Journal of Pathology and Translational Medicine

Original Articles

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.

Relationship among the Expression of Cyclin D1, p21, and p53 Protein, and Prognosis in Non-Small Cell Lung Carcinomas.: Seok Woo Yang, Sang Ho Cho, Woo Ick Yang, Woo Hee Jung, Chul Min Ahn, Doo Yun Lee; Korean J Pathol. 1999;33(12):1120-1130.

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Abstract PDF: Recently, cell cycle regulators have been suggested as new prognostic factors of the lung cancer. In this study, we evaluated the expression of cyclin D1, p21, and p53 using the X2-test, with regard to the stage of the patients, histologic type, and histologic differentiation in the 135 cases of non-small cell lung carcinomas (NSCLC). To evaluate the confounding effects among cyclin D1, p21, and p53 on X2-test analysis, we used the Mantel-Haenzel test. The NSCLC in this study included 82 cases of squamous cell carcinoma and 53 cases of adenocarcinoma. Each nuclear staining of cyclin D1, p21, and p53 was observed in 65 cases (48.1%), in 54 cases (40.0%), and in 81 cases (60.0%) of NSCLCs, respectively. Only p53 expression was significantly associated with the stage (stage I, II, IIIa) (p<0.05) and squamous cell carcinoma (p<0.05). On the other hand, cyclin D1 expression was significantly associated with the histologic differentiation. The confounding effects among cyclin D1, p21, and p53 revealed that only p21 expression changed the relationship between p53 and stage. In this regard, further study is needed.

Histological and Immunohistochemical Characteristics of Keratoacanthoma and Well Differentiated Squamous Cell Carcinoma.: Lucia Kim, Seung Kyung Hann, Kwang Gil Lee; Korean J Pathol. 2000;34(2):145-153.

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Abstract PDF: Keratoacanthoma (KA) is a rapidly growing cutaneous tumor and is difficult to distinguish from squamous cell carcinoma (SCC) on histomorphology alone. In the present study, we compared the clinicopathological and immunohistochemical findings using antibodies for p21 (WAF-1/CIP1), p53, laminin, and Ki-67 proteins in 27 cases of KA and 31 cases of well differentiated SCC. KA was characterized by occurrence in sun-exposed skin, shorter duration, and smaller size. Expression of p21 protein was increased according to the maturation and involution of KA, but there was no statistical significance. Expression of Ki-67 was decreased in the involutional stage of KA than in SCC (p<0.05). But p53 protein and Ki-67 were expressed in the cells at the periphery of both KA and SCC. The immunoexpression pattern of p53 and Ki-67 suggests that proliferative activities of the two lesions are similar. Laminin was present in the infiltrative cell nests of fully developed and involutional stages of KA, and it may be related to the healing process of KA. In conclusion, it is suggested that the degree of proliferative activity in the proliferative and fully developed stages of KA is similar to that of SCC and that p21 gene expression represents the differentiation property of KA and may be associated with its regression.

p21 Protein Expression and Cell Proliferation Activity in Human Multistep Hepatocarcinogenesis.: Kye Weon Kwon, Young Nyun Park, Chan Il Park; Korean J Pathol. 2000;34(5):325-330.

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Abstract PDF: p21 is a universal inhibitor of cyclin-dependent kinase (cdk) and of cell-cycle progression. p21 expression is variable according to the type of tissue and the pathologic condition. To study the role of p21 in the multistep hepatocarcinogenesis, the expression of p21, p53 and Ki-67 was investigated in 53 cases of inactive liver cirrhosis, 4 cases of low grade dysplastic nodules, 3 cases of high grade dysplastic nodules, 7 cases of early hepatocellular carcinomas (HCCs), 27 cases of small HCCs (< or =3 cm), and 52 cases of advanced HCCs (>3 cm). p21 expression was not detected in liver cirrhosis, low grade dysplastic nodules, high grade dysplastic nodules and early HCCs which were mitotically inactive. p21 expression was significantly increased in small HCCs and advanced HCCs which were mitotically active. p21 expression was significantly correlated with Ki-67 labelling indices. p53 protein was not expressed in liver cirrhosis, dysplastic nodules, and early HCCs. The expression of p53 protein was, however, significantly increased in small and advanced HCCs. The p21 expression was not correlated with p53 expression. Therefore, p21 is suggested to play a role in the mitotically active small and advanced HCCs, but not in the mitotically inactive lesion of dysplastic nodules and early HCC in multistep hepatocarcinogenesis. These findings suggest that homeostatic mechanism of growth control is not totally destroyed in HCC.

