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Gastric cancer is the fifth (men) and sixth (women) most common cause of cancer-related death in Germany. Despite a declining incidence of distal gastric cancer, the prognosis remains dismal: the 5‑year survival rate ranges between 35% for women and 31% for men. The majority are adenocarcinomas, which occur sporadically, familial or hereditary. Adenomas and intraepithelial neoplasms are considered as precursor lesions. Recently, whole genome sequencing and comprehensive molecular profiling described four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV) positive, microsatellite unstable, chromosomal unstable and genomically stable gastric cancer. Currently, only the TNM classification has stood the test of time for the assessment of patient prognosis. Neuroendocrine tumor types 1-3 and soft tissue tumors occur significantly less often in the stomach. Gastrointestinal stromal tumors and inflammatory fibroid polyps are among the more common soft tissue tumors of the stomach and show distinct phenotypes. This review gives an overview of the current World Health Organization (WHO) classification of gastric tumors.

A total of 313 cases of differentiated-type early gastric adenocarcinomas, including 113 cases of small-sized carcinoma (5< × ≤10 mm) and 121 cases of microcarcinoma (0< × ≤5 mm), were examined immunohistochemically to clarify the phenotypic expressions. They were classified into four categories (gastric phenotype (G-type), intestinal phenotype, gastrointestinal phenotype, and null phenotype) by a two-step process: the phenotype based on an immunoprofile of mucin core proteins (MUCs) with CDX2 (w/.CDX2-assessment); and the phenotype of MUCs only (w/o.CDX2-assessment). CDX2 expression was observed in 89.1% (279/313); it was highly expressed in 87.6% (106/121) of microcarcinomas. MUC2 expression increased as tumor size increased (P < 0.05). Compared with w/o.CDX2-assessment, w/.CDX2-assessment showed significantly fewer G-type carcinomas (P < 0.05). Each phenotype marker was less expressed in the submucosal part than in the mucosal part. In conclusion, CDX2 was a sensitive marker for assessing intestinal phenotype. A large portion of the early differentiated-type adenocarcinomas expressed CDX2 from the very early stage of carcinogenesis, and the proportion of G-type was unexpectedly low. Lower expression of each phenotype marker was considered the cause of phenotype alteration during submucosal invasion., (© 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Introduction: Gastric cancer is among the most common cancers worldwide. Despite declining incidences, the prognosis remains dismal in Western countries and is better in Asian countries with national cancer screening programs. Complete endoscopic or surgical resection of the primary tumor with or without lymphadenectomy offers the only chance of cure in the early stage of the disease. Survival of more locally advanced gastric cancers was improved by the introduction of perioperative, adjuvant and palliative chemotherapy. However, the identification and usage of novel predictive and diagnostic targets is urgently needed. Areas covered: Recent comprehensive molecular profiling of gastric cancer proposed four molecular subtypes, i.e. Epstein-Barr virus-associated, microsatellite instable, chromosomal instable and genomically stable carcinomas. The new molecular classification will spur clinical trials exploring novel targeted therapeutics. This review summarizes recent advancements of the molecular classification, and based on that, putative pitfalls for the development of tissue-based companion diagnostics, i.e. prevalence of actionable targets and therapeutic efficacy, tumor heterogeneity and tumor evolution, impact of ethnicity on gastric cancer biology, and standards of care in the East and West. Expert commentary: The overall low prevalence of actionable targets and tumor heterogeneity are the two main obstacles of precision medicine for gastric cancer.

Gastric cancer is still a relevant malignant disease with high morbidity and mortality. Current molecular genetic data show that gastric cancer, as other solid tumors as well, is not a single entity but consists of several molecular subtypes of gastric cancer with diverse biology. The increasing understanding of molecular pathways is the basis for innovative therapies. These either directly target altered signaling pathways or genes in tumor cells or as in immune checkpoint inhibitors, indirectly target tumor cells by blocking tumor-induced immune inhibition leading to improvement in the prognosis. The selection of eligible patients is a prerequisite for the successful clinical application of these targeted drugs. Pathologists play an important role in integrating tissue-based biomarkers and established pathological parameters (typing, grading and staging) into one comprehensive morphomolecular report.

Background: The current AJCC staging system for gastric cancer (AJCC7) incorporated several major revisions to the previous edition. The T and N categories and the stage groups were newly defined, and adenocarcinoma of the esophagogastric junction (EGJ) was reclassified and staged according to the esophageal system. Studies to validate these changes showed inconsistent results. The International Gastric Cancer Association (IGCA) launched a project to support evidence-based revisions to the next edition of the AJCC staging system., Methods: Clinical and pathological data on patients who underwent curative gastrectomy at 59 institutions in 15 countries between 2000 and 2004 were retrospectively collected. Patients lost to follow-up within 5 years of surgery were excluded. Patients treated with neoadjuvant therapy were excluded. The data were analyzed in total, and separately by region of treatment., Results: Of 25,411 eligible cases, 84.8 % were submitted from 24 institutions of Japan and Korea, 6.4 % from other Asian countries, and 8.8 % from 29 Western institutions. The T and N categories of AJCC7 clearly stratified the patient survival. Patients with pN3a and pN3b showed distinct prognosis in all regions, and by introducing pN3a and pN3b into a cluster analysis, we established a new stage grouping with better stratification than AJCC7, especially among stage III subgroups. Survival of Siewert type 2 and 3 EGJ tumors was better stratified by this IGCA stage grouping than by either esophageal or gastric scheme of AJCC7., Conclusions: For the next revision of AJCC classification, we propose a new stage grouping based on a large, worldwide data collection.

Introduction: Neuroendocrine Neoplasms are classified according to the new WHO classification in (1.) well differentiated neuroendocrine tumors G1 (NET G1, Ki67 ≤ 2 or mitosis count <2) and (2.) well differentiated neuroendocrine tumors G2 (NET G2, Ki67 3-20 or mitosis count 2-20) and (3.) poorly differentiated neuroendocrine carcinomas G3 (NEC G3, Ki67 > 20 or mitosis count >20)., Material and Methods: In this study 310 NENs of the Ludwig-Maximilians-University in Munich were reevaluated according to the new WHO classification., Results: 7% of the analyzed NENs were presented as neoplasias of the stomach. In NENs of the stomach three distinct subtypes are recognized: (1) type 1 associated with autoimmune chronic atrophic gastritis (2) type 2, associated with multiple endocrine neoplasia (MEN1) and Zollinger-Ellison Syndrom; and (3) type 3, sporadic tumors., Discussion: Precursor lesions (i. e. hyperplasia of the ECL cells) are found in patients with hypergastrinaemia (type 1 and 2). This article should provide insights into the diagnosis of NENs of the stomach with emphasis on the new international standard.

TNM staging is essential for clinical decision-making and prognostic prediction for patients with gastric cancer. The 7th TNM staging manual was formulated in 2009 and implemented in 2010. However, it was published that there were some deficiencies of the 7th edition of gastric cancer TNM staging system in clinical application process, and this old staging system could not meet the clinical needs. With the cooperation and promotion of the American Joint Committee on Cancer (AJCC), the International Union for Cancer Control (UICC) and the International Gastric Cancer Association (IGCA), and through the accumulation and analysis of gastric cancer big data, the 8th TNM staging system was published at the end of 2016. The updated staging system has defined the selection of staging system for esophagogastric junction cancer. It also has divided N3 into N3a and N3b, which has been incorporated into the new staging system, leading to more accurate risk stratification. Moreover, the cTNM staging system and ypTNM staging system have been added in the new staging manual. Overall, the 8th TNM staging system can facilitate more reasonable decision-making, more accurate prognostic prediction and better evaluation of therapeutic strategy. It is of high value to promote diagnostic and therapeutic standard for gastric cancer.

