Journal of Pathology and Translational Medicine

Original Articles

Mesothelin Expression in Gastric Adenocarcinoma and Its Relation to Clinical Outcomes: Song-Hee Han, Mee Joo, Hanseong Kim, Sunhee Chang; J Pathol Transl Med. 2017;51(2):122-128. Published online February 15, 2017; DOI: https://doi.org/10.4132/jptm.2016.11.18

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Background
Although surgical resection with chemotherapy is considered effective for patients with advanced gastric cancer, it remains the third leading cause of cancer-related death in South Korea. Several studies have reported that mesothelial markers including mesothelin, calretinin, and Wilms tumor protein 1 (WT1) were positive in variable carcinomas, associated with prognosis, and were evaluated as potential markers for targeted therapy. The aim of this study was to assess the immunohistochemical expression of mesothelial markers (mesothelin, calretinin, and WT1) in gastric adenocarcinoma and their relations to clinocopathological features and prognosis. Methods: We evaluated calretinin, WT1, and mesothelin expression by immunohistochemical staining in 117 gastric adenocarcinomas. Results: Mesothelin was positively stained in 30 cases (25.6%). Mesothelin expression was related to increased depth of invasion (p = .002), lymph node metastasis (p = .013), and presence of lymphovascular (p = .015) and perineural invasion (p = .004). Patients with mesothelin expression had significantly worse disease-free survival rate compared with that of nonmesothelin expression group (p = .024). Univariate analysis showed that mesothelin expression is related to short-term survival. None of the 117 gastric adenocarcinomas stained for calretinin or WT1. Conclusions: Mesothelin expression was associated with poor prognosis. Our results suggest that mesothelin-targeted therapy should be considered as an important therapeutic alternative for gastric adenocarcinoma patients with mesothelin expression.

Citations

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Immunohistochemical Analysis of HLA-DR and Secretory Component Expression in Gastric Adenocarcinoma.: Ji Youn Bae, Soo Sang Sohn, Eun Sook Chang; Korean J Pathol. 1996;30(4):293-300.

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Abstract PDF: Sixty one cases of gastric adenocarcinoma were studied immunohistochemically for expression of HLA-DR and secretory component(SC) in order to analyze the relationship between expression of these in gastric cancer cells and the adjacent mucosa. Immunostaining was detected within the cytoplasm and on the cell memgrane. The rate of HLA-DR and SC expressions in cancer cells were 59.0% and 49.2%, respectively, and 52.5%/52.5% and 31.2%/50.8% the mucosa in adjacent/remote from the site of to cancer. The SC expression in the adjacent mucosa was lower than that of the remote mucosa(p=0.027). The HLA-DR expression in the cancer cells in the intestinal type of gastric adenocarcinoma(73.9%) was higher than that of the diffuse type(14.3%) and it was statistically significant(p=0.02). The presence of an increased amount of lymphoid infiltration in the gastric mucosa was closely related to the expression of HLA-DR and SC. Decreased or absent expression of SC at the transitional mucosal cells was possibly a result of exposure to genotoxic agents due to the lack of protective function of SC-IgA. From these results, one can postulate that the expression of HLA-DR and SC may play an important role in atleration in microenvironment with lymphoid infiltration.

The Expression of CD44H and CD44v6 in Gastric Adenocarcinoma.: Myoung Jin Ju, Hae Kyung Lee, Kwang Min Lee, Dong Kyu Chung, Choo Hong Park; Korean J Pathol. 1997;31(4):326-331.