Expressions of MAGE-3, PCNA, p21, and p53 Proteins in the Hypopharyngeal Squamous Cell Carcinoma Cell Line (PNUH-12) Analysed by Bivariate Flow Cytometry.: Hee Kyung Chang, Deok Jun Kim, Hwan Jung Roh, Bang Hur, Kang Dae Lee, Spagnoli Spagnoli; Korean J Pathol. 2000;34(11):901-908.

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Abstract PDF: MAGE (melanoma antigen gene) is a tumor specific shared antigen, presented by HLA class I molecules, which is recognized by cytotoxic T lymphocytes. MAGE proteins are expressed in malignant tumor cells, in contrast to no expression in normal or benign tissues except for testis and placenta. MAGE might be a potential target for immunotherapy of malignant tumors. However, its biological aspects associated with cell cycle are not yet described. The flow cytometry is a useful tool for objective and quantitative analyses of heterogenous tumor cell population. To understand the status of MAGE related to cell cycle and its relationship with p53 as the G1 checkpoint regulator, p21, and PCNA as a proliferative index, we investigated expression of MAGE-3 protein, mutant p53, p21, and PCNA by flow cytometry and immunohistochemical stain. In addition, double stains for MAGE-3/p53, p53/PCNA, and p53/p21 were analysed with bivariate flow cytometry. DNA histograms using MAGE-3/PI (DNA) and p53/PI (DNA) were also analysed. The cell line (PNUH- 12) used for this study originated from a hypopharyngeal squamous cell carcinoma, which has point mutation (exon 7, C-->G) of p53. The expression rate of MAGE-3 was 83%, PCNA 85%, and p53 81%. No expression for p21 was identified. MAGE-3 was expressed in cytoplasm, while both PCNA and p53 were expressed in nuclei of tumor cells. With bivariate analyses, coexpression rates of MAGE-3/p53 and p53/PCNA were 0.96 and 0.97, respectively. Both MAGE-3 and p53 showed constantly high level throughout the cell cycle. These results suggest that expression of MAGE-3 and mutant p53 is not dependent on the cell cycle. p21 seems to be inactivated.

Immunohistochemical Expression of p53, p21, and mdm2 Proteins in Human Papillomavirus Positive and Negative Invasive Uterine Cervical Carcinomas.: In Seo Park, Hye Seung Han, Tae Sook Kim, Jee Young Han, Joon Mee Kim, Young Chae Chu, Tae Sook Hwang; Korean J Pathol. 2001;35(3):212-219.

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Abstract PDF: BACKGROUND
In the uterine cervical carcinoma, the inactivation of p53 protein by human papillomavirus(HPV) E6 protein has been reported to play a greater role in carcinogenesis than the mutation of the p53 gene. Therefore, the mutation of the p53 gene is rare. p21 and mdm2 proteins are induced by wild-type p53 protein and are involved in the cell cycle regulatory mechanism.
METHODS
Immunohistochemical staining for p53, p21 and mdm2 proteins was performed in 26 HPV-positive and 13 HPV-negative invasive cervical carcinomas together with 5 non-neoplastic cervical tissues.
RESULTS
The frequencies of the expression of p53, p21 and mdm2 proteins were 82.1%, 84.6% and 66.7%, respectively. The expression of p53 protein was less frequently demonstrated in HPV-positive cases than HPV-negative cases, which was statistically a negative correlation(p=0.018). The expression of p53 and p21 proteins was statistically significant(p=0.000).
CONCLUSIONS
p53, p21 and mdm2 proteins were highly expressed in both HPV-positive and HPV-negative cervical carcinomas. Significantly higher expression of p53 protain in HPV-negative cases necessitate a further study for investigating the role of p53 protein accumulation in carcinogenesis of HPV-negative cervical carcinomas. The relationship between the expression of p53 protein and p21/mdm2 proteins may indicate that p21 and mdm2 proteins also have a role in carcinogenesis, where p53 protein plays a fundamental role.

