DOT1L promotes expression of CD44 through the Wnt/ß-catenin signaling pathway in early gastric carcinoma.

To assess telomere silencing 1-like (DOTIL) gene expression within gastric cancer (GC) tissues as well as its function of promoting cancer stem cell (CSC)-mediated epithelial-mesenchymal switching, tissue samples from 8 patients each in 3 stages (normal, low-grade intraepithelial neoplasia (LGIN), as well as early gastric carcinoma (EGC)) were collected for whole-exome sequencing, which revealed differentially expressed genes (DEGs). The DEGs and their prognostic value were verified through TCGA and GTEx analyses. We also verified the role of DOT1L in EGC development. We collected samples from three patients each with LGIN and EGC for single-cell sequencing. We conducted single-cell transcriptomic analysis, DEG analysis, cell‒cell interaction analysis, and pseudotime analysis using R language. Sites and levels of DOT1L, CD44 and DOT1L expression were verified by IF. We found 703 deleterious mutation sites in the LGIN group and 389 deleterious mutation sites in the EGC group. The LGIN as well as EGC categories exhibited increased levels of DOT1L expression compared to the standard category (P<0.05) in TCGA and GTEx. DOT1L also correlated significantly with TMB (P=8.45E-06), MSI (P=0.001), and tumor proliferation index (P=7.17E-09) in the TCGA and GTEx datasets. In single cells, we found that DOT1L promotes CD44 expression via the Wnt/ß-catenin signaling pathway and the development for stemness properties within GC. In addition, we found that DOT1L, CD44 and CTNNB1 colocalize and correlate positively. In conclusion, one important CSC regulator in GC, DOT1L may be crucial in coordinating the expression of genes specific to a certain lineage during MSC development.

Clinicopathological significance of intestinal metaplasia in endoscopically resected early gastric carcinoma.

OBJECTIVE: To investigate the clinicopathological and prognostic significance of intestinal metaplasia (IM) in endoscopically resected early gastric carcinoma (EGC). METHODS: Altogether 136 consecutive cases with EGC resected by endoscopic submucosal dissection over 5 years were included and divided into the early gastric cardiac (EGCC; n = 60) and non-cardiac carcinoma (EGNCC; n = 76) groups. Goblet cell IM and subtypes were determined with histology and immunostaining. Recurrence-free survival (RFS) was compared among various IM groups. RESULTS: IM was identified in 128 (94.1%) EGC cases, including complete IM (n = 39), incomplete IM (n = 27), and mixed IM (n = 62). Incomplete IM was significantly more common in EGCC and exhibited a lower frequency of en bloc resection than the complete subtype. The frequency of synchronous or metachronous gastric tumor was significantly more common in EGCC with complete IM than in those with incomplete IM. Compared to EGC without IM, EGC with IM showed a significantly higher frequency of non-poorly cohesive carcinoma, en bloc resection, and non-eCuraC-1 grade. EGNCC with IM was significantly associated with negative resection margins and en bloc resection. The 5-year RFS was significantly lower in EGNCC patients with incomplete IM compared with those with mixed IM. The independent risk factors for RFS included tumor size >2 cm and eCuraC-1 grade. CONCLUSIONS: Subtyping IM in EGC helped predict endoscopic resectability, prognosis, and risk of synchronous or metachronous gastric tumor. The significance of IM differed between EGCC and EGNCC. Large studies with longer follow-up are warranted to validate our findings.

Prognosis of patients with early gastric carcinoma treated by endoscopic submucosal dissection and risk factors for additional postoperative surgery.

OBJECTIVE: To investigate the prognosis of patients with early gastric carcinoma (EGC) treated by endoscopic submucosal dissection (ESD) and the risk factors for additional postoperative surgery. METHODS: A retrospective analysis was performed on 100 patients with EGC admitted to our hospital from January 2017 to May 2019. According to different surgical methods, patients were divided into the ESD (n=60) and endoscopic mucosal resection (EMR) groups (n=40). Clinical efficacy, perioperative indexes, incidence of complications and risk factors for additional postoperative surgery were compared. RESULTS: The ESD group had evidently prolonged operation time (P<0.01) but similar intraoperative blood loss (P>0.05) as compared with the EMR group. In comparison to the EMR group, the gastrointestinal recovery time and length of stay in the ESD group were notably shorter (P<0.01), the rates of en bloc resection and complete resection of lesions were markedly higher (P<0.05), and the postoperative fever/infection rate was noticeably lower (P<0.05). The two surgical methods had no significant difference on the overall survival rate of patients (P=0.302). It was identified that the infiltration depth and the positive surgical margin were independent risk factors for postoperative additional surgery (all P<0.05). ROC analysis revealed that positive surgical margin was quite valuable in judging the need for additional postoperative surgery. CONCLUSION: ESD can accelerate the postoperative recovery of patients with EGC, and positive surgical margin is independently tied to additional postoperative surgery in patients after ESD.