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Abstract PDF: CD44, also known as the Hermes antigen, H-CAM, pgp-1 antigen, and extracellular matrix receptor ECM-III, is a widely distributed integral membrane protein that exists in a variety of forms with different molecular sizes ranging from 85kd to 160kd. A number of evidence implicates CD44 as a cell adhesion molecule with a possible role in tumor progression. To evaluate the possible roles of CD44 in the metastatic process of gastric carcinoma to the regional lymph nodes, we applicated immunohistochemical stains with the CD44H and CD44v6 primary antibodies onto the 2 groups of gastric adenocarcinomas. Each group was comprised of 22 primary tumors extending to the subserosa, and one group showed nodal metastasis, while the other group did not. Seventeen primary tumors (77%) out of the 22 cases with the nodal metastasis demonstrated positivity to the CD44v6, while only 9 primary tumors (41%) out of the 22 cases without nodal metastasis did. However CD44H immunoreactivity was demonstrated in tumor cells of all cases (100%) of both groups as well as in the normal cell components. These results suggest that CD44H form is not related to the metastasis to the regional lymph nodes of gastric carcinoma. However, the expression of CD44v6 seems to play a certain role in the metastatic process of the gastric carcinoma.

Correlation of Tumor Angiogenesis and nm23-H1 Expression with Lymph Node Metastasis in Proper Muscle Gastric Cancer.: Eun Sook Nam, Gu Kang, Hyung Sik Shin, Young Eui Park; Korean J Pathol. 1997;31(5):410-416.

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Abstract PDF: We studied clinicopathologic features of 44 cases of PM (proper muscle) gastric cancer, correlated the lymph node metastasis and found the result of immunohistochemical staining for tumor angiogenesis using antibodies to Factor VIII-related antigen and nm23-H1, known as meatastasis inhibitory substance. The results were as follows: 1) The average age of these 44 cases of PM gastric cancer was 55.1 years old (range 35-81). The ratio of male to female was 2.2 : 1. The tumor was located at the antrum of stomach in 72.7% of the cases. The average size of the tumor was 4.1 cm (range 0.6-9). The gross features were comprised of Borrmann type I (6.8%), II (29.6%), III (56.8%), IV (6.8%), respectively. The microscopic type was a diffuse type in 70.5% and an intestinal type in 29.5%. There were lymph node metastasis in 25 of the 44 cases (56.8%). 2) The microvessel count was higher in the lymph node positive group (average 69.3) than in the lymph node negative group (average 45.6) (P=0.004). There was a higher microvessel density in diffuse type, over 4 cm of tumor size, proximally located tumor, older than 50 years, Borrmann type II and IV, but there was no statistically significant correlation. 3) The more decreased expression of nm23-H1 was found in the lymph node positive group (56.0%) than in the lymph node negative group (31.6%), but showed no statistical significance (P=0.0142). There was no significant correlation between the expression of nm23-H1 and the other clinicopathologic factors. We suggest that the microvessel count of the tumor angiogenesis may be a prognostic factor for predicting lymph node metastasis and also help to determine the therapeutic modalities of PM gastric cancer.

Expression of H-ras, erb B2, and p53 Proteins in Gastric Intestinal Metaplasia Associated with Cellular Atypism.: Han Ik Bae, Dong Hoon Kim, Jung Ran Kim; Korean J Pathol. 1997;31(9):862-872.

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Abstract PDF: Intestinal metaplasia (IM) have long been thought to play a role in the pathogenesis of gastric intestinal adenocarcinoma, but not in that of diffuse cancer. We studied 20 normal gastric mucosa, 90 IM, 39 atypia (dysplasia or adenoma), and 51 adenocarcinoma to evaluate the expression of p53, erb B2, and H-ras p21 proteins and to assess the correlation with IM (esp. type III IM, revealing positive HID-AB/PAS for sulfomucin). Positive rate of HID-AB staining revealed an increased trend in comparison between IM, atypia and adenocarcinoma. It was the highest in mucinous carcinoma, but it was not correlated with positive oncoprotein expressions. Positive rates of oncoproteins revealed increased trends in comparison between IM, dysplasia or adenoma and adenocarcinoma in c-erb B2 and p53 (P<0.01). The positive rates were highest in intestinal adenocarcinoma (50.0% and 54.2%, respectively). Rates were lowest in biopsy tissue of IM (4.4% and 8.7%, respectively). The expression of H-ras p21 was not significant in gastric carcinogenesis. There was no significant correlation between oncoproteins and other clinical parameters, such as depth of invasion, differentiation, size and nodal metastasis of the tumors. Therefore, we suggest that p53 and erb B2 may play a role in the carcinogenesis of gastric intestinal adenocarcinoma.