Expression of Cancer-Related Genes in Epstein Barr Virus-Infected Burkitt's Lymphoma Cell Line Treated with Mitomycin C.: Woo Bom Yeom, Seol Hee Park, Min Kyung Kim, Chul Hwan Kim, In Sun Kim, Dale Lee; Korean J Pathol. 2001;35(4):271-277.

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Abstract PDF: BACKGROUND
Infection of Epstein Barr virus (EBV) into B cells drives the infected cells into the cell cycle and frequently results in lymphoblastoid cells. Mitomycin C inhibits DNA synthesis of epithelial cells as well as lymphoid cells by cross-linking with DNA. Many of the cancer cells have various pathways for escaping the responsiveness to the negative growth-regulatory effects of mitomycin C and gaining the immortalized property. The auther performed a cell culture of an EBV infected Jijoye lymphoma cell line, and compared the cell cycle and cancer related genes between the mitomycin treated- and non-treated group.
METHODS
DNA and RNA were extracted from the Jijoye cells; and EBV nuclear antigen (EBNA)-1, 2 and latent membrane protein (LMP) of EBV and p53 and p21 mRNA analyse was performed.
RESULTS
Mitomycin C blocked G2/M phase, however, mitomycin did not affect the expression of EBNA-1, 2 and LMP. Mitomycin C also increased the p21 mRNA expression without p53 mRNA increase.
CONCLUSIONS
Mitomycin C induces B cell apoptosis by blocking the G2/M phase and by increasing p21 mRNA independent to p53, which reveals the presence of an alternative pathway of p21 induction by mitomycin C in EBV positive lymphoma cells

Loss of Heterozygosity on Chromosome 9p21, 17p13 and 3p in Human Astrocytic Tumor.: Youn Soo Lee, Chang Suk Kang, Seung Myung Dong, Jung Yong Lee, Sang In Shim, Byung Kee Kim; Korean J Pathol. 2001;35(4):330-337.

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Abstract PDF: BACKGROUND
The purpose of this study was to determine the genetic abnormalities of chromosomes 9p21, 17p13.1, 3p25 and 3p14.2 in the development and progression of astrocytic tumors.
METHODS
We performed loss of heterozygosity (LOH) analysis in 41 astrocytic tumors, including 20 astrocytomas, 11 anaplastic astrocytomas and 10 glioblastomas, and correlated the results of LOH at different histopathologic grades. LOH was determined by multiplex polymerase chain reaction analysis of the DNA, which was extracted by microdissection.
RESULTS
LOH of 9p21 was found in 55.6% of astrocytomas, 54.6% of anaplastic astrocytomas and 100.0% of glioblastomas. LOH of 17p13.1 was found in 21.4% of astrocytomas, 28.6% of anaplastic astrocytomas, and 66.7% of glioblastomas. LOH of 3p25 was found in 37.5% of astrocytomas, 16.7% of anaplastic astrocytomas, and 14.3% of glioblastomas. LOH of 3p14.2 was found in 16.7% of astrocytomas, 40.0% of anaplastic astrocytomas, and 42.9% of glioblastomas. LOH on chromosome 9p21 and 17p13.1 was closely related with the histopathologic grades.
CONCLUSIONS
These results may suggest that LOH of 9p21, 17p13.1, 3p25 and 3p14.2 involves an early event of astrocytoma development and accumulates during progression. LOH of 3p25 may be involved in the tumorigenesis of astrocytoma. Identification of these LOH may illuminate the stepwise pathogenesis of astrocytic tumors and predict the possibility of malignant transformation.

Expression of p53, p21waf1/cip1, Cyclin D1 and Rb in Gastric Epithelial Proliferative Lesions.: Hyoung Joong Kim, Tae Jin Lee, Eon Sub Park, Jae Hyung Yoo; Korean J Pathol. 2002;36(4):222-231.