Distinct clinicopathological differences between early gastric cardiac and non-cardiac carcinomas: a single-center retrospective study of 329 radical resection cases.

BACKGROUND: Early gastric carcinoma is heterogeneous and can be divided into early gastric cardiac carcinoma (EGCC) and early gastric non-cardiac carcinoma (EGNCC) groups. At present, differences in clinicopathology remains obscure between EGCC and EGNCC fundus-corpus and antrum-angularis-pylorus subgroups, especially between EGCC with and without oesophageal invasion. METHODS: In this study, we studied 329 consecutive early gastric carcinoma radical gastrectomies with 70 EGCCs and 259 EGNCCs. RESULTS: Compared to the EGNCC antrum-angularis-pylorus (n = 181), but not fundus-corpus (n = 78), sub-group, EGCC showed significantly older age, lower prevalence of the grossly depressed pattern, better tumor differentiation, higher percentage of tubular/papillary adenocarcinoma, but lower frequency of mixed poorly cohesive carcinoma with tubular/papillary adenocarcinoma, and absence of lymph node metastasis (LNM) in tumors with invasion up to superficial submucosa (SM1). In contrast, pure poorly cohesive carcinoma was less frequently seen in EGCCs than in EGNCCs, but mixed poorly cohesive carcinoma with tubular/papillary adenocarcinomas was significantly more common in the EGNCC antrum-angularis-pylorus sub-group than in any other group. No significant differences were found between EGCC and EGNCC sub-groups in gender, tumor size, H. pylori infection rate, and lymphovascular/perineural invasion. EGCC with oesophageal invasion (n = 22), compared to EGCC without (n = 48), showed no significant differences in the H. pylori infection rate and oesophageal columnar, intestinal, or pancreatic metaplasia, except for a higher percentage of the former in size > 2 cm and tubular differentiation. CONCLUSIONS: There exist distinct clinicopathologic differences between EGCC and EGNCC sub-groups; EGCC was indeed of gastric origin. Further investigations with larger samples are needed to validate these findings.

Predictive Factors and Long-Term Outcomes of Early Gastric Carcinomas in Patients with Non-Curative Resection by Endoscopic Submucosal Dissection.

PURPOSE: Non-curative resection (NCR) remains problematic in some cases of early gastric carcinomas (EGCs) treated by endoscopic submucosal dissection (ESD). The aim of this study was to identify predictors of NCR, especially of eCura C1 and eCura C2 resections, before ESD and study long-term outcomes of EGC patients with NCR. PATIENTS AND METHODS: A retrospective review of medical records was conducted over an 8-year period for EGCs undergoing ESD. Clinicopathologic and endoscopic characteristics and patients' survival were analyzed. Risk factors for NCR and eCura C1 and C2 resections were assessed by logistic analyses. Survival of patients was estimated with the Kaplan-Meier method with a Log rank test. RESULTS: A total of 463 patients with 472 lesions were qualified. By univariate and multivariate analyses, the predictors for NCR and eCura C2 resections were tumor size >20 mm, tumors located in cardia-fundus, uneven surface, margin elevation, and mixed and undifferentiated types, and those for eCura C1 resection were tumors located in cardia-fundus, negative lifting sign, and mixed and undifferentiated types. The 5-year cancer-specific and cancer-free survival rates were 100.0% and 94.2%, and 95.3% and 83.4% in the curative resection (CR) and NCR groups, respectively. The 5-year cancer-specific and cancer-free survival rates were significantly greater in the CR group than that in the NCR group (P <0.0001). CONCLUSION: In this cohort, we identified various endoscopic and pathologic features of EGCs to predict NCR, especially eCura C1 and eCura C2 resections before ESD. These clinically valuable factors would be very informative to endoscopists and surgeons who perform ESD to resect EGCs.

