Nari Shin

Lymph node metastasis from intestinal-type early gastric cancer: experience in a single institution and reassessment of the extended criteria for endoscopic submucosal dissection

BACKGROUND Given the increasing use of endoscopic resection as a therapeutic modality for cases of early gastric cancer (EGC), it is very important to define strict criteria for the use of endoscopic mucosal resection and endoscopic submucosal dissection. To date, the criteria are almost entirely based on Japanese literature evaluating the risk of lymph node (LN) metastasis in patients with EGC. OBJECTIVE To analyze our own experience with the factors affecting LN metastasis and to reappraise the extended criteria for endoscopic submucosal dissection. DESIGN Retrospective, single-center study. SETTING University teaching hospital. PATIENTS This study involved 478 patients who underwent gastrectomy with LN dissection (n = 270, mucosal [m] EGC; n = 208, submucosal [sm] EGC). INTERVENTION Gastrectomy with LN dissection. MAIN OUTCOME MEASUREMENTS LN metastasis. RESULTS Overall, 12.6% (60/478) of patients with EGCs presented with LN metastasis (mEGC, 3.0% [8/270], smEGC, 25.0% [52/208]). Increased size, macroscopic type (elevated), depth of invasion, and lymphovascular invasion were associated with LN metastasis. In 270 cases of mEGC, there was no relationship between clinicopathologic features and LN metastasis. In the smEGC group, size, depth of invasion, and lymphovascular emboli were associated with an increased risk of LN metastasis. Significantly, LN metastasis was noted in EGCs falling within established extended endoscopic submucosal dissection criteria, that is, intestinal-type mucosal cancer of any size without ulcer and no lymphovascular emboli (2/146 [1.4%]) or < or =3 cm with no lymphovascular emboli and irrespective of the presence of ulceration (2/126 [1.6%]) or intestinal-type submucosal cancer (sm1, <500 microm) without lymphovascular invasion and measuring < or =3 cm in size (3/20 [15.0%]). LIMITATIONS Retrospective review of a single-center study. CONCLUSION We recommend that more centers survey their experiences of LN metastasis in cases of EGC to refine the criteria for endoscopic submucosal dissection as a therapeutic modality of intestinal-type EGC.

Mucin Expression in Gastric Cancer: Reappraisal of Its Clinicopathologic and Prognostic Significance

CONTEXT The clinical validity of mucin expression in gastric cancer is debated. Whereas several reports demonstrate a correlation between mucin expression and prognosis, others deny such an association. OBJECTIVES This survival analysis study aims to elucidate the prognostic significance of mucin expression in gastric cancer. DESIGN A retrospective survival analysis was done with 412 cases of gastric cancer characterized on the basis of MUC immunohistochemistry using MUC2, MUC5AC, MUC6, and CD10 antibodies; the cases were divided into those with a gastric, an intestinal, or a null mucin phenotype based on the predominant mucin. RESULTS There was no association between mucin expression and survival when considering overall gastric cancers or the advanced gastric cancer subtype. However, early gastric cancers with a gastric mucin phenotype showed longer survival than those with an intestinal mucin phenotype (P = .01) or a null phenotype (P = .01). In particular, MUC5AC-positive early gastric cancers resulted in longer survival than did those that did not express MUC5AC (P = .009). The loss of MUC5AC expression was identified as an independent, poor prognostic factor in early gastric cancers using the Cox regression proportional hazard model (hazard ratio, 3.50; P = .045). CONCLUSIONS MUC5AC expression is significantly associated with patient survival and can be used to predict outcomes in the gastric cancers, especially in the early gastric cancers.

Gastric pit dysplasia in adjacent gastric mucosa in 414 gastric cancers: prevalence and characteristics.

Despite wide acceptance of the chronic gastritis-intestinal metaplasia-dysplasia-carcinoma sequence, especially for intestinal-type gastric adenocarcinoma, the precise nature of the subtle precursor lesions of gastric cancer remains to be delineated. For example, pit dysplasia with surface foveolar maturation is not well defined, nor is its prevalence and biological characteristics well characterized. We have evaluated the surrounding gastric mucosa of 414 gastric cancers for the presence of gastric pit dysplasia. We investigated its relationship with various clinicopathological and immunophenotypic features of gastric adenocarcinoma, as well as the severity and extent of any surrounding gastritis and intestinal metaplasia. p53 expression and Ki-67 proliferation index were also evaluated. We have found that 21.0% (n=87) of gastric cancer cases showed pit dysplasia in adjacent gastric mucosa. Gastric cancers with pit dysplasia were significantly associated with older age, male sex, body/fundic location, and intestinal histologic type (P<0.05). Interestingly, gastric mucin-containing intestinal metaplasia (incomplete intestinal metaplasia) was highly associated with adenocarcinoma with pit dysplasia (P=0.000). In addition, MUC6 expression in gastric adenocarcinoma was associated with pit dysplasia (P=0.036). p53 overexpression and increased Ki-67 proliferation index were more evident in gastric pit dysplasia compared with adjacent gastric mucosa. We suggest that gastric pit dysplasia is an important candidate precursor of gastric adenocarcinoma and may represent another morphologic step in the pathogenesis of gastric adenocarcinoma, especially of intestinal type. More detailed prospective studies are needed to determine the precise significance of these findings.