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Abstract PDF: BACKGROUND
Aberrations of cell cycle-related genes have been reported to contribute to the formation and development of various human tumors. To investigate the gastric carcinogenesis, the expression of cell cycle-related genes (p53, p21wafl/cipl, cyclin D1 and Rb protein) compared to the morphological changes of gastric epithelial lesions were studied.
METHODS
The expression of p53, p21wafl/cipl, cyclin D1 and Rb protein was immunohistochemically studied in a series of surgical specimens including the 36 normal/regenerating lesions and the 127 gastric epithelial proliferative lesions (GEPLs). The gastric epithelial proliferative lesions consisted of 25 regenerating epithelia with atypias (REAs), 27 low grade gastric dysplasias (LGDs), 17 high grade dysplasias (HGDs), 24 early gastrc carcinomas (EGCs), and 34 advanced gastric carcinomas (AGCs).
RESULTS
The frequency of p53 protein overexpression was significantly associated with histologic grades of GEPLs (p=0.031); occurring in 4% of REAs, in 14.8% of LGDs, in 23.5% of HGDs, in 41.7% of EGCs and 58.9% of AGCs. The p21 wafl/cipl immunohistochemical reaction showed superficial eccentric positivity, representing an inverse correlation with histologic grades of GEPLs (p=0.04); occurring in 83.4% of normal/regenerating lesions, in 80% of REAs, in 74.1% of LGDs, in 29.4% of HGDs, 20.8% of EGCs and 8.8% of AGCs. Although Cyclin D1 and Rb proteins were expressed highly in the GEPLs, the frequency of both proteins were insignificantly associated with histologic grades of GEPLs (p=0.092). However, cases with both the Rb and cyclin D1 positivity were increased with statistical significance along histologic grades of GEPLs (p=0.044).
CONCLUSIONS
The altered expression of p53, p21, Rb, and cyclin D1 was considered to be related to dysplastic progression and advancement of malignancy in GEPLs. Therefore, immunohistochemical studies of cell cycle related proteins and a combined analysis may be useful for estimating and following up cases of GEPLs.

Genistein Induces G2/M Cell Cycle Arrest and Apoptosis in Rat Neuroblastoma B35 Cells; Involvement of p21(waf1/cip1), Bax and Bcl-2.: Ismail A Ismail, Ku Seong Kang, Jung Wan Kim, Yoon Kyung Sohn; Korean J Pathol. 2006;40(5):339-347.

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Abstract PDF: BACKGROUND
The effect of genistein on different types of cells has been investigated. However, its effect on the nervous system is still unclear. The aim of the present work is to explore the effect of genistein on rat neuroblastoma B35 cells.
METHODS
The effect of genistein on the proliferation of B35 cells, its cytotoxicity, the cell-cycle distribution, the ultra-structural changes and the induction of apoptosis were determined using MTT assay, LDH assay, Flow-cytometric analysis, transmission electron microscopy and Hoechst staining, respectively. Furthermore, Real-time quantitative RT-PCR and Western blotting were used to examine the transcriptional and post-translational alterations of the G2/M cell-cycle arrest marker cyclin-dependent kinase inhibitor p21(waf1/cip1) and the apoptosis-related genes after genistein treatment.
RESULTS
Genistein significantly inhibits cell survival, slightly elevates the release of lactate dehydrogenase and induced apoptosis in B35 cells. Genistein increased the number of cells at S-phase and induced cells to accumulate at the G2/M phase. These G2/M arrested cells are associated with a marked up-regulation of p21(waf1/cip1) at both the mRNA and protein levels. We observed that genistein up-regulates pro-apoptotic Bax with concurrent down-regulation of the anti-apoptotic Bcl-2 protein.
CONCLUSION
These observations suggest that the anticancer effect of genistein on B35 neuroblastoma cells is mediated through multiple cellular pathways including G2/M cell-cycle arrest and the induction of apoptosis.

Expression of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53 in Human Breast Cancers.: Dong Hoon Kim, Chan Kum Park, Ho Jung Lee, Won Mi Lee, Eun Kyung Kim, Jong Eun Joo; Korean J Pathol. 2005;39(6):391-400.