Objective: To investigate the prognostic factors of patients with lymph node-negative metastasis gastric cancer (pN0)., Methods: Clinicopathological data of patients with pN0 gastric cancer who underwent radical operation at the Department of Surgical Oncology, The First Hospital of China Medical University from May 1980 to August 2012 were collected and analyzed retrospectively., Inclusion Criteria: (1) Patients were diagnosed as gastric adenocarcinoma; (2) Postoperative pathology confirmed T1a to 4bN0M0 gastric cancer; (3) Total number of harvested lymph node was more than 15. The patients, who died within 1 month after the operation, died of other diseases, had remnant gastric cancer, or had incomplete follow-up data, were excluded. Univariate analysis was used to analyze the clinical factors that may influence the prognosis of patients with stage pN0 gastric cancer, then, those significant variables were entered into the Cox's proportional hazards regression model for multivariate analysis to obtain the independent prognostic factors for patients with pN0 gastric cancer finally. Furthermore, the prognosis of patients with pN0 advanced gastric cancer (invasive depth ≥ T2) were analyzed using the same method., Results: A total of 610 patients with pN0 gastric cancer were enrolled in the study, including 441 males and 169 females with age ranging from 19 to 83 (mean 56.4±11.0) years, D1 lymph node dissection in 45 cases, D2 lymph node dissection in 543 cases, D3 lymph node dissection in 22 cases, and 384 cases of advanced gastric cancer. The overall followed-up was 1 to 372 (median 32) months. Ninety cases (14.8%) were dead during the follow-up. The median survival was 277.7(95%CI: 257.6 to 297.8) months, and the 1-, 3-, 5-year survival rates were 96.5%, 87%, 83.2%. Univariate analysis showed that tumor diameter, depth of invasion, gross type, lymph node dissection and lymph vessel cancer embolus were related to the prognosis (all P<0.05). The 5-year survival rate of patients with tumor diameter >4 cm was significantly lower than those with tumor diameter ≤4 cm (75.6% vs. 87.8%, P=0.000). The 5-year survival rates of T1a, T1b, T2, T3 and T4 were 98.4%, 92.8%, 84.2%, 61.0% and 31.4% respectively, and the difference was statistically significant (P=0.000). In gross type, 5-year survival rate of early gastric cancer was 96.0%, and of Borrmann I( to IIII( type gastric cancer was 100%, 83.4%, 73.7% and 68.9% respectively, whose difference was statistically significant(P=0.000). The 5-year survival rates in patients undergoing lymph node dissection D1, D2 and D3 were 100%, 83.3% and 58.7%, and the difference was significant (P=0.005). The 5-year survival rate of patients with positive lymphatic cancer embolus was lower than those with negative ones (69.4% vs. 86.9%, P=0.000). Multivariate analysis showed that the gross type [Borrmann II(/early gastric cancer: HR(95% CI)=15.129(3.284 to 69.699), Borrmann III(/early gastric cancer: HR(95% CI)=14.613 (3.292 to 64.875), Borrmann IIII(/early gastric cancer: HR (95% CI)=15.430 (2.778 to 85.718),Borrmann IIIII(/early gastric cancer: HR(95%CI)=12.604 (1.055 to 150.642), P=0.025] and the positive lymphatic cancer embolus [HR(95% CI)=3.241 (2.056 to 5.108), P=0.000] were the independent prognostic factors of patients with pN0 gastric cancer. For pN0 patients with advanced gastric cancer, multivariate analysis showed that the depth of invasion [stage T3/stage T2: HR(95%CI)=1.520 (0.888 to 2.601), stage T4/stage T2: HR(95%CI)=2.235(1.227 to 4.070); P=0.031] and the positive lymphatic cancer embolus [HR(95%CI)=3.065 (1.930 to 4.868); P=0.000] were the independent risk factors influencing the prognosis., Conclusions: Positive lymphatic cancer embolus and worse gross pattern indicate poorer prognosis of patients with pN0 gastric cancer, which may be used as effective markers in evaluating the prognosis. As for pN0 advanced gastric cancer, invasion depth and positive lymphatic cancer embolus can play a more important role in the prediction.

Objective: To evaluate the clinicopathologic characteristics and prognostic difference of gastric stump cancer between non-anastomotic site and anastomotic site., Methods: Clinicopathologic data of 149 patients with gastric stump cancer undergoing operation (radical resection and palliative resection) in our department from January 1999 to June 2015 were analyzed retrospectively. Gastric stump cancer was defined as a primary carcinoma detected in the remnant stomach more than 5 years after subtotal gastrectomy for a benign disease(87 cases) or over 10 years after radical subtotal gastrectomy for a malignant disease (62 cases). Patients were divided into the anastomotic site group (72 cases) and the non-anastomotic site group (77 cases) according to tumor sites within the remnant stomach. Clinicopathologic characteristics, operative data, lymph node metastasis and prognosis were compared between the two groups., Results: Compared with non-anastomotic site group, the T stage, N stage and TNM stage were later in the anastomotic site group. Number of case of T1, T2, T3, and T4 stage in anastomotic site group was 1(1.4%), 2 (2.8%), 17(23.6%) and 52(72.2%), while such number in non-anastomotic site group was 8(10.4%), 10(13.0%), 27(35.1%) and 32(41.6%) respectively(χ 2 =17.665, P=0.001). Number of case of N0, N1, N2, and N3 in anastomotic site group was 28 (38.9%), 10 (13.9%), 23 (31.9%) and 11 (15.3%), while such number in non-anastomotic site group was 55 (71.4%), 10 (13.0%), 7 (9.1%) and 5 (6.5%) respectively(χ 2 =19.421, P=0.000). Number of case of stage I(, II(, III( and IIII( in anastomotic site group was 3(4.2%), 10(13.9%), 47(65.3%) and 12(16.7%), while such number in non-anastomotic site group was 16(20.8%), 40 (51.9%), 15(19.5%) and 6(7.8%) respectively(χ 2 =45.294, P=0.000). The histology and Borrmann classification were worse in anastomotic site group. Anastomotic site group had 19 cases(26.4%) of good differentiation and 53 cases(73.6%) of bad differentiation, while non-anastomotic site group had 43 cases (55.8%) of well-differentiated and 34 cases (44.2%) of poorly-differentiated tumors respectively(χ 2 =13.287, P=0.000). Anastomotic site group had 3 cases (4.2%) of Borrmann I(, 17 cases (23.6%) of Borrmann II(, 47 cases(65.3%) of Borrmann III( and 5 cases (6.9%) of Borrmann IIII(, while non-anastomotic site group had 18 cases (23.4%) of Borrmann I(, 16 cases (20.8%) of Borrmann II(, 34 cases (50.6%) of Borrmann III( and 4 cases (5.2%) of Borrmann IIII( respectively(χ 2 =11.445, P=0.010). Compared with non-anastomotic site group, anastomotic site group had a lower curative resection rate [63.9% (46/72) vs. 89.6% (69/77), χ 2 =13.977, P=0.000], a higher combined organ resection rate [33.3% (24/72) vs. 16.9% (13/77), χ 2 =5.394, P=0.020] and a more metastatic lymph nodes (4.3±4.9 vs. 1.9±3.6, t=3.478, P=0.000). The lymph node metastasis rates of No.4, No.10 and jejunal mesentery root lymph node in anastomotic site group and non-anastomotic site group were 15.3% (11/72) and 5.2% (4/77)(χ 2 =4.178, P=0.041), 9.7% (7/72) and 1.3% (1/77) (χ 2 =5.196, P=0.023), and 25.0% (18/72) and 3.9% (3/77)(χ 2 =13.687, P=0.000), respectively. Median followed up of all the patients was 37(2 to 154) months and the overall 5-year survival rate was 44.1%. The 5-year survival rate was 33.1% in anastomotic site group and 55.2% in non-anastomotic site group, and the difference was statistically significant between two groups (P=0.015). In the subgroup analysis according to the histology differentiation, the 5-year survival rate of patients with well-differentiation was not significantly different between two groups (43.7% vs. 56.2%, P=0.872), but the 5-year survival rate of patients with bad differentiation in anastomotic site group was significantly lower than that in non-anastomotic site group(29.8% vs. 53.8%, P=0.029)., Conclusion: Gastric stump cancer locating in anastomotic site indicates worse differentiation histology, higher lymph node metastasis rate, lower curative resection rate and poorer prognosis.

