Purpose: Wnt and mammalian target of rapamycin (mTOR) are major molecular signaling pathways associated with the development and progression of tumor, as well as the maintenance and proliferation of cancer stem cells (CSCs), in colorectal cancer (CRC). Identifying patients at risk of poor prognosis is important to determining whether to add adjuvant treatment in stage II CRC and thus improve survival. In the present study, we evaluated the prognostic value of Wnt, mTOR, and CSC markers as survival predictors in stage II CRC. Materials and Methods: We identified 148 cases of stage II CRC and acquired their tumor tissue. Tissue microarrays for immunohistochemical staining were constructed, and the expressions of CD166, CD44, EphB2, β-catenin, pS6 were evaluated using immunohistochemical staining. Results: The expressions of CD166 (p=0.045) and pS6 (p=0.045) and co-expression of pS6/CD166 (p=0.005), pS6/CD44 (p=0.042), and pS6/CD44/CD166 (p=0.013) were negatively correlated with cancer-specific survival. Cox proportional hazard analysis showed the combination of CD166/pS6 [hazard ratio, 9.42; 95% confidence interval, 2.36–37.59; p=0.002] to be the most significant predictor related with decreased cancer-specific survival. In addition, co-expression of CD44/CD166 (p=0.017), CD166/ β-catenin (p=0.036), CD44/β-catenin (p=0.001), and CD44/CD166/β-catenin (p=0.001) were significant factors associated with liver metastasis. Conclusion Specific combinations of CSC markers and β-catenin/mTOR signaling could be a significant predictor of poor survival in stage II CRC.

PURPOSE: The diagnostic criteria of gastric intraepithelial neoplasia (IEN) are controversial across the world. We investigated how many discrepancies occur in the pathologic diagnosis of IEN and early gastric carcinoma in endoscopic submucosal dissection (ESD) specimens, and evaluated the reasons of the discordance. MATERIALS AND METHODS: We retrospectively reviewed 1,202 ESD specimens that were originally diagnosed as gastric IEN and early carcinoma at 12 institutions. RESULTS: The final consensus diagnosis of carcinoma were 756 cases, which were originally 692 carcinomas (91.5%), 43 high-grade dysplasias (5.7%), 20 low-grade dysplasias (2.6%), and 1 others (0.1%), respectively. High- and low-grade dysplasia were finally made in 63 and 342 cases, respectively. The diagnostic concordance with the consensus diagnosis was the highest for carcinoma (91.5%), followed by low-grade dysplasia (86.3%), others (63.4%) and high-grade dysplasia (50.8%). The general kappa value was 0.83, indicating excellent concordance. The kappa values of individual institutions ranged from 0.74 to 1 and correlated with the proportion of carcinoma cases. The cases revised to a final diagnosis of carcinoma exhibited both architectural abnormalities and cytologic atypia. The main differential points between low- and high-grade dysplasias were the glandular distribution and glandular shape. Additional features such as the glandular axis, surface maturation, nuclear stratification and nuclear polarity were also important. CONCLUSION: The overall concordance of the diagnosis of gastric IEN and early carcinoma in ESD specimens was excellent. It correlated with the proportion of carcinoma cases, demonstrating that the diagnostic criteria for carcinoma are more reproducible than those for dysplasia.
Consensus ; Diagnosis ; Retrospective Studies ; Stomach Neoplasms

The molecular genetics of colorectal cancers (CRCs) is among the best understood of common human cancers. It is difficult to predict the prognosis and/or to predict chemoresponding in CRC patients. At present, prognosis is based predominantly on the tumor stage and pathological examination of the disease. Molecular classification of CRCs, based on genomics and transcriptomics, proposed that CRCs can be classified into at least three-to-six subtypes, depending on the gene expression pattern, and groups of marker genes representing to each subtype have also been reported. Gene expression-based subtyping is now widely accepted as a relevant source of disease stratification. We reviewed the previous studies on CRC subtyping, international consortium dedicated to large-scale data sharing and analytics recently established four consensus molecular subtypes with distinguishing features. Predictive markers identified in these studies are under investigation and large-scale clinical evaluations of molecular markers are currently in progress.
Classification* ; Colonic Neoplasms ; Colorectal Neoplasms* ; Consensus ; Gene Expression ; Genomics ; Humans ; Information Dissemination ; Molecular Biology ; Molecular Medicine ; Molecular Typing ; Prognosis

