THE KURUMEMEDICAL JOURNAL Vol.44, p.157-164,1997 ORIGINAL ARTICLE Early Gastric Cancer and Lymph Node Metastasis KIKUO KOUFUJI, JINRYO TAKEDA, ATSUSHI TOYONAGA, SHINO YOSHIHARA, YUICHI TANAKA, JUNJI OHTA, KEISHIRO AOYAGI, SHOJIRO YANG, ISSEI KODAMA AND KAZUO SHIROUZU Departments of Gastroenterology and Surgery, Kurume University School of Medicine, Kurume 830, Japan Received for publication April 2, 1997 Summary: A total of 1,845 cases of gastric cancer have been resected in our hospital during the past 18 years. Of these, 764 cases (41.5%) were early gastric cancer. The rate of lymph node metastasis was 2% in early mucosal cancer and 19.4% in early submucosal cancer (p<0.001). In the cases of early mucosal cancer, the rate of lymph node metastasis was 0.9% for the elevated type and 2.4% for the depressed type. In the cases of early submucosal cancer, the rate of lymph node metastasis was 25.3% for the elevated type and 17.3% for the depressed type. In the mucosal cancers the rate of lymph node metastasis was high in the 0-IIc and IIc+III macroscopic type, and in the poorly differentiated microscopic type. In the submucosal cancers the rate of lymph node metastasis was 40% in mucinous adenocarcinoma and 33% in papillary adenocarcinoma. There was no lymph node metastasis in any case of early gastric cancer smaller than 1cm surface diameter. Key words adenocarcinoma, mucosal cancer, lymph node metastasis, tumor size, immunohistochemical study, prognosis Introduction the stomach, with or without lymph node metastasis. Death has been thought The incidence of gastric cancer has to be more likely to occur in EGC with been perceived to be declining world- lymph node metastasis than in EGC with wide (Launois et al. 1991). The incidence no metastasis. Therefore, when EGC of death as a result of gastric cancer has without lymph node metastasis could be recently begun to decrease in Japan. diagnosed preoperatively, then minimal- This decrease has been attributed to ly invasive surgery can be selected to advances in diagnostic and therapeutic ensure a postoperative better quality of procedures, especially to the increased life. frequency of early gastric cancer (EGC) The purpose of this study was to detection in Japan (Iriyama and Suzuki, evaluate the independent influences of 1992). clinical and pathological variables on the EGC is defined as an adenocarci- incidence of lymph node metastasis and noma confined to the mucosa (m- on the prognosis in EGC. cancer) or submucosa (sm-cancer) of 157 158 KOUFUJI ET AL. Materials and Methods Immunohistochemical studies of epidermal growth factor (EGF), epider- During the 18 years between 1976 mal growth factor receptor (EGFR) and and 1993, a total of 1,845 patients with transforming growth factor-ƒ¿ (TGFƒ¿) primary gastric cancer underwent were performed to investigate the gastrectomy in the First Department of characteristics of the EGC with or Surgery, Kurume University Hospital. Of without lymph node metastasis through these, 764 (41.5%) cases were classified ABC staining using Anti-EGF polyclonal as early cancers on the basis of the antibody, Anti-EGFR polyclonal anti- pathology data. body and Anti-TGFƒ¿ monoclonal anti- These early gastric cancers included body in 75 cases of EGC. 77 (10.1%) cases of multiple EGC, 9 The 5-year-survival rate of patients (1.2%) cases of remnant-stump EGC, and with gastric cancer was assessed using 678 (88.7%) cases of a single EGC. the Kaplan-Meier method, and statistical Double EGC, such as m-cancer+ sm- analysis was made using the Generalized cancer, was classified as the sm-cancer Wilcoxon test. Other statistical analysis of the deeper infiltration. Cases of was performed using the X2 test. multiple gastric cancer, involving a combination of early gastric cancer with an advanced cancer were excluded from Results this study. Malignant lymphomas and leiomyosarcomas were also excluded. Of the 764 patients with EGC, 520 The macroscopic and microscopic were men and 244 were women (a ratio classifications of gastric cancer, cancer of 2.1:1). The age distribution and cancer location, and pathological cancer stage depth in EGC are shown in Table 1. were determined according to the EGC can be divided into three Guidelines of the Japanese Research fundamental macroscopic types, ele- Society for Gastric Cancer (1995). vated (0-I: protruded, 0-II: superficial TABLE 1. The incidence of early gastric cancer by age ( ): Number of female patients EARLY GASTRIC CANCER 159 TABLE 2. elevated), flat type (0-IIb), and depressed Macroscopic classification of early cancer type (0-IIc: superficial depressed, 0-III: and lymph node metastasis excavated). The details of this macro- scopic classification of EGC, and details of lymph node metastasis are summarized in Table 2. A mixed-pattern of these