Objective: To establish an evaluation model of peritoneal metastasis in gastric cancer, and to assess its clinical significance., Methods: Clinical and pathologic data of the consecutive cases of gastric cancer admitted between April 2015 and December 2015 in Department of General Surgery, Zhongshan Hospital of Fudan University were analyzed retrospectively. A total of 710 patients were enrolled in the study after 18 patients with other distant metastasis were excluded. The correlations between peritoneal metastasis and different factors were studied through univariate (Pearson's test or Fisher's exact test) and multivariate analyses (Binary Logistic regression). Independent predictable factors for peritoneal metastasis were combined to establish a risk evaluation model (nomogram). The nomogram was created with R software using the 'rms' package. In the nomogram, each factor had different scores, and every patient could have a total score by adding all the scores of each factor. A higher total score represented higher risk of peritoneal metastasis. Receiver operating characteristic (ROC) curve analysis was used to compare the sensitivity and specificity of the established nomogram. Delong. Delong. Clarke-Pearson test was used to compare the difference of the area under the curve (AUC). The cut-off value was determined by the AUC, when the ROC curve had the biggest AUC, the model had the best sensitivity and specificity., Results: Among 710 patients, 47 patients had peritoneal metastasis (6.6%), including 30 male (30/506, 5.9%) and 17 female (17/204, 8.3%); 31 were ≥ 60 years old (31/429, 7.2%); 38 had tumor ≥ 3 cm(38/461, 8.2%). Lauren classification indicated that 2 patients were intestinal type(2/245, 0.8%), 8 patients were mixed type(8/208, 3.8%), 11 patients were diffuse type(11/142, 7.7%), and others had no associated data. CA19-9 of 13 patients was ≥ 37 kU/L(13/61, 21.3%); CA125 of 11 patients was ≥ 35 kU/L(11/36, 30.6%); CA72-4 of 11 patients was ≥ 10 kU/L(11/39, 28.2%). Neutrophil/lymphocyte ratio (NLR) of 26 patients was ≥ 2.37(26/231, 11.3%). Multivariate analysis showed that Lauren classification (HR=8.95, 95%CI:1.32-60.59, P=0.025), CA125(HR=17.45, 95%CI:5.54-54.89, P=0.001), CA72-4(HR=20.06, 95%CI:5.05-79.68, P=0.001), and NLR (HR=4.16, 95%CI:1.17-14.75, P=0.032) were independent risk factors of peritoneal metastasis in gastric cancer. In the nomogram, the highest score was 241, including diffuse or mixed Lauren classification (54 score), CA125 ≥ 35 kU/L (66 score), CA72-4 ≥ 10 kU/L (100 score), and NLR ≥ 2.37 (21 score), which represented a highest risk of peritoneal metastasis (more than 90%). The AUC of nomogram was 0.912, which was superior than any single variable (AUC of Lauren classification: 0.678; AUC of CA125: 0.720; AUC of CA72-4: 0.792; AUC of NLR: 0.613, all P=0.000). The total score of nomogram increased according to the TNM stage, and was highest in the peritoneal metastasis group (F=49.1, P=0.000). When the cut-off value calculated by ROC analysis was set at 140, the model could best balanced the sensitivity (0.79) and the specificity (0.87). Only 5% of patients had peritoneal metastasis when their nomogram scores were lower than 140, while 58% of patients had peritoneal metastasis when their scores were ≥ 140(χ 2 =69.1, P=0.000)., Conclusion: The risk evaluation model established with Lauren classification, CA125, CA72-4 and NLR can effectively predict the risk of peritoneal metastasis in gastric cancer, and provide the reference to preoperative staging and choice of therapeutic strategy.

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.

Background/aim: The aim of this study was to establish an appropriate TNM staging system for early gastric cancer., Methodology: We evaluated 2124 patients who had undergone gastrectomy for early gastric cancer between 1989 and 2001., Results: Using the seventh edition of the American Joint Committee on Cancer (AJCC) staging system, we found no significant differences in tumor recurrence and survival between N1 and N2 cancers or between N3a and N3b cancers, whereas the survival curves for N2 and N3 cancers were quite different. Similarly, using the classification in the sixth edition of the AJCC staging system, we found no significant difference in survival between the N2 and N3 cancer groups, whereas the survival curves for N1 versus N2 or N3 cancers were quite different., Conclusions: The classifications in the sixth and seventh editions of the AJCC staging system have a limitation for T1 gastric cancer (early gastric cancer).

Gastric cancers have recently been classified into several types on the basis of molecular characterization, and the new taxonomy has shown to have clinical relevance. However, the technology required for thorough molecular classification is complicated and expensive, currently preventing widespread use. We aimed to reproduce the results of molecular classification using only simple techniques, that is, immunohistochemical analysis and in situ hybridization. We classified a cohort of 349 successive gastric adenocarcinomas into 5 subtypes, on the basis of protein or mRNA expression of MLH1, E-cadherin, p53, and Epstein-Barr virus. We observed that the subtypes presented distinct clinicopathologic characteristics and corresponded to the molecular classifications previously reported. Epstein-Barr virus -positive tumors were more common in male individuals and in the body of the stomach. Microsatellite-unstable (MSI) tumors, which showed aberrant MLH1 expression, were correlated with increased age and intestinal histology. Both types showed better overall survival than the other types. Gastric cancers with reduced expression of E-cadherin, corresponding to the epithelial to mesenchymal transition or genome stable subtypes, showed the poorest overall survival, with a high prevalence of poorly cohesive carcinoma (ie, diffuse type, of the Lauren classification system). In conclusion, we were able to reproduce a previously reported molecular classification of gastric cancers using immunohistochemical analysis and in situ hybridization. We verified the effectiveness and applicability of this method, which shows promise for use in a clinical setting in the foreseeable future.

Our understanding of the biology, genetics, and natural history of neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas has improved considerably in the last several decades and the spectrum of available therapeutic options is rapidly expanding. The management of patients with metastatic low or intermediate grade NETs has been revolutionized by the development of new treatment strategies such as molecular targeting therapies with everolimus and sunitinib, somatostatin analogs, tryptophan hydroxylase inhibitors, and peptide receptor radionuclide therapy that can be used alone or as a multimodal approach with or without surgery. To further define and clarify the utility, appropriateness, and the sequence of the growing list of available therapies for this patient population will require more high level evidence; however, data from well-designed randomized phase III clinical trials is rapidly accumulating that will further stimulate development of new management strategies. It is therefore important to thoroughly review emerging evidence and report major findings in frequent updates, which will expand our knowledge and contribute to a better understanding, characterization, and management of advanced NETs.