The risks and characteristics of the delayed bleeding after endoscopic submucosal dissection for early gastric carcinoma in cases with anticoagulants.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early gastric carcinoma. Vitamin K antagonists and direct oral anticoagulants (DOAC) were reported to increase the risk of delayed bleeding after ESD. However, the evaluation of ESD cases taking anticoagulants is scarce. We analyzed the risk and characteristics of delayed bleeding after gastric ESD in patients on anticoagulants. METHODS: We performed a retrospective observational study at a single center. Consecutive patients who underwent ESD for early gastric carcinoma and took anticoagulants, including warfarin, rivaroxaban, dabigatran, apixaban, and edoxaban, between January 2012 and December 2018, were analyzed. We also calculated delayed bleeding rates for those without anticoagulants. RESULTS: Of 1855 eligible patients who underwent gastric ESDs, 143 took anticoagulants. Delayed bleeding occurred in 30 (21.0%) cases taking anticoagulants, with 15 (19.5%) cases in the DOAC group [rivaroxaban, seven cases (21.2%); dabigatran, four cases (20.0%); apixaban, four cases (23.5%); and edoxaban, zero cases (0%)] and 15 cases (22.7%) in the warfarin group. Furthermore, 43/344 (12.5%) patients taking antiplatelets and 76/1368 (5.6%) patients without antithrombic drugs experienced delayed bleeding. Multivariable logistic analysis revealed post-heart valve replacement (OR, 6.56; 95% CI, 1.75-24.7; p < .05) as a risk for delayed bleeding in warfarin-taking patients, while no statistically significant factor was found in DOAC-taking patients. CONCLUSIONS: Anticoagulants were associated with a high incidence of severe delayed bleeding. Careful attention should be paid to patients on anticoagulants after gastric ESD, especially those on warfarin after heart valve replacement.

Very low risk of lymph node metastasis in Epstein-Barr virus-associated early gastric carcinoma with lymphoid stroma.

BACKGROUND: Epstein-Barr virus-associated early gastric carcinoma with lymphoid stroma (EBV-GCLS) is a rare variant of early gastric carcinomas. Clinicopathological features of this variant remain obscure, especially in Chinese patients. Therefore, we collected EBV-GCLS cases and studied clinicopathology and prognosis. METHODS: By a retrospective review of 595 consecutive radical gastrectomies for early gastric carcinoma from 2006 to 2018, we identified 8 (1.3%, 8/595) EBV-GCLS cases. Clinicopathologic characteristics were compared between EBV-GCLSs and 109 conventional early gastric carcinomas, which were divided into intramucosal, SM1, and SM2 subgroups. The latter 2 subgroups were classified according to the submucosal invasion depth below or over 500 µm. RESULTS: All 8 EBV-GCLSs occurred in male patients and invaded deep submucosa (SM2) without lymph node metastasis (LNM), four (50%) of which had synchronous non-gastric malignant tumors (3 gastric gastrointestinal stromal tumors and 1 primary clear cell renal cell carcinoma), and four (50%) arose in the proximal stomach. Compared to conventional early gastric carcinomas, EBV-GCLS was significantly more frequent with SM2 invasion, poor differentiation, and synchronous non-gastric carcinoma tumor, but not with age, gender, macroscopic type, location, size, perineural invasion, lymphovascular invasion, and pathologic stage. In invasion-depth stratified comparisons in the SM2 subgroup, the frequency of LNM in EBV-GCLS was significantly lower than that in conventional early gastric carcinomas (p < 0.05) and the 5-year survival rate of patients with EBV-GCLS was better than that with conventional early gastric carcinomas in 3 subgroups (100% vs 91.5, 85.7, 83.9%, respectively), although the differences did not reach a statistically significant level due to the small sample size. Significant differences among 4 subgroups were found in tumor grade, lymphovascular invasion, LNM, pathological stage, and synchronous tumor, but not in age, gender, macroscopic type, tumor size, location, perineural invasion. CONCLUSIONS: Even with poor differentiation and SM2 invasion, EBV-GCLS showed very low risk of LNM and may be a candidate for endoscopic therapy such as endoscopic submucosal dissection.

Marked thickening of muscularis mucosae and submucosa in the gastric cardia: A histopathological study of 110 surgical resection cases.