Immunohistochemical Study on the Expression of Bcl-2 and p53 Protein in Gastric Adenocarcinoma.: Joon Hyuk Choi, Won Hee Choi; Korean J Pathol. 1997;31(12):1282-1290.

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Abstract PDF: This study was carried out to investigate the immunohistochemical expression of bcl-2 and p53 protein in the intestinal type and the diffuse type of gastric adenocarcinoma by Lauren's classification. A total of 100 cases, including 50 cases of the intestinal type and 50 cases of the diffuse type from paraffin embedded gastrectomy specimens, were immunohistochemically stained for bcl-2 and p53 protein. Bcl-2 protein was expressed in 38% (19/50) of intestinal type and 30% (15/50) of diffuse type. The incidence of bcl-2 protein expression was higher in the intestinal type than in the diffuse type, but no significant correlation was present (p>0.05). p53 protein was expressed in 68% (34/50) of the intestinal type and 60% (30/50) of the diffuse type. The incidence of p53 protein expression was higher in the intestinal type than in the diffuse type, but no significant correlation was present (p>0.05). And an expression of bcl-2 and p53 protein did not correlate with depth of invasion, lymph node meatastasis and TNM stage, respectively (p>0.05). These results suggest that bcl-2 and p53 gene alteration appear to play a more important role in the carcinogenesis of the intestinal type than the diffuse type. However, there is no significant difference between the intestinaPU: The Korean Society of Pathologistsl type and the diffuse type in bcl-2 and p53 protein expression.

The Usefulness of Cytokeratin 7 and Colon Ovarian Tumor Antigen in the Differential Diagnosis of Primary and Metastatic Ovarian Tumors.: Eung Seok Lee, Hyun Deuk Cho, In Sun Kim; Korean J Pathol. 1998;32(3):201-207.

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Abstract PDF: Cytokeratin 7 has been known to be present in various types of human epithelial cells including the ovarian neoplasms, but not in colon cancers. The antibody to colon ovarian tumor antigen (COTA) has been introduced as a marker of colon and ovarian tumors. The aim of this study was to evaluate the usefulness of cytokeratin 7 and COTA in the differential diagnosis between ovarian primary and metastatic tumors. Nineteen primary ovarian epithelial tumors, seven metastatic carcinomas of the ovary from the stomach, three metastatic carcinomas of the ovary from the colon, one mucinous tumor of the ovary associated with a mucinous tumor of the appendix and pseudomyxoma peritonei, and nineteen colonic and twenty gastric adenocarcinomas were stained with monoclonal antibodies to cytokeratin 7 and COTA. The results are summerized as follows; In the primary ovarian tumors, 94.4% were positive for cytokeratin 7 and 50% were positive for COTA. In the primary colonic adenocarcinomas, 94.7% were negative for cytokeratin 7 and 68% were positive for COTA. In the metastatic ovarian tumor from the colonic adenocarcinomas, 100% were negative for cytokeratin 7 and positive for COTA. In the primary gastric adenocarcinomas, 40% were negative for cytokeratin 7 and 85% were negative for COTA. In the metastatic ovarian tumor from the gastric adenocarcinomas, 43% were negative for cytokeratin 7 and 14% were negative for COTA. From the results of this study, it could be concluded that in the differential diagnosis of primary ovarian tumors from metastatic colonic carcinomas, positive reaction for cytokeratin 7 suggests a primary ovarian tumor but a negative reaction for cytokeratin 7 and positive reaction for COTA suggest metastatic colonic carcinomas. The results of this study also reveal that cytokeratin 7 and COTA are not useful in the differential diagnosis of primary ovarian tumors from metastatic gastric carcinomas.

Expression of bcl-2 Protein in Gastric Adenoma and Adenocarcinoma.: Young Sill Kim, Byung Kee Kim, Sang In Shim; Korean J Pathol. 1998;32(4):248-254.