This article reports the guidelines for gastric cancer staging and treatment developed by the GIRCG, and contains comprehensive indications for clinical management, including radiological, endoscopic, surgical, pathological, and oncological paths.

Controversy exists over the staging of gastroesophageal junction (GEJ) adenocarcinomas. The aim of our study was to assess the adequacy of the American Joint Committee on Cancer 7th edition esophageal (E7) and gastric (G7) staging systems for GEJ tumors in a western population. All patients with GEJ adenocarcinoma who underwent curative resection from 2000 to 2012 were identified from the United States Gastric Cancer Collaborative database and assessed according to the E7 and G7 systems. Fifty-one patients were identified. Neither the E7 nor G7 system adequately stratified patients by T or N stage with a loss of distinctiveness between T1 to 4 and N0 to 3 tumors. On final stage analysis, the outcomes were similar between both systems; however, neither system, with the exception of the G7 stage I versus II, adequately stratified patients by stage (E7: I vs II, P = 0.07; II vs III, P = 0.23; G7: I vs II, P = 0.02; II vs III, P = 0.13). Histologic grade was not associated with survival (P = 0.27) and did not improve the ability to stratify patients in the E7 system. Our study identifies limitations in the proper stratification of patients with GEJ adenocarcinoma using either the American Joint Committee on Cancer 7th esophageal or gastric systems. The classification of GEJ adenocarcinoma within either system needs to be further studied in a larger patient population.

Background: Recent studies have reported that mixed-type (MT) gastric cancer, as per Lauren's classification, exhibits aggressive behavior. However, the behavior of early gastric cancer is unclear. In this study, we addressed the influence of mucosa-confined MT gastric cancer, according to Lauren's classification, on lymph node metastasis (LNM) and long-term outcomes., Methods: Among patients who underwent gastrectomy for gastric cancer from January 2000 to December 2012, 3170 had mucosa-confined gastric cancer. According to Lauren's classification, 1449 (45.7 %), 1528 (48.2 %), and 193 (6.1 %) patients had intestinal type (IT), diffuse type (DT), and MT cancer, respectively. Moreover, patients with MT cancer were histologically subdivided into IT-predominant MT (3.0 %) and DT-predominant MT (2.5 %) groups. We analyzed and compared the clinicopathological characteristics, incidence of LNM, overall survival, and recurrence-free survival between these groups., Results: Clinicopathological characteristics showed that mucosa-confined MT gastric cancer had larger size, deeper invasion, and more frequent lymphovascular invasion compared with IT or DT cancers. The LNM of MT lesions (4.7 %) was comparable with that of DT lesions (4.8 %), and multivariate logistic regression analysis indicated that Lauren's classification was a significant predictor for LNM (P < 0.001). However, the overall survival and recurrence-free survival of patients with MT lesions did not differ significantly (P = 0.506 and 0.359, respectively)., Conclusions: Thus, among patients with mucosa-confined gastric cancer, those with MT cancer as per Lauren's classification have aggressive clinical features and a risk of LNM. Hence, surgical treatment may be the preferred option in these patients.

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are currently classified as grade (G) 1, G2 and G3, in accordance with the 2010 WHO classification. G1 and G2 are named neuroendocrine tumors (NETs) whereas G3 neuroendocrine carcinomas (NECs). While advanced G1 and G2 are usually treated with several different therapies, including somatostatin analogs, chemotherapy, interferon, molecular targeted agents, peptide receptor radionuclide therapy (PRRT) and liver-directed treatments, advanced G3 NECs are usually treated with a platinum-etoposide chemotherapy, trusting their clinical homogeneity is similar to that of small cell lung cancer. However, over the last years a number of reports suggested that 2010 WHO G3 GEP NECs are more heterogeneous than expected. Therefore, we critically reviewed the literature about this topic and reported pathological and clinical considerations on 2010 WHO G3 GEP NEC category proposing new sub-categories. Over the last five years, six studies specifically investigating large series of G3 GEP NECs have been published, including around 800 patients. Tumor morphology and Ki-67 Labeling Index (that will be mentioned as Ki-67 in this manuscript) combination has been reported as a tool to define two or even three subgroups of this category with different prognosis and potentially different therapeutic approach. Prospective trials are warranted to investigate if several types of therapy other than the platinum/etoposide chemotherapy can be effective in well differentiated GEP NEN with 21-55% Ki-67 and alkylating-based chemotherapy in poorly differentiated GEP NEN with 21-55% Ki-67., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.

Purpose: Borrmann type IV gastric cancer is still detected at an advanced stage and survival rates for these patients remain poor. The purpose of this study was to provide valuable prognostic and surgical information on patients with Borrmann type IV gastric cancer., Methods: We compared the clinicopathological features of Borrmann type IV gastric cancer with those of other types of gastric cancer. Clinicopathologic features of patients with Borrmann type IV gastric cancer were evaluated as prognostic predictors by univariate and multivariate analyses., Results: The results showed that Borrmann type IV gastric cancer had more advanced and unfavorable clinicopathological factors compared with other Borrman types. The 5-year overall survival rate was 16.7%, and the median survival 25 months. The 5-year overall survival rate was influenced by tumor size, depth of invasion, lymph node metastasis, and chemotherapy. Of these, independent prognostic factors were lymph node metastasis (present vs absent, risk ratio 1.855, p=0.002) and radical (R0) resection (no vs yes, risk ratio 2.035, p<0.001). A significant survival benefit for radical resection was observed, with a 5-year overall survival rate of 30.7% compared with non-radically resected cases (4.8%)., Conclusions: Early detection and radical resection were essential to improve the prognosis of patients with Borrmann type IV gastric cancer.

Background: The classification of digestive neuroendocrine tumors is difficult due to their heterogeneity and rareness., Aims: Reclassify the digestive neuroendocrine tumors according  to  the  WHO-2010 classification .  Methods: A retrospective study included   26 patients having digestive neuroendocrine     tumors ,  is achieved  in our  Pathology  Laboratory  of the Military Hospital of  Tunis between 2000 and 2013., Results: The mean age of patients was 49.64 years. The Sex ratio was  1.36. It was 6 gastric tumors, 5 small intestine tumors , 5 pancreatic tumors, 5  appendix tumors , one hypatic tumor, one  gall bladder  tumor , one rectal tumor and one colon tumor. According to the WHO -2000 classification, tumors are categorised into 11 well differentiated  endocrine tumors, 13 well differentiated  endocrine carcinoma  and 2 poorly differentiated carcinoma . According to the WHO -2010 classification, tumors were re-evaluated as  16 neuroendocrine tumors grade 1, 6 neuroendocrine tumors grade 2 and 4 neuroendocrine carcinoma ., Conclusion: There was a concordance between the two classifications in 93% of cases. The WHO -2010 classification may allow a  better classification for the digestive neuroendocrine tumors, however there are some histological categories that remained difficult to classify.

Background: The classification of digestive neuroendocrine tumors is difficult due to their heterogeneity and rareness., Aims: Reclassify the digestive neuroendocrine tumors according  to  the  WHO-2010 classification .  Methods: A retrospective study included   26 patients having digestive neuroendocrine     tumors ,  is achieved  in our  Pathology  Laboratory  of the Military Hospital of  Tunis between 2000 and 2013., Results: The mean age of patients was 49.64 years. The Sex ratio was  1.36. It was 6 gastric tumors, 5 small intestine tumors , 5 pancreatic tumors, 5  appendix tumors , one hypatic tumor, one  gall bladder  tumor , one rectal tumor and one colon tumor. According to the WHO -2000 classification, tumors are categorised into 11 well differentiated  endocrine tumors, 13 well differentiated  endocrine carcinoma  and 2 poorly differentiated carcinoma . According to the WHO -2010 classification, tumors were re-evaluated as  16 neuroendocrine tumors grade 1, 6 neuroendocrine tumors grade 2 and 4 neuroendocrine carcinoma ., Conclusion: There was a concordance between the two classifications in 93% of cases. The WHO -2010 classification may allow a  better classification for the digestive neuroendocrine tumors, however there are some histological categories that remained difficult to classify.