OBJECTIVE: To investigate histopathologic changes of muscularis mucosae (MM) and submucosa in the gastric cardia. METHODS: We performed a histopathology study of 50 distal esophagectomies with proximal gastrectomies for esophageal squamous cell carcinoma as the study (non-cancerous cardiac) group and 60 gastrectomies for early gastric cardiac carcinoma as the cancer group. The gastroesophageal junction was defined as the distal end of squamous epithelium, multilayered epithelium, or deep esophageal glands or ducts. Gastric cardia (n = 110) was defined as the presence of cardiac and cardio-oxyntic mucosae distal to the gastroesophageal junction. RESULTS: The average thickness of MM and submucosa in the cardia was 1.04 and 1.41 mm, respectively, which was significantly thicker than that in distal stomach (n = 34) (0.22 and 0.99 mm) or distal esophagus (n = 92) (0.60 and 1.15 mm). In the cardia, thickened MM displayed frayed muscle fibers (93.3%) with a significantly higher prevalence of entrapped glands, cysts, and lymphoid follicles than in the distal stomach or distal esophagus. In the submucosa fatty changes, cysts, and abnormal arteries were significantly more common in the cardia than in the distal stomach or distal esophagus. Compared with the study group, the cardia in the cancer group showed significantly thicker MM (average 1.31 vs 0.72 mm) and submucosa (average 1.61 vs 1.16 mm), more frequent frayed MM (93.3% vs 60.0%), prolapse-like changes (50.0% vs 2.0%), and cysts (26.7% vs 4.0%). CONCLUSION: MM and submucosa of the cardia were significantly thickened, especially in early gastric cardiac carcinomas.

Bone metastasis as a recurrence of early papillary adenocarcinoma of the stomach.

Papillary adenocarcinomas of the stomach are rare and associated with a high rate of lymphovascular invasion and distant metastasis. However, the association between papillary adenocarcinoma and bone metastasis in gastric cancer remains largely unexplored. We report a rare case of bone metastasis as a recurrence of early papillary adenocarcinoma of the stomach after curative surgery. A 75-year-old man with a pedunculated polyp at the pylorus of the stomach was diagnosed with papillary adenocarcinoma after biopsy of the lesion, and the polyp was surgically resected. Pathohistological examination revealed intramucosal cancer without lymphovascular invasion or lymph node metastasis. Eight months after surgery, imaging studies showed osteolysis in the right sacrum, and the lesion was diagnosed as a bone metastasis after biopsy. The patient received palliative chemotherapy and radiotherapy for the bone metastasis, which resulted in relief of his leg pain. Subsequently, he was provided supportive care when his condition deteriorated, and he died 8 months after the diagnosis of bone metastasis. Our case shows that bone metastasis should not be overlooked, even though it is rare in gastric cancer patients. Papillary adenocarcinoma of the stomach should be carefully followed up through imaging examinations, even after curative resection.

Risk Factors of Lymph Node Metastasis in Patients with Early Pure and Mixed Signet Ring Cell Gastric Carcinomas.

Background: Early gastric carcinoma (EGC) with pure signet ring cell carcinoma (pSRCC) has been reported to have favourable prognosis and low risk of lymph node metastasis (LNM). However, risk factors of LNM and clinicopathological features for early gastric mixed signet ring cell carcinoma (mSRCC) remain poorly investigated. The aim of this study was to identify risk factors of LNM and compare clinicopathological characteristics and prognosis of early gastric pSRCC with mSRCC. Methods: This retrospective study was conducted at our center between 2005 and 2015 in 796 patients underwent radical gastrectomies combined with lymph node dissections, A total of 160 patients with early gastric SRCC underwent gastrectomies with lymph node dissections were reviewed, in which 79 cases were pSRCC and 81 cases were mSRCC. Risk factors of LNM and clinicopathologic features of these two groups were statistically compared, including age, gender, tumor location, gross pattern, size, invasion depth, lymphovascular invasion (LVI), helicobacter pylori (Hp) infection, atrophic gastritis, ulcer finding and LNM. Patients were follow-up for post-resection survival. The 5-year survival and disease-specific survival rate were estimated with the Kaplain-Meier method with a log-rank test and compared between the two groups. Results: Tumor size (P<0.05), invision depth (P<0.05) and LVI (P < 0.0001) were risk factors of LNM, LVI (P < 0.0001) was independent risk factor of LNM in 160 patients. Univariate analysis reviewed LVI (P < 0.0001) as the risk factor in the pSRCC group, and the risk factors of LNM in the mSRCC included LVI (P < 0.0001) and tumor size (P<0.05). Multivariable analysis revealed two independent risk factors in the mSRCC group: 1) tumor size (P < 0.05), and 2) LVI (P < 0.0001). The significant characteristics in two groups included the male gender (P < 0.0001), gross pattern (P < 0.05), LVI (P < 0.01), and Hp infection (P < 0.01). The difference of LNM rate between expanded indication and out of indication in 160 patients was significant (P=0.03). The overall 5-year survival rate for early gastric SRCC was 96.3%. There was no significant difference in the overall survival and disease-specific survival between the two groups. Conclusions: Although with similar post-resection survival, the independent risk factors of LNM in the early mSRCC group, compared to those in the early pSRCC group, included large tumor size and LVI. Early gastric mSRCC had more aggressive clinicopathological features than pSRCC.