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Abstract PDF: The bcl-2 oncoprotein confers a survival advantage to cells by blocking programmed cell death. Overexpression of bcl-2 probably plays a role in tumorigenesis, and the expression of the bcl-2 protein has been investigated in many kinds of tumors. However, there have been only a few reports on expression of bcl-2 in human gastric adenocarcinoma. The aim of this study was to investigate the relationship between the expression of bcl-2 protein and several clinical and pathological parameters such as age, tumor site, size, histological type, depth of invasion, Lauren's classification, and grade. Immunohistochemical staining using monoclonal bcl-2 protein antibody, clone 124, was performed on paraffin embedded specimens from 23 gastric adenomas and from 45 gastric adenocarcinomas. The results are as follows. 1. Variable intensity of epithelial staining was noted from case to case, although the lymphocytic component showed similar intensity in all examples. The staining was located at the gland and mucous neck region of non-neoplastic epithelium. 2. The more differentiated type of gastric adenocarcinoma showed the higher expression rate and intensity. 3. The relationship between the expression rates of bcl-2 protein and tumor grade (adenoma early gastric adenocarcinoma advanced gastric adenocarcinoma) was statistically significant. The reactivity in adenoma was somewhat stronger with a uniform pattern, while in adenocarcinoma it was much weaker with a heterogenous pattern. 4. Intestinal type carcinomas by Lauren's criteria showed a higher expression rate and intensity than diffuse type. These results suggest that the bcl-2 expression would be found in the early phase of gastric tumorigenesis, and the expression rate and intensity would decrease according to the tumor progression.

Correlation between Expression of p53 and Bcl-2 Protein and Epstein-Barr Virus Detection in Gastric Adenocarcinoma.: Ki Jung Yun, Weon Cheol Han, Hyung Bae Moon, Sang Woo Juhng; Korean J Pathol. 1998;32(8):574-580.

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Abstract: Epstein-Barr virus (EBV) has been known to be associated with a wide variety of neoplastic conditions including nasopharyngeal carcinoma, Hodgkin's disease, and non-Hodgkin's lymphoma. Recent studies reveal the presence of EBV in certain subtypes of gastric carcinoma in which EBV appears to be pathogenetically related. To evaluate the relationship between EBV and gastric adenocarcinoma, we examined EBV DNA using direct in situ polymerase chain reaction, and expression of p53 protein and bcl-2 protein using immunohistochemical staining method on paraffin embedded tissues. The materials consisted of one hundred twenty-eight gastric adenocarcinomas and twenty benign peptic ulcers. EBV DNA was detected in 14 of 128 gastric adenocarcinomas (10.9%). p53 protein was positive in 10 of 14 EBV positive adenocarcinomas (71.4%) and in 61 of 114 EBV negative adenocarcinomas (53.5%). Bcl-2 protein was positive in 2 of 14 EBV positive adenocarcinomas (14.3%) and in 19 of 114 EBV negative adenocarcinomas (16.7%). The above results indicate that EBV is associated with gastric adenocarcinoma, and p53 protein may play a role in carcinogenesis of EBV in gastric adenocarcinoma.

Expression of p21 and p53 Proteins in Gastric Adenocarcinoma.: Yun Jung Kim, Young Hee Choi, Kyoung Chan Choi, Young Euy Park; Korean J Pathol. 1999;33(3):187-192.

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Abstract PDF: Fifty-four adenocarcinomas of stomach were investigated to assess the expression of p21 and p53 using an immunohistochemical method. The relationship between p21 and p53 expression and the clinicopathologic parameters were analysed. The staining pattern of p21/p53 were: p21+/p53+, p21-/p53+, p21+/p53-, and p21-/p53- in 30, 12, 8, and 4 cases, respectively. Loss of p21 expression was observed in 16 of 54 tumor tissues (29%). p21 expression, however, had an inverse correlation with vascular invasion and depth of tumor invasion. The p21 and p53 protein expression showed intratumoral heterogeneity. In 63% of the adenocarcinoma, a proportional relationship was found between p21 and p53 immunostaining. The present results suggest that p53 independent induction of p21 expression may be involved in the molecular mechanism of these tumors, and expression of p21 protein may be related to a favorable prognosis in gastric adenocarcinomas.