Gastric cancer(GC) is a highly heterogeneous malignancy. The present widely used histopathological classifications have gradually failed to meet the needs of individualized diagnosis and treatment. Development of technologies such as microarray and next-generation sequencing (NGS) has allowed GC to be studied at the molecular level. Mechanisms about tumorigenesis and progression of GC can be elucidated in the aspects of gene mutations, chromosomal alterations, transcriptional and epigenetic changes, on the basis of which GC can be divided into several subtypes. The classifications of Tan's, Lei's, TCGA and ACRG are relatively comprehensive. Especially the TCGA and ACRG classifications have large sample size and abundant molecular profiling data, thus, the genomic characteristics of GC can be depicted more accurately. However, significant differences between both classifications still exist so that they cannot be substituted for each other. So far there is no widely accepted molecular classification of GC. Compared with TCGA classification, ACRG system may have more clinical significance in Chinese GC patients since the samples are mostly from Asian population and show better association with prognosis. The molecular classification of GC may provide the theoretical and experimental basis for early diagnosis, therapeutic efficacy prediction and treatment stratification while their clinical application is still limited. Future work should involve the application of molecular classifications in the clinical settings for improving the medical management of GC.

BACKGROUND The World Health Organization (WHO) histological classification for gastric cancer is widely accepted and used. However, its impact on predicting lymph node metastasis and recurrence in early gastric cancer (EGC) is not well studied. MATERIAL AND METHODS From 1987 to 2005, 2873 EGC patients with known WHO histological type who had undergone curative resection were enrolled in this study. In all, 637 well-differentiated adenocarcinomas (WD), 802 moderately-differentiated adenocarcinomas (MD), 689 poorly-differentiated adenocarcinomas (PD), and 745 signet-ring cell adenocarcinomas (SRC) were identified. RESULTS The distribution of demographic and clinical features in early gastric cancer among WD, MD, PD, and SRC were significantly different. Lymph node metastasis was observed in 317 patients (11.0%), with the lymph node metastasis rate being 5.3%, 14.8%, 17.0%, and 6.3% in WD, MD, PD, and SRC, respectively. Univariate and multivariate analyses indicated that gender, tumor size, gross appearance, depth of invasion, and WHO classification were significantly associated with lymph node metastasis. Recurrence was observed in 83 patients (2.9%), with the recurrence rate being 2.2%, 4.5%, 3.0%, and 1.6% in WD, MD, PD, and SRC, respectively. Multivariate analysis confirmed that MD, elevated gross type, and lymph node metastasis were independent risk factors for recurrence in EGC. MD patients showed worse disease-free survival than non-MD patients (P=0.001). CONCLUSIONS WHO classification is useful and necessary to evaluate during the perioperative management of EGC. Treatment strategies for EGC should be made prudently according to WHO classification, especially for MD patients.

The frequency of molecular studies aimed to analyze promoter methylation of tumor suppressor genes and global proteomics in gastric carcinogenesis is increasing. Nonetheless, only a few considered the different types of stomach cells, the tumor location and the influence of Helicobacter pylori and Epstein Barr virus infection (EBV). Molecular differences relating to anatomical and histological tumor areas were also recently described. The authors propose a molecular classification of gastric cancer, dividing it into four subtypes: tumors positive for EBV; microsatellite unstable tumors; genomically stable tumors and tumors with chromosomal instability. RESUMO A frequência de estudos moleculares visando a analisar os promotores de metilação de genes supressores de tumor e proteômica globais na carcinogênese gástrica está aumentando. No entanto, apenas alguns consideraram os diferentes tipos de células do estômago, a localização do tumor e a influência da infecção por Helicobacter pylori e pelo vírus Epstein-Barr (EBV). Diferenças moleculares relacionadas com áreas tumorais anatômicas e histológicas também foram recentemente descritas. Os autores propõem uma classificação molecular de câncer gástrico, dividindo-o em quatro subtipos: tumores positivos para o EBV; tumores microssatélite instáveis; tumores genomicamente estáveis ​​e tumores com instabilidade cromossômica.

Background: The anatomical Siewert classification for adenocarcinoma of the oesophagogastric junction (OGJ) was dictated by the potential differences in tumour epidemiology and pathology. However, there are some uncertainties whether the distinction of true carcinoma of the cardia (type II) and subcardial gastric cancer (type III) is of clinical value., Methods: Using a multicentre data set, we studied 243 patients with OGJ adenocarcinomas who underwent gastric resections between 1998 and 2008. Postoperative complications and long-term survival were compared to evaluate the potential differences in clinically relevant outcomes., Results: A group of 109 patients with Siewert type II and 134 with Siewert type III OGJ adenocarcinoma was identified. Both groups showed similar baseline characteristics, including clinical symptoms and duration of diagnostic delay. However, the prevalence of node-negative cancers and superficial (T1-T2) lesions was significantly higher among type II tumours, i.e. 42% vs 21% (P = 0.003) and 43% vs 20% (P = 0.045), respectively. Morbidity and mortality rates were 25% and 3.7%, respectively, but types and incidence of postoperative complications were not affected by the anatomical location of the tumour. The overall median survival was significantly longer for Siewert type II tumours (42 vs 16 months; P < 0.001). However, only patients' age >70 years, depth of tumour infiltration, lymph node metastases, distant metastases, and radical resection were identified as independent prognostic factors using the Cox proportional hazards model., Conclusion: The topographic-anatomic sub-classification of OGJ adenocarcinomas does not correspond to relevant differences in clinical parameters of safety and efficacy of surgical treatment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Gastric adenocarcinoma, a single heterogeneous disease with multiple epidemiological and histopathological characteristics, accounts for approximately 10% of cancers worldwide. It is categorized into four histological types: papillary adenocarcinoma (PAC), tubular adenocarcinoma (TAC), mucinous adenocarcinoma (MAC), and signet ring cell adenocarcinoma (SRC). Effective differentiation of the four types of adenocarcinoma will greatly improve the treatment of gastric adenocarcinoma to increase its five-year survival rate. We reported here the differentiation of the four histological types of gastric adenocarcinoma from the molecularly structural viewpoint of confocal Raman microspectroscopy. In total, 79 patients underwent laparoscopic or open radical gastrectomy during 2008-2011: 21 for signet ring cell carcinoma, 21 for tubular adenocarcinoma, 14 for papillary adenocarcinoma, 6 for mucinous carcinoma, and 17 for normal gastric mucosas obtained from patients underwent operation for other benign lesions. Clinical data were retrospectively reviewed from medical charts, and Raman data were processed and analyzed by using principal component analysis (PCA) and linear discriminant analysis (LDA). Two-dimensional plots of PCA and LDA clearly demonstrated that the four histological types of gastric adenocarcinoma could be differentiated, and confocal Raman microspectroscopy provides potentially a rapid and effective method for differentiating SRC and MAC from TAC or PAC.

Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics., (© 2016 The Authors Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Endoscopic resection is performed in undifferentiated-type early gastric cancer (UD-EGC), including poorly differentiated (PD) adenocarcinoma and signet ring cell (SRC) carcinoma. We previously found that different approaches are needed for PD adenocarcinoma and SRC carcinoma for curative resection. However, according to the 2010 WHO classification, diffuse-type PD adenocarcinoma and SRC carcinoma are categorized in the "poorly cohesive carcinomas." Thus, we assessed whether the WHO classification is helpful when endoscopic resection is performed for treatment of UD-EGC., Methods: We analyzed clinicopathological features of 1295 lesions with SRC carcinoma and PD adenocarcinoma treated by open surgery. We recategorized them into intestinal-type PD adenocarcinomas and poorly cohesive carcinomas (SRC carcinoma, diffuse-type PD adenocarcinoma). We also recategorized 176 lesions treated by endoscopic resection into intestinal-type PD adenocarcinomas and poorly cohesive carcinomas., Results: According to the open surgery data, the rates of lymph node metastasis (LNM) and lymphovascular invasion were significantly lower in SRC carcinoma than in diffuse-type and intestinal-type PD adenocarcinomas. The rates of LNM and lymphovascular invasion were significantly higher in diffuse-type PD adenocarcinoma than in SRC carcinoma. Endoscopic resection data showed no recurrence if the carcinoma was curatively resected. However, the commonest cause of noncurative resection was different in SRC carcinoma and PD adenocarcinoma. A positive lateral margin was the commonest cause in SRC carcinoma versus a positive vertical margin in both intestinal-type and diffuse-type PD adenocarcinoma., Conclusions: The clinical behavior differs in diffuse-type PD adenocarcinoma and SRC carcinoma. On the basis of LNM and outcomes of endoscopic resection, the recent WHO classification may not be helpful when endoscopic resection is performed for treatment of UD-EGC.

This review reports 3 of recently published molecular classifications of the 3 main gastro-intestinal cancers: gastric, pancreatic and colorectal adenocarcinoma. In colorectal adenocarcinoma, 6 independent classifications were combined to finally hold 4 molecular sub-groups, Consensus Molecular Subtypes (CMS 1-4), linked to various clinical, molecular and survival data. CMS1 (14% MSI with immune activation); CMS2 (37%: canonical with epithelial differentiation and activation of the WNT/MYC pathway); CMS3 (13% metabolic with epithelial differentiation and RAS mutation); CMS4 (23%: mesenchymal with activation of TGFβ pathway and angiogenesis with stromal invasion). In gastric adenocarcinoma, 4 groups were established: subtype "EBV" (9%, high frequency of PIK3CA mutations, hypermetylation and amplification of JAK2, PD-L1 and PD-L2), subtype "MSI" (22%, high rate of mutation), subtype "genomically stable tumor" (20%, diffuse histology type and mutations of RAS and genes encoding integrins and adhesion proteins including CDH1) and subtype "tumors with chromosomal instability" (50%, intestinal type, aneuploidy and receptor tyrosine kinase amplification). In pancreatic adenocarcinomas, a classification in four sub-groups has been proposed, stable subtype (20%, aneuploidy), locally rearranged subtype (30%, focal event on one or two chromosoms), scattered subtype (36%,<200 structural variation events), and unstable subtype (14%,>200 structural variation events, defects in DNA maintenance). Although currently away from the care of patients, these classifications open the way to "à la carte" treatment depending on molecular biology., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the rationality of N3 classification and its sub-classification in the 7th UICC/AJCC TNM classification system., Methods: Clinicopathological data of 610 patients with stage N3 advanced gastric cancer who underwent standard D2 and D2+ radical surgery at the Department of Surgical Oncology, The First Hospital of China Medical University, from January 1980 to March 2010 were analyzed retrospectively. Patients were divided into N3a and N3b groups, and clinicopathological characteristics and prognosis were compared between N3a and N3b patients. Overall survival rate was determined using the Kaplan-Meier estimator. The log-rank test was used to identify differences between the survival curves of different groups. In multivariate analysis, Cox proportional hazard model was used to identify independent factors associated with prognosis., Results: Among 610 patients, 426 were men and 184 were women, 394 were N3a and 216 were N3b, with a mean age of(57±11) years old (range 23 to 83). A total of 19 842 lymph nodes were examined, in which 9 575 nodes were positive, with the metastatic ratio of 48.3%. The 5-year overall survival rate was 20.0%. Univariate analysis of prognostic factors suggested that tumor location (P=0.000), tumor size (P=0.003), Borrmann type (P=0.000), pathologic type (P=0.043), lymphatic vessel invasion (P=0.000), growth pattern (P=0.019), invasion depth (P=0.000), resection extent (P=0.000) and N3 sub-classification (P=0.000) were significantly associated with the prognosis of N3 patients. Further analysis showed that tumor size (P=0.028), invasion depth (P=0.000) and gastric resection extent (P=0.002) were significantly associated with the prognosis of N3a patients, while Borrmann type (P=0.034), lymphatic vessel invasion (P=0.002), invasion depth (P=0.008) and resection extent (P=0.003) were significantly associated with the prognosis of N3b patients. Multivariate analysis revealed that lymphatic vessel invasion (P=0.009), resection extent (P=0.001), invasion depth (P=0.000) and N3 sub-classification (P=0.000) were independent prognostic factors of N3 patients; resection extent (P=0.004) and invasion depth (P=0.001) were independent prognostic factors of N3a patients; lymphatic vessel invasion (P=0.006) and invasion depth (P=0.009) were independent prognostic factors of N3b patients. Comparison of 5-year survival rate revealed that there was significant difference between T2-4N3a and T2-4N3b patients (P=0.000), while there was no significant difference between T2N3a and T2N3b patients (P=0.140). On the contrary, there were significant differences between T3N3a and T3N3b patients, T4aN3a and T4aN3b patients, T4bN3a and T4bN3b patients, respectively (all P<0.05). Further comparison demonstrated that there were significant differences between T4aN3a and T4bN3a patients, T4aN3b and T4bN3b patients, respectively (P=0.000, P=0.041). Besides, there were no significant differences in 5-year survival rate between T2N3 (at present, staged as III(A), T3N3a (III(B) and T4aN3a (III(C) patients(P=0.506), and T3N3b (III(B), T4aN3b (III(C) and T4bN3a (III(C) patients(P=0.283), respectively., Conclusions: N3 sub-classification should be included in the final TNM classification system. It is suggested that T2N3, T3N3a and T4aN3a may be categorized into III(A stage, T3N3b, T4aN3b and T4bN3a may be categorized into III(B stage,T4bN3b may be categorized into III(C stage or IIII( stage.

The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques.

Gastric cancer is the third greatest global cause of cancer-related deaths. Despite its high prevalence, only recently have comprehensive genomic surveys shed light on its molecular alterations. As surgery is the only curative treatment strategy and chemotherapy has shown limited efficacy, new treatments are urgently needed. Many molecular therapies for gastric cancer have entered clinical trials but-apart from Trastuzumab and Ramucirumab-all have failed. We analyze the current knowledge of the genetic 'landscape' of gastric cancers, elaborating on novel, preclinical approaches. We posit that this knowledge lays the basis for identifying bona fide molecular targets and developing solid therapeutic approaches, requiring accurate patient selection and taking advantage of preclinical models to assist clinical development of novel combination strategies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are rare neoplasms with heterogeneous clinical behavior and potential long-term survival. In 2006/2007, the European Neuroendocrine Tumors Society introduced an important parameter, grade (based on mitoses and Ki-67 proliferation rate), which became part of the latest 2010-WHO classification. Since this is an important tool in the choice of therapeutic algorithm of patients with NETs, our aim was to audit whether retrospective reclassification is possible and feasible and correlate pathological findings with survival. From the histopathology archive, 338 GEP-NETs (1994-2014) were identified, of which 250 were diagnosed pre-2010 and 80 of these have needed, up till now, classification (morphology and grade-mitotic count/Ki-67). Morphology was well differentiated (WD) in 74 cases while only 6 cases were poorly differentiated (PD). Grade was reclassified: G1-45 cases (56 %); G2-28 cases (35 %); G3-7 cases (9 %). Overall survival (OS) in WD NETs was strikingly better compared to PD neoplasms. Differences in OS between grade were statistically significant (p < 0.0001) and, in particular, grade identified a subgroup of patients with WD lesions but with less favorable clinical behavior (OS at 5 years: G1-89 %; G2-48 %; G3-0 %; G1 vs G2 p = 0.03). Feasibility analysis quantified time for reclassification to be between 45 and 64 min/case. Our series confirms the importance of grade in prognostic stratification and underlines that reclassification is feasible, and may prove worthwhile in patient management, especially in view of the potential long survival of patients with NETs and risk of use of inappropriate therapies.