Micropapillary early gastric carcinoma with distinct clinicopathological features, high risk for lymph node metastasis, and dismal prognosis: a multicenter clinicopathological study of 29 cases identified in 1890 early gastric carcinoma radical gastrectomies.

Clinicopathology and risk factors of lymph node metastasis (LNM) in micropapillary early (pT1) gastric carcinoma (MEGC) remain elusive because of the extreme rarity. In this multicenter study, we investigated 1890 consecutive radical resections of early gastric carcinoma diagnosed with the World Health Organization criteria and identified 29 (1.5%) MEGC cases with a small (≥5%) micropapillary component. MEGC showed a male predominance (male-to-female ratio, 21:8). Most (93.1%; 27/29) tumors invaded submucosa. Lymphovascular invasion was detected in 14 (48.3%) of 29 cases. LNM was found in 13 cases (44.8%; 11 identified with a routine hematoxylin-eosin stain and 2 additional cases with a positive pancytokeratin immunostain). Overall, independent risk factors for LNM in early gastric carcinoma included patient age of 62 years or less, female sex, noncardiac location, ulcerative pattern, tumor size of greater than 2 cm, submucosal invasion, Lauren diffuse type, lymphovascular invasion, and MEGC. In MEGC, advanced pathologic stages were demonstrated in 6 (20.7%) of 29 cases. The 5-year overall survival rate of MEGC patients was 58.6%. Submucosal invasion, lymphovascular invasion, and LNM were significantly more frequent in the MEGC group than in the non-MEGC groups. Advanced pathologic stages were significantly more common in MEGC than in nonmicropapillary Lauren intestinal- but not diffuse-type early gastric carcinomas. In conclusion, MEGC demonstrated a high propensity for lymphovascular invasion, LNM with advanced stages, and dismal prognosis.

Linked Color Imaging Highlights Flat Early Gastric Cancer.

While linked color imaging (LCI) may allow flat early gastric cancer to be detected early, the endoscopic and pathological features of lesions detected by LCI remain poorly described. Screening esophagogastroduodenoscopy performed on a 68-year-old woman revealed a yellowish, flat lesion shown to be reddish in its central area, located in the anterior wall of the gastric lower body on white light imaging (WLI). On LCI, the lesion was highlighted as an orangish, flat lesion shown to be purple-colored in its central area, surrounded by lavender-colored tissue. Endoscopic submucosal dissection performed led to the patient being diagnosed with tubular adenocarcinoma, well-differentiated type (tub1), pT1a (M). This case suggests that LCI may prove more useful than WLI for the detection of flat early gastric cancer lesions.

Differential analysis of lymph node metastasis in histological mixed-type early gastric carcinoma in the mucosa and submucosa.

AIM: To investigate the relationship between histological mixed-type of early gastric cancer (EGC) in the mucosa and submucosa and lymph node metastasis (LNM). METHODS: This study included 298 patients who underwent gastrectomy for EGC between 2005 and 2012. Enrolled lesions were divided into groups of pure differentiated (pure D), pure undifferentiated (pure U), and mixed-type according to the proportion of the differentiated and undifferentiated components observed under a microscope. We reviewed the clinicopathological features, including age, sex, location, size, gross type, lymphovascular invasion, ulceration, and LNM, among the three groups. Furthermore, we evaluated the predictors of LNM in the mucosa-confined EGC. RESULTS: Of the 298 patients, 165 (55.4%) had mucosa-confined EGC and 133 (44.6%) had submucosa-invasive EGC. Only 13 (7.9%) cases of mucosa-confined EGC and 30 (22.6%) cases of submucosa-invasive EGC were observed to have LNM. The submucosal invasion (OR = 4.58, 95%CI: 1.23-16.97, P = 0.023), pure U type (OR = 4.97, 95%CI: 1.21-20.39, P = 0.026), and mixed-type (OR = 5.84, 95%CI: 1.05-32.61, P = 0.044) were independent risk factors for LNM in EGC. The rate of LNM in mucosa-confined EGC was higher in the mixed-type group (P = 0.012) and pure U group (P = 0.010) than in the pure D group, but no significant difference was found between the mixed-type group and pure U group (P = 0.739). Similarly, the rate of LNM in the submucosa-invasive EGC was higher in the mixed-type (P = 0.012) and pure U group (P = 0.009) than in the pure D group but was not significantly different between the mixed-type and pure U group (P = 0.375). Multivariate logistic analysis showed that only female sex (OR = 5.83, 95%CI: 1.64-20.70, P = 0.028) and presence of lymphovascular invasion (OR = 13.18, 95%CI: 1.39-125.30, P = 0.020) were independent risk factors for LNM in mucosa-confined EGC, while histological type was not an independent risk factor for LNM in mucosa-confined EGC (P = 0.106). CONCLUSION: For mucosal EGC, histological mixed-type is not an independent risk factor for LNM and could be managed in the same way as the undifferentiated type.