fundamental types, such as IIa+IIc, or IIc+III, was fairly common, and so we classified all the mixed-patterns as a fourth fundamental type. The four macroscopic types and the rate of lymph node metastasis are summarized in Table 3. The rate of lymph node metastasis was highest in this mixed- pattern type. Correlation of the tumor size in the 3 fundamental types with the rate of lymph node metastasis is summarized in Table 4. In EGC smaller than 10mm in diameter, there was no lymph node metastasis. The incidence rate of lymph node metastasis in both m- and sm-cancer and the longitudinal cancer location are summarized in Table 5. The rate of lymph node metastasis was 2.0% in m- cancer and was 19.4% in sm-cancer (p< 0.001). The rate of lymph node metas- tasis according to the cross-sectional TABLE 3. cancer location is summarized in Fig. 1. Macroscopic classification and rate of The correlation of the macroscopical lymph node metastasis and pathological details to the rate of lymph node metastasis in both m-and sm-cancer is summarized in Table 6. According to pathological classification, the incidence of node metastasis was higher in cases of poorly differentiated adenocarcinoma (7.3%) and of signet ring cell carcinoma (2.1%) in m-cancer, and was higher in cases of mucinous adenocarcinoma (40%) and of papillary adenocarcinoma (33%) in sm-cancer. Seven (87.5%) of the 8 m-cancers with positive lymph node metastasis n(+) 160 KOUFUJI ET AL. TABLE 4. Size of tumor and rate of lymph node metastasis TABLE 5. Lymph node metastasis according to the longitudinal cancer location Nine remnant-stump early cancers were included as being in C region, while multiple *:p<0.001 cancers were included in the dominant tumor location. The immunohistochemical studies and any correlation with lymph node metastasis are summarized in Table 7. The positivity of EGF was 57.1% in lymph node positive (n(+)) cases, and was 11.8% in node negative (n(-)) cases (p<0.001). The positivity of EGFR was 85.7% in n(+) cases and 35.5% in n(-) Fig. 1. Lymph node metastasis rates cases (p<0.05). according to the cross-sectional cancer The incidence of EGC and histo- location. logical cancer stage are summarized in Table 8. Two positive synchronous were 0-IIc or 0-IIc+III type associated hepatic metastasis and two n3 were with an ulcer or an ulcer scar. When the included in stage IV. EGC were classified into 5 types The postoperative prognosis of the according to the depth of cancer EGC according to the cancer depth is invasion as shown in Fig. 2, then the shown in Fig. 3. The prognosis of the lymph node metastasis rate was 1.3% in EGC according to the absence or m-cancer and 11.2% in sml cancer (p< presence of lymph node metastasis is 0.001). shown in Fig. 4. EARLY GASTRIC CANCER 161 TABLE 6. Lymph node metastasis rates according to macro- and microscopic type Mucosal (m) cancer pap: papillary adenocarcinoma, tub 1: well differentiated tubular adeno. ca., tub2: moderately diff. adeno., por: poorly diff. adeno., muc: mucinous adeno., sig: signet-ring cell ca., others: carcinoid TABLE 7. Immunohistochemical studies and n factor in early gastric cancer EGF: epidermal growth factor, EGFR: epidermal growth factor receptor, TGF ƒ¿: transforming growth factor-ƒ¿, *: p<0.001, **: p<0.05 TABLE 8. Incidence of early gastric cancer according to histological stage Fig. 2. Lymph node metastasis rate according to the depth of cancer invasion in early gastric cancer. n1=stage II, n2=stage III, m: mucosa, mm: mucosal membrane, sm: stage IV=H(+): 2, n3: 2 submucosa, mp: muscularis propria *: p<0 .001, **: p<0.01, ***: p<0.05 162 KOUEUJI ET AL. Fig. 3. Prognosis of early gastric Fig. 4. Prognosis of early gastric cancer according to the cancer depth. cancer according to n-factor. Discussion should be considered during endoscopic examination. These accompanying lesions The incidence of EGC continues to were mainly a superficial type m-cancer increase in Japan, due mainly to of less than 10 mm in diameter (Koufuji improved detection through mass et al. 1995). screening in addition to advances in Metastasis from the EGC to the radiographic, endoscopic and biopsy regional lymph nodes of the stomach techniques. The frequency of EGC was was found to be the most important 41.5% of the total number of resected factor in selecting the surgical man- gastric cancers in the present study. agement because such lymph node Macroscopically, EGC of depressed type metastasis is recognized as a high-risk was more frequent than EGC of elevated factor for hematogenous recurrence. type. In the abstracts from the 63rd The rate of lymph node metastasis was Meeting of the Japanese Research 0.9% in elevated and was 2.4% in Society for Gastric Cancer (1994), we depressed macroscopic type in m- counted 533 (2.5%) cases of m-cancer cancer.