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Abstract PDF: BACKGROUND
Cell cycle progression is governed by cell cycle regulators and inhibitors such as the cyclin dependent kinases (CDK), p27(Kip1), p21(WAF1/Cip1) and p53. The purpose of this study was to correlate expressions of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53 with the various clinicopathologic prognostic parameters of human breast cancers.
METHODS
The paraffin-embedded tissue sections from 102 patients with human breast carcinomas were examined by performing immunohistochemical staining. The primary antibodies used for immunohistochemical staining were mouse monoclonal antibody to human p34(cdc2), p27(Kip1), p21(WAF1/Cip1), p53, ER and PR.
RESULTS
The expression rates of p34(cdc2), p21(WAF1/Cip1) and p53 were 29.3%, 40.2% and 49.1% in breast carcinomas, respectively. In normal breast tissues, p34(cdc2), p21(WAF1/Cip1) and p53 were not expressed. The p34(cdc2) was expressed in the cytoplasm of cancer cells. The expression rate of p27(Kip1) was 29.3% in breast carcinomas and 100% in normal breast tissues, so the loss of p27(Kip1) expression in breast cancer was noted. The high expression of p21(WAF1/Cip1) in neoplastic cells was associated with the p53 expression (p=0.03). The expression of p27(Kip1) was correlated with that of the progesterone receptor (PR) (p=0.04) and the expression of p21(WAF1/Cip1) was correlated with that of positivity for estrogen receptor (ER) (p=0.04) and PR (p=0.04). No correlation was demonstrated between the mean patient survival and the expression rate of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53.
CONCLUSIONS
The loss of the normal cell growth cycle by the abnormal expression of cyclin dependent kinases and their inhibitors and the steroid hormones may play an important role in human breast carcinogenesis. The p53 dependent p21(WAF1/Cip1) pathway, the p27(Kip1) protein loss and the cdc2 overexpression were important in development and progression of human breast cancer.

Expression of FHIT and p21 in Gastric Adenocarcinoma.: Hyun Joo Choi, Byung Kee Kim, Jinyoung Yoo, Seok Jin Kang, Chang Suk Kang; Korean J Pathol. 2004;38(1):35-41.

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Abstract PDF: BACKGROUND
The fragile histidine triad (FHIT) gene, located on the human chromosome 3p14.2, is frequently inactivated by its deletion in a number of human tumors, including gastric carcinomas. Its protein product, FHIT is presumed to have a tumor suppressor function. p21, one of the tumor markers acts as a regulator of the cell cycle, and inhibits cell proliferation.
METHODS
The association of the expressions of FHIT and p21 protein, with clinicopathological features, such as age, gender, tumor size, histological type, depth of invasion, lymph node metastasis, lymphatic and vascular invasion, grade and stage were investigated, and correlation of their expressions with p21 expression in 82 gastric adenocarcinomas attempted by immunohistochemical staining.
RESULTS
Of the 82 tumors analyzed, 58 (70.7%) were markedly reduced, or completely negative, for FHIT protein expression. The loss of FHIT expression was correlated with the depth of invasion (p=0.000), lymph node metastasis (p=0.001), lymphatic invasion (p=0.000), histological grade (p=0.000) and tumor stage (p=0.000). The loss of p21 expression was correlated with lymph node metastasis (p=0.026) and lymphatic invasion (p= 0.017), but not with the histological grade and tumor stage. The comparison of the FHIT and p21 protein expressions showed significant correlation (p=0.035).
CONCLUSIONS
The loss of FHIT and p21 expressions may be a useful indicator of the post diagnostic prognosis. Also, FHIT could be related to cell cycle arrest.

Expression of p21, p53 and bcl-2 Proteins in Invasive Ductal Carcinoma of the Breast.: Hyang Jeong Jo, Ki Jung Yun, Hyung Bae Moon; Korean J Pathol. 2003;37(6):393-399.

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Abstract PDF: BACKGROUND
This study was designed to investigate the prognostic significance of p21, p53, and bcl-2 proteins in invasive ductal carcinoma of the breast.
METHODS
Seventy-two cases of invasive ductal carcinoma were examined by immunohistochemical staining for p21, p53 and bcl-2 proteins. The results were correlated with clinicopathological variables, including age, tumor size, histologic grade, nuclear grade, lymph node status, estrogen receptor (ER) and progesterone receptor (PR) expression.
RESULTS
Of 72 cases, p21, p53 and bcl-2 proteins were positive in 25 (34.8%), 35 (50.0%) and 27 (37.5%), respectively. There were no statistically significant correlations between the p21 protein expression and the other clinicopathological variables. The expression of p53 protein, however, showed a significant relation to ER expression, and that of bcl-2 was positively correlated with tumor size. In survival analysis, p21, p53, and bcl-2 proteins, nuclear grade and lymph node status were associated with survival rate.
CONCLUSIONS
These results indicate that p21, p53, and bcl-2 proteins might play a role in tumorigenesis of breast carcinoma. In addition, the increased expression of p21, p53, and bcl-2 proteins could be used as factors suggesting poor prognosis in breast carcinomas.

