Journal of Pathology and Translational Medicine

Original Articles

Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer: Hye Jung Hwang, Soo Kyung Nam, Hyunjin Park, Yujun Park, Jiwon Koh, Hee Young Na, Yoonjin Kwak, Woo Ho Kim, Hye Seung Lee; J Pathol Transl Med. 2020;54(5):378-386. Published online July 1, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.01

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Background
Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC.
Methods
Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative expression. In 18 cases (15.0%) with discrepant TP53 mutation and p53 IHC results, p53 IHC was repeated.
Results
Strong expression of p53 was associated with TP53 missense mutations, negative expression with other types of mutations, and weak expression with wild-type TP53 (p<.001). The sensitivity for each category was 90.9%, 79.0%, and 80.9%, and the specificity was 95.4%, 88.1%, and 92.3%, respectively. The TNM stage at initial diagnosis exhibited a significant correlation with both TP53 mutation type (p=.004) and p53 expression status (p=.029). The Kaplan-Meier survival analysis for 109 stage II and III GC cases showed that patients with TP53 missense mutations had worse overall survival than those in the wild-type and other mutation groups (p=.028). Strong expression of p53 was also associated with worse overall survival in comparison to negative and weak expression (p=.035).
Conclusions
Results of IHC of the p53 protein may be used as a simple surrogate marker of TP53 mutations. However, negative expression of p53 and other types of mutations of TP53 should be carefully interpreted because of its lower sensitivity and different prognostic implications.

Citations

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Mesenchymal Stromal Cells Promote Tumor Progression in Fibrosarcoma and Gastric Cancer Cells: Byunghoo Song, Bokyung Kim, Se-Ha Choi, Kyo Young Song, Yang-Guk Chung, Youn-Soo Lee, Gyeongsin Park; Korean J Pathol. 2014;48(3):217-224. Published online June 26, 2014; DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.3.217

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Abstract PDF

Background

Extensive evidence has accumulated regarding the role of mesenchymal stromal cells (MSCs) in tumor progression, but the exact effects and mechanisms underlying this role remain unclear. We investigated the effects of MSC-associated tumor progression in MSC-sarcoma models and a gastric cancer metastatic model.

Methods

We conducted an in vitro growth kinetics assay and an in vivo tumor progression assay for sarcoma cells and gastric cancer cells in the presence or absence of MSCs.

Results

MSC-cocultured human fibrosarcoma cells (HT1080) showed accelerated growth compared with HT1080 alone (79- vs 37-fold change, p<.050). For HT1080, human MSC-coinjected tumors showed significantly greater and highly infiltrative growth compared to those of HT1080 alone (p=.035). For mouse fibrosarcoma cells (WEHI164), mouse MSC-coinjected tumors had greater volume than those of WEHI164 alone (p=.141). For rat sarcoma cells (RR1022), rat MSC-coinjected tumors exhibited greater volume and infiltrative growth than those of RR1022 alone (p=.050). For human gastric cancer cells (5FU), tumors of 5FU alone were compact, nodular in shape, and expansile with good demarcation and no definite lung metastatic nodules, whereas tumors grown in the presence of human MSCs showed highly desmoplastic and infiltrative growth and multiple lung metastasis.

Conclusions

We observed morphological evidence for MSC-associated tumor progression of fibrosarcomas and gastric cancer cells.

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Review

CpG Island Hypermethylation in Gastric Carcinoma and Its Premalignant Lesions: Gyeong Hoon Kang; Korean J Pathol. 2012;46(1):1-9. Published online February 23, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.1.1

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Abstract PDF

Gastric cancers arise through a multistep process characterized by the progressive accumulation of molecular alterations in which genetic and epigenetic mechanisms have been implicated. Gastric cancer is one of the human malignancies in which aberrant promoter CpG island hypermethylation is frequently found. Helicobacter pylori and Epstein-Barr virus, which are known carcinogens for gastric cancer, are closely associated with enhanced hypermethylation of CpG island loci in gastric non-neoplastic epithelial cells and cancer cells, respectively. Aberrant CpG island hypermethylation occurs early in the multistep cascade of gastric carcinogenesis and tends to increase with the step-wise progression of the lesion. Approximately 400 genes that are actively expressed in normal gastric epithelial cells are estimated to be inactivated in gastric cancers as a result of promoter CpG island hypermethylation. In this review, a variety of information is summarized regarding CpG island hypermethylation in gastric cancer.