Risk factors of lymph node metastasis in 1620 early gastric carcinoma radical resections in Jiangsu Province in China: A multicenter clinicopathological study.

OBJECTIVE: To investigate risk factors of lymph node metastasis (LNM) in early gastric carcinoma (EGC) in four tertiary medical centers in Jiangsu Province, China. METHODS: Among 10 097 consecutive combined gastric cancer radical resections, 1903 EGC were identified and reviewed, 283 excluded and 1620 included in the study. All pathological and some endoscopic reports were reviewed for patients' characteristics, tumor location, gross features, and the number of lymph nodes retrieved and involved. Two pathologists independently investigated the pathological features of tumor type, differentiation, invasion depth, lymphovascular invasion (LVI), and perineural invasion. The data were statistically analyzed to identify risk factors for LNM. RESULTS: The average number of lymph nodes retrieved was 17.5 per patient. LNM was diagnosed in 15.5%. By univariate analysis, significant risk factors for LNM included age ≥ 41 years, female sex, size over 1 cm, submucosal invasion, poor differentiation, poorly cohesive carcinoma, micropapillary adenocarcinoma, adenocarcinoma mixed with signet-ring cell carcinoma, LVI, perineural invasion, and distal gastric location. By multivariate analysis, independent risk factors for LNM were size ≥ 3 cm (odds ratio [OR] 1.9), poor differentiation (OR 2.5), adenocarcinoma mixed with signet-ring cell carcinoma (OR 1.7), LVI (OR 5.8) and submucosal invasion (OR 2.9). In contrast, size < 3 cm and ulcer were not significant risk factors. Early cardiac carcinoma (OR 0.4) had significantly lower risk. CONCLUSIONS: Independent risk factors for LNM in EGC in Chinese patients included tumor size ≥ 3 cm, poor differentiation, submucosal invasion, adenocarcinoma mixed with signet-ring cell carcinoma and LVI. Early cardiac carcinoma had a significantly lower risk for LNM.

Clinicopathology of Early Gastric Carcinoma: An Update for Pathologists and Gastroenterologists.

BACKGROUND: The WHO defines early gastric carcinoma (EGC) as invasive carcinoma up to the submucosal layer, regardless of nodal metastasis. The recent study results indicate that EGC varies in location, histology, nodal metastasis, and prognosis. SUMMARY: The heterogeneity in EGC may be related to various types of epithelial stem cells. The most important stem cells include Lgr5+ cells at the base of a gastric unit in the antrum-pylorus-cardia, Mist1+ cells at the isthmus/Troy+ cells at the base in the corpus-fundus, and Sox2+ cells at the base in almost all regions. Dysregulation of these cells along with environmental factors transform stem cells in different regions into malignancy in genetically susceptible populations. KEY MESSAGE: The 2 most vulnerable regions for EGC have been found along the lesser curvature: the cardia in elderly patients and antrum-angularis in mid-aged and elderly patients. Most hereditary early-onset gastric carcinomas are concentrated in the corpus-fundus of young women. By histology, the most common EGC type is tubular adenocarcinoma in many growth patterns, starting in the neck of a gastric unit. Worse prognosis has been found in early papillary, compared to tubular, adenocarcinoma, related to deeper penetration, more lymphovascular invasion, and more liver and nodal metastases. Contrary to the common belief, intramucosal signet ring cell carcinoma demonstrates low risk of nodal metastasis, comparable to early intestinal-type EGC. PRACTICAL IMPLICATIONS: The overall risk for nodal metastasis in EGC is low but significant. It is urgent to organize multicenter studies on risk of nodal metastasis in EGC in order to establish more reliable clinical practice guidelines to treat EGC patients.

Carbon Dioxide versus Air Insufflation in Gastric Endoscopic Submucosal Dissection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) with air insufflation is commonly used for the staging and treatment of early gastric carcinoma. However, carbon dioxide (CO2) use has been shown to cause less post-procedural pain and fewer adverse events. The objective of this study was to compare the post-procedural pain and adverse events associated with CO2 and air insufflation in ESD. METHODS: A systematic search was conducted for randomized control trials (RCTs) comparing the two approaches in ESD. The Mantel-Haenszel method was used to analyze the data. The mean difference (MD) and odds ratio (OR) were used for continuous and categorical variables, respectively. RESULTS: Four RCTs with a total of 391 patients who underwent ESD were included in our meta-analysis. The difference in maximal post-procedural pain between the two groups was statistically significant (MD, -7.41; 95% confidence interval [CI], -13.6 - -1.21; p=0.020). However, no significant differences were found in the length of procedure, end-tidal CO2, rate of perforation, and postprocedural hemorrhage between the two groups. The incidence of overall adverse events was significantly lower in the CO2 group (OR, 0.51; CI, 0.32-0.84; p=0.007). CONCLUSIONS: CO2 insufflation in gastric ESD is associated with less post-operative pain and discomfort, and a lower risk of overall adverse events compared with air insufflation.

Expression of coproporphyrinogen oxidase is associated with detection of upper gastrointestinal carcinomas by 5-aminolevulinic acid-mediated photodynamic diagnosis.

BACKGROUND: 5-Aminolevulinic acid is a precursor of photosensitizing protoporphyrin IX and has been applied for photodynamic diagnosis of brain and bladder tumors with few side effects. Although most upper gastrointestinal tumors can be detected during photodynamic diagnosis, some tumors containing signet-ring cells cannot be visualized. Here, we aimed to assess whether proteins involved in the absorbance, activation, and turnover of protoporphyrin IX altered the fluorescence signal in gastric cancer. METHODS: Aminolevulinic acid-mediated photodynamic diagnosis was performed in 23 lesions from 20 patients using an endoscope equipped with a blue laser light that caused red fluorescence emission of photosensitizing protoporphyrin IX. Red fluorescence signal and intensity was assessed during photodynamic diagnosis procedures. Lesions were resected by endoscopic and/or laparoscopic surgery, and specimens were immunostained and assessed for the expression of ATP-binding cassette sub-family G member 2, oligopeptide transporter-1, and coproporphyrinogen oxidase. RESULTS: Photodynamic diagnosis was negative in four cases (17.4%). Three cases of photodynamic diagnosis-negative lesions were signet-ring cell carcinomas, and only one case was differentiated adenocarcinoma (intestinal type). Twenty intestinal type, photodynamic diagnosis-positive lesions showed high expression of coproporphyrinogen oxidase, whereas signet-ring cell carcinomas were all negative. Oligopeptide transporter-1 immunoreactivity was significantly higher in tumors of intestinal type. ATP-binding cassette sub-family G member 2 expression tended to be higher in luminal surface tumors than in intestinal type tumors. CONCLUSION: Aminolevulinic acid-mediated photodynamic diagnosis provided good detection of upper gastrointestinal tumors of intestinal type but not diffuse type tumors, such as signet-ring cell carcinomas, possibly owing to coproporphyrinogen oxidase expression.

Worse Prognosis in Papillary, Compared to Tubular, Early Gastric Carcinoma.

Purpose: Papillary early gastric carcinoma (EGC) is uncommon but shows worse prognosis in our most recent study in a Chinese population with unknown reasons. The aim of the present study was to further investigate risk factors for worse prognosis in patients with papillary adenocarcinoma, compared to those with tubular adenocarcinoma. Methods: We searched the electronic pathology databank for radical gastrectomy cases over an 8-year period at a single medical center in Nanjing, China, and identified consecutive 240 EGC cases that were classified as either papillary (n=59) or tubular (n=181) EGC tumors in accordance with the World Health Organization (WHO) gastric cancer diagnosis criteria. We investigated and compared clinicopathologic risk factors for prognosis between papillary and tubular EGC groups. All patients were followed up and their 5-year survival rate was compared statistically with the Kaplan-Meier method with a log rank test. Results: Compared to tubular EGCs, papillary EGCs were significantly more common in elderly patients, more frequently occurred in the proximal stomach with protruding/elevated growth patterns, submucosal invasion, and a micropapillary component. Although lymphovascular invasion (16.9%), nodal (13.6%) and distant (11.8%) metastases in papillary EGCs were more frequent than those (8.3%, 7.2%, and 3.7%, respectively) in tubular EGCs, the differences approached but did not reach statistically significant levels. Significant risk factors for nodal metastasis included lymphovascular invasion in both EGC groups, but the ulcerative pattern and submucosal invasion only in tubular EGCs. The 5-year survival rate was significantly worse in papillary (80.5%) than in tubular (96.8%) EGCs. Conclusions: Compared to tubular EGCs, papillary EGCs diagnosed with the WHO criteria in Chinese patients were more frequent in elderly patients, proximal stomach and showed the significantly worse 5-year survival rate with more protruding/elevated growth patterns and the micropapillary component. Further studies in larger samples are urgently needed to validate these findings for precision individualized EGC patient management.

Histologic purity of signet ring cell carcinoma is a favorable risk factor for lymph node metastasis in poorly cohesive, submucosa-invasive early gastric carcinoma.

BACKGROUND: The prediction of biologic behavior of poorly cohesive early gastric carcinoma (EGC) is an important issue in the selection of the treatment modality. To elucidate the risk factors for lymph node metastasis (LNM) of poorly cohesive EGC, we focused on the histologic purity of the poorly cohesive component and evaluated the impact of this factor on LNM. METHODS: We divided poorly cohesive EGC into (1) pure signet ring cell (SRC) carcinoma, which was defined as composed only of signet ring cells or poorly cohesive cells and (2) mixed SRC carcinoma, defined as poorly cohesive carcinoma with minor tubular components. We reviewed the clinicopathologic features, including age, sex, location, size, depth, lymphovascular invasion (LVI), LNM, ulceration, and intestinal metaplasia between the two groups in a large series of poorly cohesive, submucosa-invasive EGC (n = 317). RESULTS: LNM was found in 58 cases (18.3 %). Mixed SRC carcinoma histologic type (p < 0.001), larger tumor size (more than 2 cm) (p = 0.012), and the presence of LVI (p < 0.001) were associated with LNM. Pure SRC carcinomas accounted for 56.2 % (178/317) of the cases. Fourteen pure SRC carcinomas (7.8 %) showed LNM, whereas 44 mixed SRC carcinomas (31.9 %) exhibited LNM (p < 0.001). On multivariate logistic regression, the presence of LVI (odds ratio 6.737; 95 % confidence interval 2.714-16.720; p < 0.001) and mixed SRC carcinoma histologic type (odds ratio 4.674; 95 % confidence interval 2.370-9.216; p < 0.001) were independent predictors of LNM in poorly cohesive, submucosa-invasive EGC. CONCLUSIONS: The presence of a tubular component in SRC carcinoma was a risk factor for LNM in poorly cohesive, submucosa-invasive EGC. On the basis of this finding, we propose that the presence of a minor tubular component or the purity of the poorly cohesive/SRC carcinoma component should be reported in daily pathologic practice.

Expression of Runx-3 and β-catenin proteins in early gastric cancer and their clinical significance / 临床与实验病理学杂志

Purpose To evaluate the relationship between the expression of Runx-3 and β-catenin protein in EGC with the clinical factors.Methods Immunohistochemistry (IHC) was used to detect the expression of Runx-3 and β-catenin protein in 30 cases of normal gastric mucosa and 49 cases of EGC.Results The expression rate of Runx-3 protein in normal gastric mucosa (86.67％) was significantly higher than that in EGC tissues (34.69％) (P ＜ 0.05).β-catenin staining was strongly positive (100％) in normal gastric mucosa compared with that in EGC (57.14％) (P ＜ 0.05),while the abnormal expression rate of β-catenin (0) was significantly lower than that in EGC tissues (75.51％) (P ＜ 0.05).No correlation was found between the expression of Runx-3 and β-catenin protein with the clinicopathological factors,including sex,age,and tumor size except vessel invasion.Conclusion The reduced expression of Runx-3 in EGC indicates that it may be used as a favorable marker for the diagnosis of EGC.The loss of β-catenin protein membrane expression while ectopic expressed on nuclear or cytoplasm in EGC and the membrane expression of β-catenin protein is completely absent in the early stage of vascular invasion suggesting that the expression of β-catenin protein is closely related to the occurrence and development of EGC.A join-detection of Runx-3 and β-catenin expression will be helpful for the diagnosis of EGC.