Squamous Cell Carcinoma Arising in Mature Cystic Teratoma of the Ovary: a Report of Six Cases and Immunohistochemistry of the p53 Protein and p21WAF1/CIP1.: Kyung Hee Kim, Kwang Sun Suh, Joo Heon Kim, Dong Wook Kang, Dong Hoon Kim, Seong Ho Kim, Jong Ho Back, Mee Ja Park; Korean J Pathol. 2003;37(5):316-319.

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Abstract: BACKGROUND
Mature cystic teratoma is a common type of ovarian tumor. Although squamous cell carcinoma (SCC) is the most common carcinoma in malignant transformations of ovarian mature cystic teratomas, SCC arising in a mature teratoma is rare.
METHODS
This paper reports four cases of invasive SCC, a case of an adenosquamous cell carcinoma and a case of a pure in situ SCC arising in a mature cystic teratoma including a clinicopathological evaluation and an immunohistochemical study of the p53 protein and p21WAF1/CIP1.
RESULTS
The mean age of the patients was 60 years. The sizes of the mature cystic teratomas in all cases were greater than 7.5 cm in the largest diameter. Five cases showed the nuclear accumulation of the p53 protein with no p21WAF1/CIP1 immunoreactivity. The other case showed the nuclear accumulation of p21WAF1/CIP1 without p53 expression. There was a significant inverse relationship between the p53 protein level and p21WAF1/CIP1 expression.
CONCLUSION
A clinicopathological evaluation showed that a SCC arising from a mature cystic teratoma must be included in a differential diagnosis when the patient is over 42 years of age and the size of a mature cystic teratoma is greater than 75 mm in the largest diameter. It is suggested that p53 overexpression is implicated in the malignant transformation, and the p21WAF1/CIP1 expression level is dependent on alterations in the level of the p53 protein in these tumors.

Expression of BrdU and C-Ha-ras in Experimentally Induced Enzyme Altered Foci of the Liver and Hepatocellular Carcinoma.: Myung Sook Kim, Woo Ho Kim, Yong Il Kim; Korean J Pathol. 1994;28(6):584-595.

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Abstract PDF: For sequential phenotypic changes including enzyme altered hepatocytic foci, hyperplastic nodules, hepatocellular adenomas and carcinomas were produced in Sprague-Dawley rats by Solt-Farber method (administration of diethylnitrosamine and acetylaminofluorene (AAF), and partial hepatectomy). The immunohistochemical expressions of glutathione S transferase P (GST-P) and bromodeoxyuridine (BrdU) were assessed for selective proliferative activity in the enzyme altered foci and the subsequently developed lesions by double immunohistochemical staining technique. Immunoreactive areas against GSTP gradually increase from early period of carciogenesis. BrdU labeling in such areas remained high during the first week. but decreased thereafter. BrdU labeling index remained low in the GSTP negative area throughout the experimental period. This suggests that cells in the enzyme altered foci keep away from the suppressor effect of AAF in contrast to the normal cells in which their growth are inhibited by AAF. BrdU labeling index remained very low in both hyperplastic nodule and adenoma which were prevalent during the mid-experimental period, but increase markedly in carcinoma. The long period of low BrdU labeling index seems to correspond to the "slowly growing step of persistent nodule" during hepatocarcinogenesis. The differentiation index, a ratio of S phase fraction between GSTP positive and negative areas, was low in adenoma-developing period and high in carcinoma-developing period. C-Ha-ras p21 was not expressed in foci of enzyme altered hepatocyte and hyperplasia, but highly positive in carcinoma. This indicates that the c-Ha-ras may involve the late step of hepatocarcinogenesis.

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