Gastric cancer (GC), a heterogeneous disease characterized by epidemiologic and histopathologic differences across countries, is a leading cause of cancer-related death. Treatment of GC patients is currently suboptimal due to patients being commonly treated in a uniform fashion irrespective of disease subtype. With the advent of next-generation sequencing and other genomic technologies, GCs are now being investigated in great detail at the molecular level. High-throughput technologies now allow a comprehensive study of genomic and epigenomic alterations associated with GC. Gene mutations, chromosomal aberrations, differential gene expression and epigenetic alterations are some of the genetic/epigenetic influences on GC pathogenesis. In addition, integrative analyses of molecular profiling data have led to the identification of key dysregulated pathways and importantly, the establishment of GC molecular classifiers. Recently, The Cancer Genome Atlas (TCGA) network proposed a four subtype classification scheme for GC based on the underlying tumor molecular biology of each subtype. This landmark study, together with other studies, has expanded our understanding on the characteristics of GC at the molecular level. Such knowledge may improve the medical management of GC in the future., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR., (©2016 American Association for Cancer Research.)

Over recent decades we have witnessed a shift in the anatomical distribution of gastric cancer (GC), which increasingly originates from the proximal stomach near the junction with the oesophagus. In parallel, there has been a dramatic rise in the incidence of oesophageal adenocarcinoma (OAC) in the lower oesophagus, which is associated with antecedent Barrett oesophagus (BO). In this context, there has been uncertainty regarding the characterization of adenocarcinomas spanning the area from the lower oesophagus to the distal stomach. Most relevant to this discussion is the distinction, if any, between OAC and intestinal-type GC of the proximal stomach. It is therefore timely to review our current understanding of OAC and intestinal-type GC, integrating advances from cell-of-origin studies and comprehensive genomic alteration analyses, ultimately enabling better insight into the relationship between these two cancers.

Gastroduodenal neuroendocrine tumors are rare but an increase in incidence has been recognized worldwide over the past 35 years. At the same time the prognosis of patients has substantially improved because the majority of these tumors can now be detected at an early stage. Neuroendocrine neoplasms (NENs) of the stomach are the most frequent neoplasms of neuroendocrine origin in the gastrointestinal tract. The therapeutic management of these tumors is complicated by the fact that they must be classified not only by staging and grading but also according to their pathophysiological background (types). These types differ in biological behavior and therefore have an influence on the therapeutic concept. Because more than 90 % of duodenal NENs are often asymptomatic and are as a rule identified at a curable stage, resection of the tumor should always be the first line of therapy. The therapeutic strategies vary from local endoscopic resection (duodenotomy with excision) up to pancreas retaining duodenectomy and pylorus retaining or classical Whipple procedures. This article presents the various surgical approaches to gastric and duodenal NENs.

Gastric dysplasia is a neoplastic lesion and a precursor of gastric cancer. The Padova, Vienna, and World Health Organization classifications were developed to overcome the discrepancies between Western and Japanese pathologic diagnoses and to provide a universally accepted classification of gastric epithelial neoplasia. At present, the natural history of gastric dysplasia is unclear. Much evidence suggests that patients with high-grade dysplasia are at high risk of progression to carcinoma or synchronous carcinoma. Therefore, endoscopic resection is required. Although patients with low-grade dysplasia have been reported to be at low risk of progression to carcinoma, due to the marked histologic discrepancies between forceps biopsy and endoscopic specimens, endoscopic resection for this lesion is recommended, particularly in the presence of other risk factors (large size; depressed gross type; surface erythema, unevenness, ulcer, or erosion; and tubulovillous or villous histology). Helicobacter pylori eradication in patients with dysplasia after endoscopic resection appear to reduce the incidence of metachronous lesions.

To investigate the efficacy of Taxanes- and Oxaliplatin-based chemotherapies (TC and OC) in the treatment of gastric cancer patients after D2 gastrectomy with different Lauren types. In this study, 299 patients of gastric adenocarcinoma with D2 lymph node dissection were reviewed between 2007 and 2014. Chemotherapies were classified as Oxaliplatin-based and Taxanes-based regimen. Treatment outcomes were analyzed according to different Lauren types, such as the intestinal type, diffuse type, and mixed type groups, respectively. The disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used for univariate analysis, and Cox regression was used for multivariate analysis. In diffuse type gastric cancer, the Oxaliplatin-based arm had a longer median DFS and OS compared with Taxanes-based arm (DFS: 47.0 vs 28.6 months, P = 0.04; OS: 51.9 vs 34.5 months, P = 0.048). The chemotherapy regimen was an independent prognostic factor for DFS and OS of diffuse type gastric cancer patients by multivariate analysis (P = 0.01). In the intestinal type, although the DFS and OS of intestinal type patients in TC group were higher than those in OC group (DFS: 53.4 vs 42.4 months; OS: 69.7 vs 57.8 months), there was no statistical significance observed (both P > 0.05). For the mixed type, the 2 different chemotherapy regimens achieved similar median DFS and OS. In a conclusion, the patients of diffuse type were more sensitive to OC, and the intestinal type patients may be benefit from TC. Therefore, it will be of benefit for gastric patients by introducing Lauren classification clinically and to help the choice of chemotherapy regimen for gastric patients after D2 gastrectomy.

Gastric cancer is a complex disease that is affected by multiple genetic and environmental factors. For the precise diagnosis and effective treatment of gastric cancer, the heterogeneity of the disease must be simplified; one way to achieve this is by dividing the disease into subgroups. Toward this effort, recent advances in high-throughput sequencing technology have revealed four molecular subtypes of gastric cancer, which are classified as Epstein-Barr virus-positive, microsatellite instability, genomically stable, and chromosomal instability subtypes. We anticipate that this molecular subtyping will help to extend our knowledge for basic research purposes and will be valuable for clinical use. Here, we review the genomic and epigenomic heterogeneity of the four molecular subtypes of gastric cancer. We also describe a mutational meta-analysis and a reanalysis of DNA methylation that were performed using previously reported gastric cancer datasets.

Purpose: This study examined the prognosis of the "node-negative with eLNs ≤ 15" designation and the additional value of incorporating it into the pN1 designation in the seventh edition of the N classification., Methods: From January 2000 to September 2010, a total of 1258 gastric cancer patients (patients with eLNs > 15 or node-negative with eLNs ≤ 15) undergoing radical gastric resection were enrolled in this study. We incorporated node-negative patients with eLNs ≤ 15 into pN1 and compared this designation with the current 7th edition UICC N stage for 3, 5-year overall survival by univariate and multivariate analysis. Homogeneity, discriminatory ability, and monotonicity of gradients in the hypothetical N stage and the UICC N stage were compared using linear trend χ2, likelihood ratio χ2 statistics, and Akaike information criterion (AIC) calculations., Results: Node-negative patients with eLNs ≤ 15 had worse survival compared with those with eLNs > 15. In univariate and multivariate analyses, the hypothetical N stage showed superiority to the 7th edition pN staging. The hypothetical staging system had higher linear trend and likelihood ratio χ (2) scores and smaller AIC values compared with those for the TNM system, which represented the optimum prognostic stratification., Conclusions: Node-negative patients with eLNs ≤ 15 can be considered to be incorporated into the pN1 stage in the 7th edition of the TNM classification.

