], lymphovascular invasion [7] [20] [21] [22], and lymph node involvement by endoscopic ultrasound (EUS) [13] have also been associated with nodal metastasis and should be taken into account in considering treatment decisions. The SEER database lacks these data so we were unable to characterize the risk of spread using these variables. Ulceration, lymphovascular invasion, and findings of concern on EUS increase risk; patients with these findings should be considered to have higher odds of nodal spread and should be further considered for surgical resection and/or nodal dissection.

Similarly, the database does not contain information on hereditary gastric cancers, which may behave differently with regard to lymph node metastasis. While we were able to exclude patients who received neoadjuvant radiotherapy, we were unable to exclude patients who received neoadjuvant chemotherapy. As patients with more concerning presentations may be more likely to receive neoadjuvant chemotherapy, this may have tended to increase the apparent rates of nodal involvement (a conservative bias). Patients with T1 tumors are not typically referred for chemotherapy, so this is presumed to represent a small fraction of the analysis cohort. Nevertheless, we are limited in our ability to evaluate for this exposure.

Overall, the rates reported here for lymph node involvement in early-stage gastric adenocarcinoma are higher than those reported in Japan [20] and South Korea [21] [22]. This may relate to the limitations posed above (the inability to exclude hereditary cases of gastric cancer, or the inability to further stratify according to tumor ulceration or lymphovascular invasion), but it is also possible that there is a true difference between the rates of spread, which could reflect genetic and/or dietary differences between East Asian and US populations. Finally, the differences could be impacted by screening programs in Asian countries where gastric cancer is more prevalent.

Gastric adenocarcinomas are being increasingly considered for endoscopic management in the USA [17]; in the advanced stages, they are aggressive tumors with high mortality. Patients with early-stage gastric adenocarcinoma should be appropriately counseled on treatment options, weighing potentially negative oncologic outcomes with endoscopic management against the surgical morbidity and quality of life implications associated with major organ resection. Recommendations should involve a multispecialty approach or tumor board and prioritize patient preference and input into the decision-making process.

Our data suggest that low grade T1a gastric adenocarcinomas less than 4 cm in size are associated with rates of lymph node metastasis less than 5 % and represent the best subset for an endoscopic approach. Patients with T1a lesions greater than 4 cm, lesions with high grade histology, and patients with T1b lesions may benefit from lymph node dissection. With greater understanding of the risks of spread by tumor characteristics, we hope to inform and refine the discussion of options and allocation among the various treatment modalities.

Competing interests

Field F. Willingham, MD, MPH serves as primary investigator for clinical research trials of the following companies: COOK, Cancer Prevention Pharmaceuticals, RedPath Technologies, Xlumena. Qiang Cai, MD, PhD is a consultant for Boston Scientific, Acts as a speaker for ARIAS, and serves on the scientific advisory board for MicroTech.

Acknowledgments

This manuscript was supported in part by a development grant from the Department of Medicine at Emory University School of Medicine. Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The data contained in this manuscript were presented in part at the annual Georgia Gastroenterologic and Endoscopic Society Meeting in Atlanta, Georgia on 17 September 2016; as an oral presentation at the Emory University Department of Medicine Research Day in Atlanta, Georgia on 28 October 2016; and as an oral presentation at Digestive Disease Week in Chicago, Illinois on 7 May 2017.

• References

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Corresponding author

• References

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• 8 Green PH, O'Toole KM, Slonim D. et al. Increasing incidence and excellent survival of patients with early gastric cancer: experience in a United States medical center. Am J Med 1988; 85: 658-661
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• 10 Shin N, Jeon TY, Kim GH. et al. Unveiling lymph node metastasis in early gastric cancer. World J Gastroenterol 2014; 20: 5389-5395
  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
• 14 Choi AH, Nelson RA, Merchant SJ. et al. Rates of lymph node metastasis and survival in T1a gastric adenocarcinoma in Western populations. Gastrointestinal Endosc 2016; 83: 1184-1192
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar