| Objective:The aim of this study is to clarify the clinicopathologic features and prognosis of the patients with early gastric cancer(EGC) and investigate the regularity of lymph node metastasis, estimate the therapeutic efficacy of endoscopic microinvasive therapy , assess the incidence of micrometastases of lymph nodes and multiple gene expression and investigate the correlation between lymph nodal micrometastases and multiple gene expression and prognosis. Methods:1. 308 patients with one lesion and 22 patients with multiple lesions both treated surgically for EGC from 1983 to 2005 were analyzed retrospectively.245 patients with one lesion and 20 patients with multiple lesions were followed up by outpatient clinic,telephone and letter.2. Endoscopic mucosal resection (EMR) was performed on 15 lesions in 14 patients.Other endoscopic microinvasive treatment was performed on 13 lesions in. 12 patients. Of the 27 patients, 24 patients were followed up.3. Expression of VEGF and TGF- β 1 was detected in 130 patients by using immunohistochemistry. A total of 1631 lymph nodes from 182 patients, which were histologically confirmed as pNO by using conventional hematoxylin and eosin (H&E) stains, were performed immunohistochemistry by use of monoclonal anti-human cytokeratin 20 antibodies.Results:1. Of the 308 EGC patients with one lesion,81.8%had symptom . The clinical presentation of EGC is aspecific.The most frequent symptom was epigastric pain.They still presented weight loss, anorexia, hematemesis and melena. 9.1% patients had alimentary tract hemorrhage. The positive rate ofdouble-contrast barium upper gastrointestinal radiography was 70.1 % . The positive rate fecal occult blood test was 5.8%. The positive rates of serum CEA,CA199, CA724, CA153 and CA125 were 5.9%,3.8%,4.1%,0% and 6% respectively. The combined positive rate of 5 tumor markers was 10.5%.The maxium tumor size was 7cm. The rates of tumor size of lcm or less, 2cm or less, 4cm or less and 7cm or less were 27.2%,28.6%,31.2% and 13.0% respectively. 178 patients (57.8%) with mucosal gastric cancer and 130 patients (42.2%) with submucosal gastric cancer were diagnosed. Most lesions were located in the antrum (41.2%). 27.3% lesions were located in the angle. 18.2% lesions were located in the cardia or fundus. 13.3% lesions were located in the corpus. Differentiated type accounted for 68.5%EGCs.85.4% patients had a depressed or mixed type of cancer.2. The paracarcinomatous mucosal middle-severe atrophy rate in =^60 years (66.7 %), differentiated type (60.7 % ), or distal stomach (57.6 %) group washigher significantly than that in <60 years (39.6%), undifferentiated type (42.3 %), or proximal stomach (46.8 %) group. The paracarcinomatous mucosal middle-severe intestinal metaplasia rate in ^60 years (62.6%), differentiated type (59.2 %), distal stomach (57.6%) or ^4cm (54.9%) group was higher significantly than that in <60 years (38.1%), undifferentiated type (36.1%), proximal stomach (35.1%) or >4cm (32.5%) group. The paracarcinomatous mucosal middle-severe dysplasia rate in differentiated type (75.8% ) or mucosa (69.7% ) group was significantly higher than that in undifferentiated type (24.7 %) orsubmucosa (46.2%) group.3. The rates of lymph node metastasis in early gastric cancer,mucosal cancer and submucosal caner were 9.9% (28/282) ,2.5% (4/157) and 19.2% (24/125) respectively.The average maximum dimension of lymph node with metastasis was 0.9cm,which of lymph node without metastasis was 0.8cm (P=0.450). The average minimum dimension of lymph node with metastasis was 0.3cm,which of lymph node without metastasis was 0.3cm (P=0.607). The average tumor size ofgastric mucosal cancer with lymph node metastasis was 5.Ocm,which of gastric mucosal cancer without metastasis was 1.9cm (P=0.000). The average tumor size of gastric submucosal cancer with lymph node metastasis was 3.2cm,which of gastric submucosal cancer without metastasis was 2.6cm (P=0.030).In the multivariate logistic regression model,lymphatic vesselinvolvement(P=0.000,OR=8.568),submucosal invasion(P=0.018,OR=4.234),a larger tumor size (>2cm)(/>=0.020,OR=4.12) and undifferentiated type(P=0.040,OR=2.710) were found to be independent risk factors for lymph node metastasis in early gastric cancer.To analyze subgroup, lymphatic vessel involvement and a larger tumor size (>2cm) were significantly related to lymph node metastasis in mucosal cancer.The histologic type lost significant correlation with lymph node metastasis in mucosal cancer. Tumor size of 2cm or less in mucosal cancer were found to have no lymph node metastasis and lymphatic vessel involvement(0/108). Tumor size between 2cm and 4cm without lymphatic vessel involvement in mucosal cancer were found to have no lymph node metastasis(0/26).Lymphatic vessel involvement,a larger tumor size (>2cm) and undifferentiated type were significantly related to lymph node metastasis in submucosal cancer.No lymph node metastasis was observed in 25 patients with submucosal invasion who showed none of the three risk factors,whereas 72.7% (8/11) of patients with all the three factors had lymph node metastasis.4. 30 patients developed recurrent disease (median 28 months).The l-year,3-year,5-year,7-year, 10-year and 15-year recurrence rates were 5.49%,8.44 %,11.27%,14.83%,16.39% and 37.79% respectively. 13 patients with mucosal gastric cancer developed recurrent disease (median 24 months).The l-year,3-year,5-year,7-year,10-year and 15-year recurrence rates were 4.23%,6.68 %,7.75%,9.34%,9.34% and 28.24% respectively. 17 patients with submucosal gastric cancer developed recurrent disease (median 31 months).The l-year,3-year,5-year,7-year, 10-year and 15-year recurrence rates were 7.39 %,11.14%,16.54%,24.49%,29.69% and 64.85% respectively.Cox multivariateanalysis showed that submucosal invasion (P=0.044, OR=2.172) was a positive independent risk factor and paracarcinomatous mucosal middle-severe intestinal metaplasia (P=0.047, OR=0.0460) was a negative independent risk factor for recurrence. 76.7 % ( 23/30 ) recurrent patients hadn't curative resection indication.They didn't undergo surgery again. 23.3% (7/30) recurrent patients had curative resection indication^ of whom underwent curative resection and 3 of whom didn't undergo surgery because of poor health.Histology after surgery showed 3 patients were early remnant gastric cancer without lymph node metastasis and one patient was advanced remnant gastric cancer with regional lymph node metastasis.The patient with advanced remnant gastric cancer had survived for 28 month without tumor.Logistic regression analysis showed paracarcinomatous mucosal middle-severe intestinal metaplasia (/>=0.016, OR= 17.000 ) was a positive independent predictor for second surgery. Examinations including endoscopy were performed in 86.7% (26/30) patients after operating at least per 1-2 years.5. The l-year,3-year,5-year,7-year, 10-year and 15-year survival rates were 97.85 % ,94.32 % ,92.23 % ,90.94 % ,86.24 % and 71.86% respectively.In a univariate analysis,survival rate was correlated with depth of invasion(P=0.0034) ,histologic type (Z^O.0104) , paracarcinomatous mucosal atrophy(P=0.0148) ,intestinal metaplasia (P=0.0127) and lymph node metastasis(P=0.0363 ) .Submucosal invasion,undifferentiated type and lymph nodemetastasis reduced survival rate. Paracarcinomatous mucosal middle-severeatrophy and intestinal metaplasia increased survival rate. Cox multivariateanalysis showed that submucosal invasion (P=Q.0\ 1, OR=3.479) was a positiveindependent risk factor and paracarcinomatous mucosal middle-severe atrophy(P=0.032, OR=0.354) was a independent protective factor for survival.6. There were 2.3 % (7/308) EGC patients with synchronous other primary carcinomas. There were 5.3% (13/245) EGC patients with metachronous other primary carcinomas after gastrectomy including 8 lung cancers,2 liver cancer,2pancreatic cancers and 1 prostatic carcinoma.Only one patient was 58 years ,and other 12 patients were elderly. The intervals between second primary carcinoma and gastric cancer were 1.7-16.5 years. The average intervals were 8.7+4.5 years. The median intervals were 8.3 years.7. 14 patients with EGC only received EMR treatment. Serious complications(hemorrhea) were found in one of the 14 patients. 12 patients were followed up with endoscopy.8 patients were cured after first EMR.Of 8 patients,6 patients were mucosal gastric cancer with tumor size of 2cm or less(type I, type II a, type II b and type II a + II c) and 2 patient was mucosal and submucosal gastric cancer with tumor size of less lcm (both type He ) .4 patients were residual. Of 4 patients, 2 patients were submucosal gastric cancer with tumor size of lcm or more(both type II c+ II a) and 2 patient were mucosal gastric cancer with tumor size of lcm or less (both type He), one patient of mucosal gastric cancer with tumor size of lcm (typeHe ) were cured after second EMR,one patient of submucosal gastric cancer with tumor size of 1.2cm (type II c+ II a) were still residual after fourth EMR,one patients gave up treatment,and one patients were cured by gastrectomy. The first cure rate was 66.7% (8/12) and accumulative cure rate was 75 % (9/12) .12 patients with 13 lesions underwent other endoscopic minimally invasive treatment including argon plasma coagulation (APC), high frequency electric coagulation, golden probe electric coagulation, holmium laser, Nd: YAG laser and light motive power. 11 patients were followed up with endoscopy,of which 5 patients with 6 lesions were cured.The cure rate of lesion was 50% (6/12) .The treatment times of every lesion was 1-4 and the average treatment times was 2.The tumor size was 0.4-1.5cm and the average tumor size was lcm.4 lesions were located in cardia and 2 lesions were located in antrum,including 1 elevated lesion(type I ),3 depressed lesions(type II c) and 2 mixed lesions(typellc+ II a and type II a+ II c).The residual patients with minimally invasive treatment could be radicallycured by gastrectomy in a certain time.One patient undergoing holmium laser treatment was operated after 2 months,one patient undergoing EMR was operated after 15 months and one patient undergoing minimally invasive combination treatment was operated after 25 months.Histology after operating proved EGC without