Expression of Matrix Metalloproteinase-1,2,3 and Type IV Collagen in Gastric Adenocarcinoma: Influence on Lymph Node Metastasis and Prognosis.: Eun Sun Jung, Byung Gee Kim, Jo Hyun Park, Sang In Shim; Korean J Pathol. 1999;33(4):251-258.

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Abstract PDF: Matrix metalloproteinases are believed to play an important role in tumor invasion and metastasis. But little is known about the role of them in the gastric adenocarcinoma. We investigated the expression of matrix metalloproteinase-1,2,3 in eighty paraffin blocks of the primary gastric adenocarcinoma tissues with immunohistochemistry and analysed their correlation with lymph node metastasis and survival. MMP-1,2,3 were expressed most intensely in the fibroblasts around the tumor stroma. In our study the increased immunoreactivity of MMP-2 only showed statistically significant correlation with lymph node metastasis (P=0.0517, Odd's ratio=2.274). But MMP-1,2,3 all were correlated with survival. Type IV collagen was observed in the vascular basement membranes and tumor basement membranes and showed statistically significant correlation with lymph node metastasis (P=0.0002, Odd's ratio=0.194) and prognosis (P=0.0001). The immunoreactivity of MMP-2 and type IV collagen was inversely correlated (Kendall's Tau-b correlation = 0.37482, P=0.0001). Our results suggest that in human gastric adenocarcinoma the increased immunoreactivity of MMP-2 and the decreased immunoreactivity of type IV collagen has an important role in lymph node metastasis and prognosis. MMP-1,3 are not correlated with lymph node metastasis but correlated with survival. The mechanism responsible for the production of MMP by the host fibroblasts remains obscure and requires further investigation.

Detection Rate of Helicobacter Pylori in Gastric Adenocarcinoma and Effect of Helicobacter Pylori Infection on Proliferative Activity of Gastric Epithelium.: Young Lyun Oh, Geung Hwan Ahn; Korean J Pathol. 1999;33(8):581-588.

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Abstract PDF: Helicobacter pylori infection has been shown to be associated with gastric carcinoma. However, despite the frequent detection of seropositivity for H. pylori and histologic detection in biopsy specimen, histologic detection rate of H. pylori in surgical specimens has been low. In this study, we investigated the prevalence of H. pylori infection in gastrectomy specimens bearing gastric adenocarcinoma and compared it with both endoscopic biopsy and serologic results. H. pylori infection was identified by Giemsa stain in the mucosa stripped from the tumor, body, and antrum in 61 gastrectomy specimens. We evaluated the effect of H. pylori infection on gastric mucosal cell proliferation by using monoclonal antibody for Ki-67. H. pylori detection rate using Giemsa stain was higher in gastrectomy specimens (67.3%) compared to that (48.1%) of biopsy specimens (p=0.006). The detection rate was higher in body than that of antrum or tumor site in the same patients (p=0.001). The H. pylori seropositivity was 60.5% and relatively nonspecific. The mean value of Ki-67 labeling index in the H. pylori-positive group was higher than that in the H. pylori-negative group (p<0.05). The increase in gastric epithelial cell proliferation was not influenced by the location of the tumor or the site of the specimen. The results suggest that the actual prevalence of H. pylori infection in patients with gastric carcinoma is considerably higher than that evaluated on endoscopic biopsy specimens. In addition, the increased cell proliferation in the H. pylori-positive group suggests some evidence that H. pylori may be involved in gastric carcinogenesis.

Expression of CD44 Splicing Variants v4/5 and v6 in Gastric Adenocarcinoma and Its Relationship with Prognostic Factors.: Lee So Maeng, Hae Kyung Lee, Byung Kee Kim, Eun Jung Lee; Korean J Pathol. 2000;34(2):119-124.