MUC5AC and MUC5B enhance the characterization of mucinous adenocarcinomas of the lung and predict poor prognosis.

From the viewpoint of histogenesis, lung adenocarcinoma can be subdivided into two groups: terminal respiratory unit (TRU) and non‐TRU types. We recently reported a non‐TRU type adenocarcinoma designated as ciliated adenocarcinoma (we now prefer central type adenocarcinoma). We suggest reasons that mucinous adenocarcinoma should encompass central type adenocarcinoma to represent its biological characteristics as non‐TRU type adenocarcinoma.

Polycomb protein EZH2 expression in diffuse large B-cell lymphoma is associated with better prognosis in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.

Abstract Polycomb group (PcG) proteins are evolutionarily conserved regulators of gene expression that contribute to normal lymphocyte development, and are involved in malignant transformation of these cells. Recently, BMI1 and EZH2 have been shown to be involved in lymphomagenesis and oncogenesis. We tried to elucidate the role of EZH2 as a prognostic factor for diffuse large B-cell lymphoma (DLBCL). High-level expression of EZH2 (EZH2 ≥ 70%) was associated with superior overall survival (OS) of 85.8% compared to low expression (EZH2 < 70%), with OS of 44.5% (p = 0.005). Subgroup analysis showed that the activated B-cell (ABC) subtype with high EZH2 expression had the highest overall survival (p = 0.011). In analysis of EZH2 expression within low International Prognostic Index (IPI) score, high EZH2 expression had a significant statistical correlation with longer OS (p = 0.034). With high IPI score, high EZH2 expression tended to be associated with longer OS (p = 0.130). Our results showed that EZH2 expression had a high prognostic relevance to survival outcomes. We demonstrated that DLBCL was associated with increased expression of the EZH2 PcG protein and Ki67. The distribution of EZH2 expression was wider than that of Ki67. In summary, increased EZH2 expression of tumor cells was associated with improvements in OS.

Decreased Muc5AC expression is associated with poor prognosis in gastric cancer

Mucins reportedly play numerous key roles in carcinogenesis, including in tumor invasion, regulation of differentiation and tumor cell proliferation. We investigated the effect of Muc5AC, a secreted mucin, on the invasiveness/migratory capability of gastric cancer cells and the prognostic significance of Muc5AC in gastric cancer patients. The clinicopathological and prognostic significance of Muc5AC expression was validated using immunohistochemical analysis in 412 gastric cancer patients. Differential gene expression was investigated using complementary DNA microarray analysis of 48 fresh tumor tissue samples. Silencing of Muc5AC by using a small hairpin RNA‐containing lentivirus increased the invasion and migration of SNU216 and AGS cells as well as Akt phosphorylation and the expression of vascular endothelial growth factor and matrix metalloproteinase‐7, which were blocked by inhibitors of the phosphatidylinositol 3‐kinase/Akt pathway. Loss of Muc5AC expression was significantly associated with tumor progression (advanced T stage; p = 0.004), lymph node metastases (p = 0.001), lymphovascular invasion (p < 0.0001), and increased tumor size (p = 0.027). Lower MUC5AC expression was identified as an independent poor prognostic factor in diffuse‐type gastric cancer by using the Cox regression proportional hazard model (hazard ratio, 2.39; p = 0.043). Complementary DNA microarray analysis revealed 86 differentially expressed genes, including genes related to metastasis and invasion, in gastric cancer tissues with high (≥25%) and low (<25%) Muc5AC expression levels. Low Muc5AC expression increased the invasion and migration of gastric cancer cells and could be a useful biomarker of poor prognosis in gastric cancer.

High-throughput Protein and mRNA Expression-based Classification of Gastric Cancers Can Identify Clinically Distinct Subtypes, Concordant With Recent Molecular Classifications.

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.