PURPOSE: The importance of Helicobacter pylori eradication after endoscopic resection (ER) of gastric neoplasms remains controversial. In this study, we clarified the importance of H. pylori eradication for metachronous lesions after ER. MATERIALS AND METHODS: This study included 3,882 patients with gastric neoplasms who underwent ER. We included patients infected with H. pylori who received eradication therapy. Among them, 34 patients with metachronous lesions after ER and 102 age- and sex-matched patients (nonmetachronous group) were enrolled. Background mucosal pathologies such as atrophy and intestinal metaplasia (IM) were evaluated endoscopically. The expression levels of CDX1, CDX2, Sonic hedgehog (SHH), and SOX2 were evaluated based on H. pylori eradication and the development of metachronous lesions. RESULTS: The eradication failure rate was higher in the metachronous group than in the nonmetachronous group (P=0.036). Open-type atrophy (P=0.003) and moderate-to-severe IM (P=0.001) occurred more frequently in the metachronous group. In patients with an initial diagnosis of dysplasia, the eradication failure rate was higher in the metachronous group than in the nonmetachronous group (P=0.002). In addition, open-type atrophy was more frequent in the metachronous group (P=0.047). In patients with an initial diagnosis of carcinoma, moderate-to-severe IM occurred more frequently in the metachronous group (P=0.003); however, the eradication failure rate was not significantly different between the two groups. SHH and SOX2 expression was increased, and CDX2 expression was decreased in the nonmetachronous group after eradication (P<0.05). CONCLUSIONS: Open-type atrophy, moderate-to-severe IM, and H. pylori eradication failure were significantly associated with metachronous lesions. However, eradication failure was significantly associated with dysplasia, but not carcinoma, in the metachronous group. Thus, H. pylori eradication may play an important role in preventing metachronous lesions after ER for precancerous lesions before carcinomatous transformation.
Atrophy ; Diagnosis ; Hedgehogs ; Helicobacter pylori* ; Helicobacter* ; Humans ; Metaplasia ; Pathology ; Recurrence* ; Stomach Neoplasms*

BACKGROUND/AIMS: It is difficult to precisely detect the lateral margin during endoscopic submucosal dissection (ESD) for signet ring cell carcinoma (SRC) because SRC often expands to lateral direction through the lamina propria. Thus, the aim of this study was to classify the intramucosal spreading patterns of SRC and to analyze the patients' clinicopathological findings according to the spreading patterns. METHODS: The intramucosal spreading patterns of SRC were classified as expansive or infiltrative types. A total of 100 surgical and 42 ESD specimens were reviewed. RESULTS: In the surgical specimens, the proportions of expansive and infiltrative types were 44% and 56%, respectively. The infiltrative type was more commonly associated with old age, atrophy, and intestinal metaplasia in surrounding mucosa and the absence of Helicobacter pylori compared with the expansive type. In ESD specimens, the proportions of expansive and infiltrative types were each 50%. When lateral margin-positive lesions were compared with -negative lesions, larger size, residual lesion, and the lack of a neutrophil infiltration were more significantly associated with lateral margin-positive lesions. All cases with residual tumors in lateral margin-positive lesions were classified as the infiltrative type. CONCLUSIONS: SRC surrounded with atrophy and/or intestinal metaplasia often spreads subepithelially in the margin. This finding may suggest that a larger safety margin is necessary in this type during ESD.
Adult ; Carcinoma, Signet Ring Cell/*pathology/*surgery ; Dissection/*methods ; Female ; Gastric Mucosa/pathology ; *Gastroscopy ; Humans ; Intestines/pathology ; Male ; Metaplasia/pathology ; Middle Aged ; Neoplasm Invasiveness ; Retrospective Studies ; Stomach/pathology ; Stomach Neoplasms/*pathology/*surgery