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Case Report

Gastric Adenocarcinoma with Coexistent Hepatoid Adenocarcinoma and Neuroendocrine Carcinoma: A Case Report.: Aeri Kim, Sang Woon Kim, Sun Kyo Song, Young Kyung Bae; Korean J Pathol. 2009;43(1):79-82.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.1.79

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Abstract PDF

This report represents a very rare case of a gastric adenocarcinoma that was coexistent with hepatoid adenocarcinoma and neuroendocrine carcinoma. A 77-year-old man was admitted to our hospital due to a huge ulcerofungating mass identified at the proximal body of the stomach. After a pathological diagnosis of the tumor as a poorly differentiated adenocarcinoma was made, the patient underwent a total gastrectomy with lymph node dissection. Microscopically, the tumor consisted of three morphologically distinct components-tubular adenocarcinoma, hepatoid adenocarcinoma and neuroendocrine carcinoma. The hepatoid adenocarcinoma component resembled a hepatocellular carcinoma and produced alpha-fetoprotein. The neuroendocrine carcinoma component was positive for chromogranin and synaptophysin immunostains. This is an example of the diverse morphological and immunophenotypical differentiation of gastric carcinomas.

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Original Articles

Alteration of Phospholipase C Activity in Human Gastric Cancer Tissues.: Young Ok Kim, Moo Youn Cho, Sung Do Lee, Sung Sook Kim, Pann Ghill Suh, Man Ha Huh; Korean J Pathol. 1996;30(3):210-217.

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Abstract PDF: Phospholipase C (PLC) plays a pivotal role in transmembrane signal transduction pathway for cellular proliferation differentiation and growth. Thus far, there have been few reports in which PLC activity was investigated in human malignant neoplastic tissues. In the present study, we evaluated PLC activity in 23 human gastric cancer tissues and normal mucosal tissues to investigate whether alteration of PLC activity is associated with gastric cancer. The amount of [14C] diacylglycerol, one of the earliest products of inositol phospholipid hydrolysis by PLC, was measured by thin layer chromatography. Also, expression of PLC-gamma1, which is one of the most important PLC isozymes,was examined by immunohistochemistry using specific monoclonal antibody directed against PLC-gamma1. The results are summarized as follows. PLC activity in all 23 gastric cancer tissues (1.35+/-1.04 units/mg of protein) was significantly higher than normal mucosal tissues (0.28+/-0.21 units/mg of protein) (P<0.001). PLC activity in gastric cancer tissues was not correlated with histologic grade (P>0.05). PLC-gamma1 immunoreactivity was detected in all of 23 cases studied. The intensity and extent of PLC-gamma1 immunoreactivity was not correlated with PLC enzyme activity, although stronger intensity was demonstrated in malignant cells in comparison to normal gland epithelial cells. The present study provides the first evidence of significant elevation of PLC activity in human stomach cancer tissues. Our results strongly suggest that PLC might be involved in tumorigenesis and/or progression(uncontrolled continuous cycling of cells) of human gastric cancer. Further studies are needed to elucidate the role of elevated PLC activity in cancer tissues.

Immunohistochemical Study of p53 and nm23-H1 Protein in Gastric Carcinoma.: Duck Hwan Kim, Yoen Ju Kim, Seon Eun Yang, Sung Suk Paeng, Hee Jin Chang, Jung Il Suh, Hyo Sook Park; Korean J Pathol. 1996;30(7):587-594.

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Abstract PDF: The p53 gene, which resides on the short arm of chromosome 17, has been described as a tumor suppressor gene playing a role of G1 checkpoint monitering DNA damage, but mutation of this gene has been shown in numerous types of human cancers. The nm23-H1 gene encodes human NDP(nucleotide diphosphate) kinase. The expression of nm23-H1 gene was postulated to inversely correlate with metastatic potential of malignant tumors. We examined immunohistochemical expression in 30 cases of stomach cancers including 10 cases each of early gastric cancers(EGC), advanced gastric cancers without lymph node involvement, and advanced gastric cancers with lymph node involvement, which were stained with mouse monoclonal antibody of p53(PB53-12) and nm23-H1. Positive nuclear staining of p53 was frequently found in advanced gastric cancers with lymph node involvement (80%). The lymph node positive group showed high expression of p53(80%), and low expression of nm23-Hl(30%) than lymph node negative group. There was no significant correlation of p53 and nm23-H1 expression with tumor size, invasion depth, TNM stages, distant metastasis and histologic differentiation. Based on the present study, the expression of p53 and down regulation of nm23-H1 are thought to be correlated with tumor progression and lymph node involvement, and may be a useful prognostic factor in gastric cancers.