A comparative analysis of available classifications of gastric neuroendocrine tumors was performed. It was showed that there were many contradictions regarding the issues of termi- nology and, in particular, criteria for determining the degree of differentiation of these tumors that significantly influenced on the choice of methods of treatment. There were unclearly marked symptoms of benign tumors, treatment of which could be conducted by endoscopy removal. There was absent the category of high- and moderately differentiated neuroendocrine tumors that metastasized by lymph and blood. Malignant tumors were represented by just low-differentiated malignancies although now many researchers noted the heterogeneity of this group and a different response to therapeutic agents. Up to now there were no standard methods for determining the pro- liferative level because any discrepancies between a number of mitoses and Ki67 index might be. Proliferative activity in tumor itself was often heterogeneous and it was necessary to select a specific point in tumor to determine its grade. Despite a proof of endodermal origin and the presence of combined tumors with epithelial component (mucocarcinoid, adenoneuroendocrine, amphicrine carcinoma) gastric neuroendocrine tumors were considered as a separate group in contrast to such standard symbols in pathology as adenomas and carcinomas. Thus it is necessary to accumulate further material for the standardization of nomenclature and more accurate determina- tion of malignant potential of tumors with the aim of studying the effect of various methods of treatment.

Neuroendocrine tumors (NET) are malignancies with an increasing incidence rate. NETs are graded or classified by the expression level of Ki67, a proliferation marker in Grade 1 and 2 tumors. Out of 120 patients who visited our hospital between 2003 and 2012, 40 were classified as G2 NET. This study was mainly designed to investigate a new threshold for optimising the Ki67 system. Patients were subdivided into two new groups according to Ki67 (group 1 = 3-9%, group 2 = 10-20%). Twenty-five patients were allocated to group 1 and 15 to group 2. The primary tumor originated in 46% from the foregut and 68% NET were functionally active. Patients were treated in 88 versus 60% by surgery, 48 versus 80% by somatostatin analogs, 0 versus 20% by chemotherapy, 2,5 versus 0% by Everolimus and 32 versus 47% underwent peptide receptor radionuclide therapy. Group 1 patients showed a significantly (p = 0.01) better survival compared with group 2 and also a significant difference of Chromogranin A (p = 0.03) and alkaline phosphatase (p = 0.01). In addition, all patients with elevated lactate dehydrogenase showed a significantly (p = 0.03) shorter survival. Prognostic relevance of G2 NETs may be improved by using a new boundary. Patients with Ki67 of 3-9% showed a better response to current treatment methods and significantly longer survival compared to group 2. Thus, our data clearly show that patients with higher G2 proliferation index should be treated differently. Finally, LDH has been found to be a new prognostic factor in patients with G2 NET.

The investigation of prognostic factor for gastric cancer is still desirable because of dismal prognosis in gastric cancer. Lauren's classification is currently a useful histological classification. There are few large series evaluating the prognostic significance of Lauren's classification in gastric cancer. From January 1987 to December 2013, a total of 3071 patients received gastrectomy for gastric cancer. According Lauren's classification, 1423(46.3%) patients were intestinal type, 1000 patients (32.6%) were diffuse type, and 648 patients (21.1%) were mixed type. The clinicopathological characteristics and prognosis in Lauren's classification were analyzed in these patients. Our results showed that patients with intestinal type gastric cancer (57.7%) had a better 5-year overall survival than diffuse type (45.6%) and mixed type (43.4%, P < 0.001). The clinicopathological characteristics showed that gastric cancer patients with intestinal type were older (P < 0.001), male predominant (P < 0.001), smaller tumor size (P < 0.001), distal stomach predominant (P < 0.001), relative well differentiated (P < 0.001), less advanced Borrmann type (P < 0.001), less scirrhous type stromal reaction(P < 0.001), less infiltrating type of Ming's histology type(P < 0.001), less tumor invasion depth and less lymphovascular invasion (P < 0.001). Multivariate analysis with overall survival as an endpoint showed that age (P = 0.005), Borrmann classification (P < 0.001), pathological T category (P = 0.023), pathological N category (P < 0.001) and Lauren's classification (P = 0.003) were significant correlated in gastric cancer. Lauren's classification is an independent prognostic factor in gastric cancer patient undergoing gastrectomy. Lauren's classification can serve as a prognostic marker for gastric cancer patient receiving gastrectomy. The clinicopathological appearance and prognosis of mixed type gastric cancer is similar to diffuse type gastric cancer.

Gastric cancer is a heterogeneous disease encompassing diverse morphological (intestinal versus diffuse) and molecular subtypes (MSI, EBV, TP53 mutation). Recent advances in genomic technology have led to an improved understanding of the driver gene mutational profile, gene expression, and epigenetic alterations that underlie each of the subgroups, with therapeutic implications in some of these alterations. There have been attempts to classify gastric cancers based on these genomic features, with an aim to improve prognostication and predict responsiveness to specific drug therapy. The eventual aims of these genomic studies are to develop deep biological insights into the carcinogenic pathway in each of these subtypes. Future large-scale drug screening strategies may then be able to link these genomic features to drug responsiveness, eventually leading to genome-guided personalized medicine with improved cure rates.

Unlabelled: The gastrointestinal tract (GIT) is the most common anatomic site of extranodal non-Hodgkin lymphoma (NHL) involvement. The classification criteria of lymphoma have changed in recent decades, and few large-sample studies regarding subtype analysis of lymphoma have been performed in this site., Aim: Therefore, the present study was conducted to analyze the histological subtype distribution of the GIT., Method: All patients in a single institution with a diagnosis of primary NHL in the GIT were enrolled between January 2007 and April 2014. The patients were categorized according to the WHO (2008) classification of tumors of hematopoietic and lymphoid tissue., Result: A total of 1,010 eligible cases diagnosed as NHL were collected in this study. The male:female ratio was 1.7:1 and the median age was 55 years. The percent of patients with lymphoma involvement in the stomach was 52% (n = 522), and the remaining 48% (n = 484) had intestinal tract involvement. Histologically, diffuse large B cell lymphoma (DLBCL) was the most common subtype in all of the GIT lymphoma cases, and was also the most common subtype in cases involving the stomach (78%) and the intestinal tract (53%). The incidence of DLBCL and mucosa-associated lymphoid tissue lymphoma in the stomach was significantly higher than the incident in the intestinal tract (p < 0.01). T and NK cell lymphoma was significantly more common in the intestinal tract than in the stomach (p < 0.01). Extranodal NK/T cell lymphoma nasal type (ENKTL-N) was the most common subtype of T and NK cell lineage lymphoma in GIT and was also the second most common intestinal tract-involved lymphoma., Conclusion: DLBCL was the most frequent lymphoma in the stomach and in the intestinal tract. T and NK cell lineage lymphoma had a higher occurrence in the intestinal tract than in the stomach. ENKTL-N was the most frequent subtype of lymphoma derived from NK/T cell lineage, and was the second most common lymphoma among all intestinal tract lymphomas., (© 2015 S. Karger AG, Basel.)