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Abstract PDF: CD44, an integral membrane glycoprotein expressed by many cell types, serves as the principal transmembrane hyaluronate receptor and may be a determinant of metastatic and invasive behavior in carcinomas. This study was performed to investigate the relationship between CD44 splicing variants v4/5 and v6 expression and histopathologic prognostic factors (depth of tumor invasion, histologic classification, vascular and lymphatic invasion, and lymph node metastasis) in 107 gastric adenocarcinomas. In 107 cases of gastric carcinoma, the immunohistochemical stainining for CD44 v4/5 and CD44 v6 gave the following results. CD44 v4/5 was expressed in 40.2% and CD44 v6 in 67.3% of gastric carcinomas. The expression of CD44 v4/5 was correlated with histologic classification by Lauren (p<0.05), lymphatic invasion (p<0.05), and lymph node metastasis (p<0.004). In contrast, expression of CD44 v6 had no impact on prognostic markers. This study suggests the role of CD44 v4/5 in invasion, metastasis, and its prognostic significance in gastric adenocarcinoma.

Clinicopathologic Characteristics of Replication Error-Positive Gastric Adenocarcinoma in Korean.: Jae Hyuk Lee, Mi Hwa Kim, Wan Sik Lee, Young Jin Kim, Mi Sun Jee, Kwang Min Lee, Sang Woo Juhng, Chan Choi; Korean J Pathol. 2000;34(7):488-493.

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Abstract PDF: The purpose of this study is to obtain the clinicopathological characteristics of replication error-positive (RER ) gastric adenocarcinoma in Korean, and to identify the significance of RER in adenoma stage of gastric carcinogenesis. Microsatellite instability was examined at D2S71, D2S119, D3S1067, D6S87, D11S905, DM, AR, VWF, HPRT, and BAT-26 loci. Frameshift mutation of BAX gene was analyzed in RER tumors. Normal and tumor DNA of 76 cases of gastric carcinoma and 25 cases of adenoma were examined. RER was found in 8 of 76 cases (10.5%), and it was more frequently found in adenocarcinoma of female (17.7%) than those of male (4.8%). The frequency of RER was not different between the histologic types, age of the patient, anatomical location of the carcinoma, and the stage. The RER found in adenoma suggests that RER contributes to the malignant transformation early in the adenoma stage of the gastric carcinogenesis. None of the RER tumors revealed frameshift mutation of the BAX gene.

Diagnostic Significance of the CEA, AgNORs and PCNA in the Gastric Dysplasia and Adenocarcinoma.: Weon Cheol Han, Hyung Bae Moon; Korean J Pathol. 1995;29(1):61-67.

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Abstract PDF: This study aimed to differentiate gastric mucosal lesions such as the inflammatory gastric mucosa, gastric dysplasia and adenocarcinoma, using the CEA(carcinoembryonic antigen), AgNORS(Nucleolar organizer regions) and PCNA(proliferating cell nuclear antigen) stains. The tissue samples were taken from 30 cases of inflammatory gastric mucosa (19 gastritis and 11 regenerative hyperplasia), 28 cases of gastric dysplasia (9 mild dysplasia, 10 moderate dysplasia and 9 severe dysplasia) and 21 cases of gastric adenocarcinoma. The CEA was expressed in 16 of 21 adenocarcinomas(76%), but in neither inflammatory nor dysplastic gastric mucosae. The mean number of AgNORs per nucleus was 1.54 in inflammatory gastric mucosa, 1.80 in gastric dysplasia, and 1.88 in adenocarcinoma. The number of AgNORs was increased in dysplasia and adenocarcinoma compared to the inflammatory gastric mucosa without statistical significance. The percentage of the PCN A positive cells was 35.2% in inflammatory gastric mucosa, 44.1 % in gastric dysplasia, and 69.0% in gastric adenocarcinoma. The positivity of the PCNA was significantly increased in adenocarcinoma compared to the inflammatory gastric mucosa and dysplasia. In conclusion, the frequency of the CEA positive staining was increased in the gastric adenocarcinoma, and so CEA stain will be able to provide an additive method for the differential diagnosis between severe dysplasia and adenocarcinoma of the stomach.

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