BACKGROUND/AIMS: The usefulness of immunohistochemistry to screen for the microsatellite instability (MSI) phenotype in gastric cancer remains unclear. Moreover, the prognostic value of MSI phenotypes in gastric cancer has been debated. METHODS: The clinicopathologic parameters and survival outcomes of 203 MSI-high (MSI-H) and 261 microsatellite-stable (MSS) advanced gastric cancers (AGCs) were compared. Next, we compared the immunohistochemistry results for hMLH1 and hMSH2 with those of a polymerase chain reaction (PCR)-based method. Kaplan-Meier curves and a Cox proportional hazard regression model were used to conduct survival analyses. RESULTS: The MSI-H AGCs were correlated with older age (p<0.001), female gender (p=0.018), distal location (p<0.001), larger size (p=0.016), and intestinal type (p<0.001). Multivariate analysis revealed that the MSI-H phenotype was an independent favorable factor that was related to overall survival in patients with AGC (p<0.001). Compared with the PCR-based analysis, immunohistochemistry exhibited high sensitivity (91.1%) and specificity (98.5%) in the detection of MSI phenotypes. CONCLUSIONS: MSI-H gastric cancers have distinct clinicopathologic features and better prognoses, which suggests the necessity of MSI analysis in gastric cancer. Immunohistochemistry can be a useful and reliable screening method in the assessment of MSI status in gastric cancer.
Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Immunohistochemistry/*statistics & numerical data ; Kaplan-Meier Estimate ; Male ; *Microsatellite Instability ; Middle Aged ; Phenotype ; Polymerase Chain Reaction ; Predictive Value of Tests ; Prognosis ; Proportional Hazards Models ; Sensitivity and Specificity ; Sex Factors ; Stomach Neoplasms/*genetics/mortality

BACKGROUND: Epstein-Barr virus associated gastric lymphoepithelioma-like carcinoma (LELC) is characterized by the intensive infiltration of lymphoid cells, the presence of EBV, and the better prognosis over typical adenocarcinoma. Thus, it was assumable that viral latent proteins may be responsible for the recruitment of a certain T cell repertoire to EBV-associated gastric carcinoma. METHODS: To examine above possibility, EBV gene expression in gastric carcinoma tissues and usage of TCR among the tumor infiltrating lymphocytes were analyzed. RESULTS: EBV specific DNA and EBERs RNA were detected in 4 out of 30 patients. RT-PCR analysis revealed that all 4 of EBV-positive tumor tissues expressed EBNA1 mRNA and BARTs and LMP2a was detected only one sample out of 4. However, the EBNA2 and LMP-1 transcripts were not detected in these tissues. CD8+ T cells were the predominant population of infiltrating lymphocytes in the EBV-positive gastric carcinoma. According to spectra type analysis of infiltrating T cells, 10 predominant bands were detected by TCR Vbeta CDR3 specific RT-PCR from 4 EBV-positive tumor tissues. Sequence analysis of these bands revealed oligoclonal expansion of T cells. CONCLUSION: These findings suggest that clonally expanded T cells in vivo might be a population of cytotoxic T cells reactive to EBV-associated gastric carcinoma.
Adenocarcinoma ; DNA ; Gene Expression ; Herpesvirus 4, Human ; Humans ; Lymphocytes ; Lymphocytes, Tumor-Infiltrating ; Prognosis ; Proteins ; RNA ; RNA, Messenger ; Sequence Analysis ; T-Lymphocytes