Expression of E-cadherin and p53 Proteins in Gastric Adenocarcinoma.: Sook Hee Hong, Mee Sook Roh; Korean J Pathol. 1999;33(2):80-87.

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Abstract: The gastric carcinoma shows various molecular and genetic alterations in its development and progression. There are evidences that the changes of the expression of cell adhesion molecules affect the morphogenesis of the tumor as well as the tumor progression and metastasis. The purpose of this study is the evaluation of the expression pattern of a cell adhesion molecule, E-cadherin, and a tumor suppression gene, p53, by immunohistochemical stain and the relationship of their expressions with clinicopathologic findings in gastric adenocarcinoma tissue. The E-cadherin expression was absent or reduced in 93 cases (73.2%) and p53 was positive in 98 cases (77.2%) of 127 gastric adenocarcinomas. The frequency of reduced E-cadherin expression was significantly higher in poorly differentiated adenocarcinomas (p=0.04) and in diffuse type (p=0.01), but that of p53 positivity was not significantly correlated with tumor differentiation. Both proteins showed no correlation with depth of invasion, lymph node and distant metastasis, and tumor stage. There was no correlation between E-cadherin and p53 expression. This study indicates that the altered expressions of E-cadherin and p53 are associated with the development of intestinal and diffuse types of gastric adenocarcinoma and the differentiation of the gastric adenocarcinoma is affected by cell adhesion mediated by E-cadherin, but the modes of tumor progression and metastasis are not affected by E-cadherin and p53.

Predictive Factors of Epstein-Barr Virus Association in Gastric Adenocarcinoma.: Young Su Kim, Sang Chul Nam, Man Hoon Han, Ji Yun Jeong, Sun Kyun Park, In Soo Suh, Han Ik Bae; Korean J Pathol. 2008;42(4):193-197.

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Abstract PDF: BACKGROUND
It is important to detect Epstein-Barr virus (EBV) in the setting of gastric cancer so that early viral targeted therapy and prevention can be undertaken. The aim of this study was to investigate the predictive clinicopathologic factors for EBV-related gastric cancer.
METHODS
The archival tumor tissues from 335 patients with gastric cancer were examined using tissue microarray. The detection of EBV was performed using EBV mRNA in situ hybridization (EBV-ISH), and the results were compared against clinicopathologic factors.
RESULTS
EBV-related gastric cancers were identified in 21 of 335 investigated cases (6.27%). The anatomical predisposition of EBV-related cancers to manifest in the upper stomach was statistically significant (p<0.001). EBV-related cancers were almost always (20/21) accompanied by lymphoid stroma. No differences in age, sex, histologic differentiation, or T or N stage were noted between EBV-positive and EBV-negative gastric carcinomas.
CONCLUSIONS
The association of EBV with gastric adenocarcinomas could be predicted when tumors with lymphoid stroma occurred in the upper stomach.

Mucin Phenotype and CDX2 Expression as Prognostic Factors in Gastric Carcinomas.: Chan Kwon Jung, Kyo Young Song, Gyeongsin Park, Cho Hyun Park, Myeong Gyu Choi, Young Seon Hong, Kyo Young Lee; Korean J Pathol. 2007;41(3):139-148.

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Abstract PDF: Background
: Mucin phenotypic markers and CDX2 are widely expressed in gastric carcinomas, however, recent studies have produced conflicting results regarding whether the expression patterns of these markers have clinicopathologic significance.
Methods
: We examined samples from 217 gastric carcinoma patients immunohistochemically to determine if the expression of mucin phenotypic markers and CDX2 was correlated with postoperative survival and other clinicopathologic factors.
Results
: All tumors were phenotypically classified as gastric (type G, 81 cases), gastric and intestinal mixed (type GI, 55 cases), intestinal (type I, 43 cases), or unclassified (type U, 38 cases). The occurrence of type G and GI tumors was positively correlated with tumor progression whereas that of type U tumors was negatively correlated with tumor progression. CDX2 expression was correlated with type I tumors. Tumors that expressed MUC5AC or MUC6 had a better prognosis than those that did not. When the relationship between phenotype and prognosis was considered, type GI had the best prognosis, followed by type G, then type U.
Conclusions
: The mucin phenotypic markers may be useful for predicting tumor progression and survival in patients with gastric carcinomas. Additionally, CDX2 may play an important role in gastric carcinogenesis of type I tumors.