Pathologic definition and number of lymphovascular emboli: impact on lymph node metastasis in endoscopically resected early gastric cancer

Endoscopic submucosal dissection (ESD) is widely accepted as an appropriate treatment modality for early gastric cancer (EGC). Accepted indications for ESD are mostly based on the risk of lymph node (LN) metastasis in EGC. The presence of lymphovascular emboli (LVEs) is the most important risk factor for predicting LN metastasis, but the criteria for diagnosing LVEs are inconsistent and controversial. Here, we defined LVE as the presence of tumor cells within a space according to the following criteria: (1) red cells or lymphocytes surrounding the tumor cells, (2) an endothelial cell lining, and (3) attachment to the vascular wall. We reviewed a series of 102 patients with EGC who underwent gastrectomy after ESD, evaluated the definition of LVE, counted the number of LVEs in ESD specimens, and validated the significance of the definition and number of LVEs with regard to the presence of LN metastasis in gastrectomy specimens using receiver operating characteristic (ROC) curve analysis. Overall, 13 instances (12.7%) of LN metastasis were identified among 102 patients with EGC who underwent gastrectomy after ESD. The LN metastasis-positive group showed higher numbers of definite (4.46 ± 2.45 versus 0.19 ± 0.07), suspicious (3.15 ± 0.76 versus 0.62 ± 0.14), and probable (1.62 ± 0.43 versus 0.43 ± 0.10) LVEs in ESD specimens than the LN metastasis-negative group. In ROC analysis, the area under the ROC curve was 0.851 (95% confidence interval [CI], 0.711-0.991) for definite LVEs, compared with 0.82 (95% CI, 0.698-0.960) for suspicious LVEs and 0.72 (95% CI, 0.549-0.891) for probable LVEs. We recommend the use of strict LVE criteria to predict LN metastasis and determine the need for surgical intervention after ESD.

Unveiling lymph node metastasis in early gastric cancer

With respect to gastric cancer treatment, improvements in endoscopic techniques and novel therapeutic modalities [such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD)] have been developed. Currently, EMR/ESD procedures are widely accepted treatment modalities for early gastric cancer (EGC). These procedures are most widely accepted in Asia, including in Korea and Japan. In the present era of endoscopic resection, accurate prediction of lymph node (LN) metastasis is a critical component of selecting suitable patients for EMR/ESD. Generally, indications for EMR/ESD are based on large Japanese datasets, which indicate that there is almost no risk of LN metastasis in the subgroup of EGC cases. However, there is some controversy among investigators regarding the validity of these criteria. Further, there are currently no accurate methods to predict LN metastasis in gastric cancer (for example, radiologic methods or methods based on molecular biomarkers). We recommend the use of a 2-step method for the management of early gastric cancer using endoscopic resection. The first step is the selection of suitable patients for endoscopic resection, based on endoscopic and histopathologic findings. After endoscopic resection, additional surgical intervention could be determined on the basis of a comprehensive review of the endoscopic mucosal resection/endoscopic submucosal dissection specimen, including lymphovascular tumor emboli, tumor size, histologic type, and depth of invasion. However, evaluation of clinical application data is essential for validating this recommendation. Moreover, gastroenterologists, surgeons, and pathologists should closely collaborate and communicate during these decision-making processes.

Clinical outcomes of small cell neuroendocrine carcinoma and adenocarcinoma of the gallbladder

AIM To compare the demographics and survival rates between gallbladder adenocarcinoma (GB-adenocarcinoma) and small cell neuroendocrine carcinoma of the gallbladder (GB-NEC-SCC). METHODS From March 2007 to September 2012, patients who underwent resection of tumor stage T2/T3 GB cancer were enrolled for this study. Forty-two patients were included in this study, including 38 diagnosed with GB-adenocarcinoma and four diagnosed with GB-NEC-SCC. In the GB-adenocarcinoma group, a radical operation was performed in 28 patients, and ten patients underwent simple cholecystectomy. In the GB-NEC-SCC group, a radical operation was performed in three patients, and one patient underwent simple cholecystectomy. Comparative analysis of the two groups was performed, including clinicopathologic features and survival rates. RESULTS The median age of the patients was 68 y (range: 35-83 years) and females comprised 26/42 of the patients. GB-adenocarcinoma patients were significantly older than GB-NEC-SCC patients (67.89 ± 11.15 vs 55.75 ± 10.31 years; P = 0.029). The median tumor size in GB-adenocarcinoma patients was 2.56 ± 1.75 cm and 3.98 ± 3.74 cm in GB-NEC-SCC patients; however, there was no significant difference between the two groups. For tumors > 2 cm, T stage (T2 vs T3), lymphovascular invasion, perineural invasion, lymph node metastasis and lymph node ratio showed no significant differences between the two groups. The overall survival rate of the 42 patients at five years was 77.0%. In the GB-adenocarcinoma group, the overall five-year survival rate was 74.8%, and survival in the GB-NEC-SCC group was 100%, which was not significantly different between the two groups. CONCLUSION The strategy for treating patients with GB-NEC-SCC should be similar to that used for treating GB-adenocarcinoma, including radical cholecystectomy and liver resection.