BACKGROUND: We investigated the prognostic significance of tumor regression grade (TRG) after preoperative chemoradiation therapy (preop-CRT) for locally advanced rectal cancer especially in the patients without lymph node metastasis. METHODS: One-hundred seventy-eight patients who had cT3/4 tumors were given 5,040 cGy preoperative radiation with 5-fluorouracil/leucovorin chemotherapy. A total mesorectal excision was performed 4-6 weeks after preop-CRT. TRG was defined as follows: grade 1 as no cancer cells remaining; grade 2 as cancer cells outgrown by fibrosis; grade 3 as a minimal presence or absence of regression. The prognostic significance of TRG in comparison with histopathologic staging was analyzed. RESULTS: Seventeen patients (9.6%) showed TRG1. TRG was found to be significantly associated with cancer-specific survival (CSS; P = 0.001) and local recurrence (P = 0.039) in the univariate study, but not in the multivariate analysis. The ypN stage was the strongest prognostic factor in the multivariate analysis. Subgroup analysis revealed TRG to be an independent prognostic factor for the CSS of ypN0 patients (P = 0.031). TRG had a stronger impact on the CSS of ypN (-) patients (P = 0.002) than on that of ypN (+) patients (P = 0.521). In ypT2N0 and ypT3N0, CSS was better for TRG2 than for TRG3 (P = 0.041, P = 0.048), and in ypN (-) and TRG2 tumors, CSS was better for ypT1-2 than for ypT3-4 (P = 0.034). CONCLUSION: TRG was found to be the strongest prognostic factor in patients without lymph node metastasis (ypN0), and different survival was observed according to TRG among patients with a specific histopathologic stage. Thus, TRG may provide an accurate prediction of prognosis and may be used for f tailoring treatment for patients without lymph node metastasis.
Humans ; Lymph Nodes ; Multivariate Analysis ; Neoplasm Metastasis ; Prognosis ; Rectal Neoplasms ; Recurrence

BACKGROUND: Metastasis is one of the most important characteristics of cancer in terms of its impact on patient survival. Unfortunately, identification of altered genes during tumor metastasis is limited. METHODS: Using high-throughput microarrays containing 19K spotted human oligonucleotides, gene expression of primary and matched metastatic colon cancer were compared in previous study. Although DNA microarray analysis did not demonstrate complete classification of primary and metastatic carcinoma, 80 differentially expressed genes were identified. Among these, expression of osteopontin, matrix metalloproteinase-1 (MMP-1) and serpin A1 was assessed using immunohistochemistry in a validation set containing 43 pairs from tissue microarrays. RESULTS: The expression of osteopontin was significantly higher in metastatic carcinoma than in primary carcinoma, as indicated by mRNA expression. The expression of MMP-1 was significantly lower in metastatic carcinoma. Expression of serpin A1 was not correlated with the microarray results. CONCLUSIONS: Osteopontin and MMP-1 expression successfully classified primary and metastatic colorectal carcinomas and further studies on their clinical application is encouraged.
alpha 1-Antitrypsin ; Colonic Neoplasms ; Colorectal Neoplasms ; Gene Expression ; Humans ; Immunohistochemistry ; Matrix Metalloproteinase 1 ; Neoplasm Metastasis ; Oligonucleotide Array Sequence Analysis ; Oligonucleotides ; Osteopontin ; RNA, Messenger

Achalasia is a rare neurological deficit of the esophagus that produces an impaired relaxation of the lower esophageal sphincter and decreased motility of the esophageal body. Achalasia is generally accepted to be a pre-malignant disorder, since, particularly in the mega-esophagus, chronic irritation by foods and bacterial overgrowth may contribute to the development of dysplasia and carcinoma. We present a case of a 51-year-old man with achalasia combined with esophageal cancer who has had dysphagia symptoms for more than 20 years. Since there was a clinically high possibility of supraclavicular lymph node metastasis, concurrent chemoradiation therapy was scheduled. After the third cycle of chemoradiation therapy, transthoracic esophageolymphadenectomy was performed. Histopathological examination of the main esophagus specimen revealed no residual carcinoma. And the entire regional lymph node areas were free of carcinoma except for one azygos metastatic lymph node. In summary, achalasia is a predisposing factor for esophageal squamous cell carcinoma. Although surveillance endoscopy in achalasia patients is still controversial, periodic screening for cancer development in long-standing achalasia patients might be advisable.
Carcinoma, Squamous Cell ; Deglutition Disorders ; Endoscopy ; Esophageal Achalasia ; Esophageal Neoplasms ; Esophageal Sphincter, Lower ; Esophagus ; Humans ; Lymph Nodes ; Mass Screening ; Middle Aged ; Neoplasm Metastasis ; Relaxation