Significance of Cyclin E, p53, E-cadherin, and beta-Catenin Expressions in Gastric Adenocarcinomas.: Long Pei Xuan, Mi Ja Lee, Chae Hong Suh; Korean J Pathol. 2004;38(4):213-220.

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Abstract PDF: BACKGROUND
Gastric cancer is reported to be one of the leading causes of mortality in Korea. Our aim was to evaluate the clinicopathologic usefulness of cyclin E, p53, E-cadherin and beta-catenin expressions in gastric adenocarcinomas.
METHODS
Immunohistochemical staining was performed on the 40 early gastric carcinoma (EGC) cases and 69 advanced gastric carcinoma (AGC) cases to examine the relationship with the clinicopathologic parameters.
RESULTS
Cyclin E and p53 expressions were significantly lower in the mucosal or submucosal invasion group compared with those in the muscle invasion and subserosal or serosal invasion groups. Cyclin E expression was significantly higher in the node-positive group compared with that in the node-negative group. The loss of beta-catenin expression was significantly higher in the node-negative group. p53 expression was significantly higher in the intestinal type group than that in the diffuse type group. Loss of E-cadherin expression was significantly higher in the diffuse type group. Cyclin E expression correlates with p53 expression.
CONCLUSIONS
The depth of invasion seems to correlate with cyclin E and p53 expressions. Lymph node metastasis may correlate with loss of beta-catenin expression.

Expression of Alpha Fetoprotein, Transforming Growth Factor, Epidermal Growth Factor and Alpha-1-Antitrypsin in Gastric Cancer.: Sook Guem Jeong, Hwan Jun Choi, Ja Young Koo, Man Ha Huh; Korean J Pathol. 1994;28(5):485-492.

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Abstract PDF: The immunohistochemical expression of transforming growth factor-beta(TGF-beta), epidermal growth factor(EGF) and alpha-1-antitrypsin(AAT) was studied in 47cases of endoscopic biopsy matearials of gastric carcinoma to determine me correlation to the expression of alpha fetoprotein(AFP). And immunoreactivity of the antigens was correlated to me degree of tumor infiltrating lymphocytes and histologic differentiation of the tumors. And the results were analyzed to elucidate pathological AFP-producing gastric cancer. The results were summarized as follows. AFP immunoreactivity was demonstrated in 30 cases(63.8%) of the tumors, TGF-beta in 26 cases(55.3%), EGF in l4 cases(29.8%) and AAT in l0 cases(21.3%). The incidence of expression of the antigens was significantly higher in the cases of elevated serum AFP(>2ng/ml) than that of the cases with normal serum AFP(p<0.05). There was no relation between the expression of antigens and histological differentiation of gastric cancer. The expression of AFP and TGF-beta revealed good correlation(k=0.72). The relation between expression of TGF-beta and AAT and the degree of tumor infiltrating lymphocytes disclosed negative correlation(p<0.05). These results suggest that TGF-beta and AAT prodution contribute to the worse prognosis of AFP-producting gastric cancer. Possible immunosuppressive action of TGF-beta and AAT in the cancer tissue is discussed.

Mutation of Adenomatous Polyposis Coli Gene in Human Stomach Cancer.: Won Sang Park, Mun Gan Rhyu, Sug Hyung Lee, Yun Jun Chung, Gum Ryong Kim, Choo Soung Kim; Korean J Pathol. 1993;27(1):34-39.