metastasis.8. VEGF and TGF-P 1 expression was detected in 17.7% and 46.9% patients with early gastric cancer. Lymph node micrometastases was observed in 13.2% patients. The rate of positive lymph node was 4.1%.No correlation was observed between the incidence of lymph node micrometastases and various clinicopathologic parameters, including age, gender, tumor size, location, macroscopic type, histological type, depth of invasion, lymphatic vessel involvement, paracarcinomatous mucosal atrophy, intestinal metaplasia and dysplasia. No correlation was observed between expression of VEGF and various clinicopathologic parameters. Multivariate analysis indicated that TGF- P 1 expression was correlated with lymph node metastasis and paracarcinomatous intestinal metaplasia.No correlation were found between VEGF expression,TGF-3 1 expression, lymph node micrometastases and prognosis. Conclusions:1. The clinical presentation of EGC is aspecific.Some patients have no clinical symptom.Endoscopy for finding EGC is prior to other tests.The rates of fecal occult blood test and serum tumor markers including CEA,CA199,CA724,CA153 and CA125 are very low. Double-contrast barium upper gastrointestinal radiography may be complementary in detecting synchronous multiple EGC.Most EGCs are located in antrum and angle.Macroscopic type is mostly depressed and mixed.Most of them are differentiated.2. Age, histological type, location and tumor size effect background mucosal lesion in patients with EGC.It may be associated with difference of gastric cancer genesis. The paracarcinomatous mucosal atrophy and intestinal metaplasia areobvious in patients of elderly,differentiated type,distal stomach,and tumor size of 4cm or less.3. Lymphatic vessel involvement,submucosal invasion,tumor size of 2cm or more,and undifFerentiated type are independent risk factors of lymph node metastasis in EGC. EMR can be applied for EGC patients with tumor size of 2cm or less and without ulcer formation. The resected specimens should be carefully examined by serial sections at 2 mm intervals. If histopathology revealed mucosal invasion and the resection margin is clear, surgery is not recommended. If histopathology revealed submucosal invasion with differentiated histology and without lymphatic vessel involvement, reduced gastrectomy is recommended. If histopathology revealed submucosal invasion with undifferentiated histology or lymphatic vessel involvement, gastrectomy with D2 lymph node dissection is recommended. For some mucosal cancers, extended EMR is indicated for EGCs with tumor size of 4cm or less. If histopathology revealed mucosal invasion without lymphatic vessel involvement and the resection margin is clear, surgery is not recommended.4. Early gastric cancer patients with submucosal invasion have a high risk of recurrence and they with paracarcinomatous mucosal middle-severe intestinal metaplasia have a low risk of recurrence.The recurrent patients with paracarcinomatous mucosal middle-severe intestinal metaplasia have the possibility of curative resection.The follow-up examinations including endoscopy every one or two years contributed to find early remnant gastric cancer,which was not significantly useful to perform second curative resection for the recurrent patients with metastasis after gastrectomy.5. Submucosal invasion is a independent risk factor and paracarcinomatous mucosal middle-severe atrophy is a independent protective factor for survival.6. Preoperatively we must be careful of synchronous multiple primary early gastric cancer. Postoperatively we must be careful of metachronous multiple primary other tumors.Patients undergoing surgery for early gastriccancer,especially elderly,may have a circa 5.3% risk of a second tumor and should be periodically checked for other tumors, mainly in the digestive system, respiratory system and urinary system.7. EMR is effective for radical treatment of mucosal gastric cancer with differentiated type,tumor size of 2cm or less,and elevated type lesions.lt may also be effective for radical treatment of mocosal gastric cancer with tumor size of lcm or less and depressed type lesions. Curative treatment of submucosal gastric cancer with tumor size of lcm or less and without deep penetration into the submucosal layer is possible by EMR. EMR may be insufficient treatment for submucosal early gastric cancers with tumor size of more than lcm.Other endoscopic minimally invasive treatments including APC, electric coagulation and laser are useful for treatment of early gastric cancer.They can be used alone,and also combined with EMR. When the treatment times of the lesion is more than 4,it is difficult to cure the lesion.The residual patients with minimally invasive treatment could be radically cured by gastrectomy in a certain time.8. Expression of VEGF and TGF- P 1 and lymph node micrometastases in EGC have no influence on prognosis. But immunohistochemical expression of TGF- 3 1 is one of the useful predictors for estimating lymph node metastasis, we should choose D2 gastrectomy for those early gastric caners with TGF- 3 1 expression.
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