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Abstract PDF: Recently the adenomaatous polyposis coli(APC) gene, a tumor suppressor gene, was identified and the cDNA was cloned from chromosome 5q21. Allelic deletion or point mutation of tumor suppressor genes(TSGs) has been considered as an important mechanism in development of human tumor. Point mutations affecting APC gene are seen in the hereditary syndrome, adenomatous polyposis and spordic colon cancer. However, the mutation of APC gene and other TSGs have not been described in gastric cancer. In order to identify the mutation of exon 11 of APC gene for gastric cancer, we amplified DNA extracted from paraffin-embedded tissues by polymerase chain reaction(PCR) and digested the PCR products with restriction enzyme Rsa I. We examined the DNA extracted from paraffin-embedded 44 gastric cancer tissues with lymph nodes. Eighteen(41%) among 44 were informative for the study exon 11 of the APC gene, and we found loss of heterozygosity(LOH) for APC in 6/18(33.3%). These data suggest that the point mutation or the base change of APC gene commonly occurs in gastric cancer. We conclude that the mutation of APC gene is strongly connected with development of human gastric cancer.

Pathological Study on the Early Gastric Cancer.: Weon Young Choi, Dong Su Suk, Sun Keong Lee; Korean J Pathol. 1991;25(3):206-214.

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Abstract PDF: Pathological study was performed on the 135 cases (137 lesion) of early gastric cancer (EGC) diagnosed during the period from 1970 to 1988. The gastrectomy specimens were obtained from Pusan National University Hospital and Pusan Paik Hospital. The statistical analysis was applied on the point of pathological and epidemiological aspects. The results obtained were summarized as follows: 1) The proportion of patients with EGC of all gastric cancer diagnosed in Pusan area during the period of 1970 to 1974 was 1.3%, those during 1975 to 1979 was 1.7%, those during 1980 to 1984 was 7.8%, and those during 1985 to 1988 was 20.0% respectively. 2) The model age group was 6th decade in both sexes. The average age of patients with EGC was 50. 1-year-old in men and 47. 9-year-old in women respectively. The sex ratio (M/F) was 2 : 1 but it was lower for young people than for old people. 3) The proportion of sites involved by the EGC in the stomach was as follows : the antrum 61%, the body 39%, and the cardia and fundus 0.01%. The intestinal type cancer more frequently involved the lower portion than the upper portion of the stomach. 4) Regarding the distribution of the gross types of EGC, the elevated group (Type I, IIa) accounted for 14%, the flat type (Type IIb) accounted for 4%, and the depressed group (Type IIc, III) accounted for 82%. There was no correlation between the gross type and the depth of the lesion. The elevated group was more frequent in intestinal type than in diffuse type. 5) The size distribution of the EGC was as follows : 46% of the lesions were smaller than 2.0 cm in diameter, 47% were between 2.1 to 5.0 cm, and 7% were larger than 5.1 cm. There was no correlation between the size of the lesion and the gross type. 6) The intestinal type of EGC was 77 lesions (56.2%) and the diffuse type 60 lesions (43.8%). The ratio of both types (I/D) was 1.3 : 1, and it was lower for younger people than for old people. 7) Ten of 135 cases (7%) had lymph node metastases. The metastatic rate of EGC confined to submucosa was much higher than that of EGC confined to mucosa only, but the metastatic rate was not related with the size of the lesion.

Immunohistochemical Study on the Ha-ras p21 Expression in the Gastric Carcinoma.: Kwang Min Lee, Joo Yong Yoo; Korean J Pathol. 1990;24(1):1-9.

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Abstract PDF: We have investigated an immunohistochemical expression of the Human-Ha-ras oncogene product p21 in tumor cells of the primary mass and metastatic lymph nodes with different histological features of gastric cancer by using avidinbiotin complex immunoperoxidase method in formalin-fixed tissue sections from 73 cases of primary tumor mass and 23 cases of metastatic lymph node. Histologic type of the gastric cancer was classification. The results obtained were as follows: 1) Expression of Ha-ras p21 was consistantly increased in the well differentiated tubular adenocarcinoma as compared with poorly differentiated tubular adenocarcinoma (p<0.01), and was substantially decreased in mucinous carcinoma and signet ring cell carcinoma. 2) Signet ring cell carcinoma showed that positive immunoperoxidase reaction for Ha-ras p21 exhibited in the majority of immature signet ring cell with scant cytoplasm rather than in the mature signet ring cells which have abundant cytoplasm filled with mucin. This findings indicate that mucin production from the tumor cell was not correlated with activation of ras gene in the tumor tissue of gastric carcinoma. 3) In general Ha-ras p21 expression was enhanced in the metastatic tumor cells of the regional lymph node compared with primary tumor, especially it was consistantly increase in the well differentiated tubular adenocarcinoma.

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