Journal of Pathology and Translational Medicine

Review

Pathology-MRI Correlation of Hepatocarcinogenesis: Recent Update: Jimi Huh, Kyung Won Kim, Jihun Kim, Eunsil Yu; J Pathol Transl Med. 2015;49(3):218-229. Published online May 15, 2015; DOI: https://doi.org/10.4132/jptm.2015.04.15

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Understanding the important alterations during hepatocarcinogenesis as well as the characteristic magnetic resonance imaging (MRI) and histopathological features will be helpful for managing patients with chronic liver disease and hepatocellular carcinoma. Recent advances in MRI techniques, such as fat/iron quantification, diffusion-weighted images, and gadoxetic acid-enhanced MRI, have greatly enhanced our understanding of hepatocarcinogenesis.

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Multi-phasic magnetic resonance imaging of hemodynamic interchanges in hepatocarcinogenesis
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Pathologic, Molecular, and Prognostic Radiologic Features of Hepatocellular Carcinoma
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Gadoxetate-enhanced dynamic contrast-enhanced MRI for evaluation of liver function and liver fibrosis in preclinical trials
Jimi Huh, Su Jung Ham, Young Chul Cho, Bumwoo Park, Bohyun Kim, Chul-Woong Woo, Yoonseok Choi, Dong-Cheol Woo, Kyung Won Kim
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Journal of Gastrointestinal Cancer.2018; 49(3): 302. CrossRef

Original Articles

Uncommon and Rare Human Papillomavirus Genotypes Relating to Cervical Carcinomas: Na Rae Kim, Myunghee Kang, Soon Pyo Lee, Hyunchul Kim, Jungsuk An, Dong Hae Chung, Seung Yeon Ha, Hyun Yee Cho; Korean J Pathol. 2014;48(1):43-49. Published online February 25, 2014; DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.1.43

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Abstract PDF

Background

Human papillomavirus (HPV) is an oncogenic virus in cervical cancer and most invasive carcinomas (ICs) are caused by HPV16 and 18. However, the roles and contributions of other uncommon and rare genotypes remain uncertain.

Methods

HPV genotypes were retrospectively assessed using an HPV DNA chip that can specify up to 32 HPV genotypes. We arbitrarily regarded genotypes accounting for less than 6% of the total as uncommon and rare genotypes.

Results

A total of 3,164 HPV-positive cases were enrolled. In groups 2A, 2B, 3, and unclassified HPV genotypes, 2.4% of cases with uncommon HPV genotypes (68, 26, 34, 53, 66, 69, 70, 73, 40, 42, 43, 44, 54, 55, 61, 62, 6, and 11) showed high grade squamous intraepithelial lesions and ICs. There were no HPV32- and 57-infected cases.

Conclusions

We found that the uncommon and rare HPV genotypes may provide incremental etiologic contributions in cervical carcinogenesis, especially HPV68, 70, and 53. Further studies on these uncommon and rare HPV genotypes will be of importance in establishing the significance of genotypes in different regions, especially in planning a strategy for further vaccine development as well as follow-up on the effectiveness of the currently used vaccines.

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Overall accuracy of cervical cytology and clinicopathological significance of LSIL cells in ASC‐H cytology
S. H. Kim, J. M. Lee, H. G. Yun, U. S. Park, S. U. Hwang, J.‐S. Pyo, J. H. Sohn
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Human papillomavirus genotyping by Linear Array and Next-Generation Sequencing in cervical samples from Western Mexico
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Impact of human papillomavirus coinfections on the risk of high-grade squamous intraepithelial lesion and cervical cancer
Adela Carrillo-García, Sergio Ponce-de-León-Rosales, David Cantú-de-León, Verónica Fragoso-Ontiveros, Imelda Martínez-Ramírez, Asunción Orozco-Colín, Alejandro Mohar, Marcela Lizano
Gynecologic Oncology.2014; 134(3): 534. CrossRef
Human papillomavirus 66‐associated subungual squamous cell carcinoma
Jin Hee Kang, Hwa young Ahn, Miri Kim, Shin Taek Oh, Baik Kee Cho, Hyun Jeong Park
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A Study on the DNA Ploidy and Expression of c-erbB-2 Oncogen in the Ovarian Carcinomas.: Jong Jae Jung, Chang Soo Park, Sang Woo Juhng; Korean J Pathol. 1997;31(1):15-22.

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Abstract PDF: To evaluate the relationships among the c-erbB-2 oncogene expression, DNA ploidy and other prognostic factors, an immunohistochemical study of the c-erbB-2 oncogene product and flow cytometric analysis of DNA ploidy were performed in paraffin sections of 42 cases of ovarian carcinomas. The results were as follows: 1) The positive reaction for c-erbB-2 oncogene product was observed mainly along the cytoplasmic membrane, and occasionally within the cytoplasm of the tumor cells. 2) Overall the positivity of c-erbB-2 oncogene expression was 45.2% of the ovarian carcinomas. By the histological types, the positivity was 35.7% in serous carcinoma, 80.0% in mucinous carcinoma, and 45.2% in endometrioid carcinoma; by the degree of differentiation, 57.1% in well differentiated carcinoma, 40.0% in moderately differentiated, and 27.3% in poorly differentiated; by the nuclear grading, 58.3% in grade I, 52.6% in grade II, and 18.2 % in grade III; and by the clinical staging, 57.1% in stage I, 42.8% in stage II, and 35.0% in stage III. The expression of the c-erbB-2 oncogene in the ovarian carcinomas was higher in the tumors of good differentiation, of the lower nuclear grade and of the lower clinical stage. 3) The incidence of DNA aneuploidy in the cases positive for the c-erbB-2 oncogene expression(47.3%) was higher than that in the negative cases(31.4%). From the above results, therefore, it is suggested that the c-erbB-2 oncogene may be involved in the early stage of ovarian carcinogenesis. Also suggested is that ovarian carcinomas positive for the c-erbB-2 oncogene in the early stages may have higher probability of having a DNA aneuploid cell line during the progress of the tumors.

Expression of bcl-2 Protein in Colorectal Adenoma and Adenocarcinoma and its Relationship with p53 and Apoptosis.: Ae Ree Kim, Seong Jin Cho, Nam Hee Won, Yang Seok Chae; Korean J Pathol. 1997;31(5):417-426.

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Abstract PDF: Either increased cellular proliferation or decreased death might result in an expansion of their numbers in the oncogenic process. Cellular apoptosis represents an autonomous suicide pathway that helps to restrict the cell number. However bcl-2 and mutant p53 inhibit programmed cell death. To determine whether the bcl-2 gene is activated during colorectal tumorigenesis and whether it has any relationship with p53 and apoptosis, we studied the expression of bcl-2 and p53 in the normal colonic mucosa, in the adenomatous polyps and in the adenocarcinomas using the immunohistochemical method. Also we evaluated the status of apoptosis using the in situ end labeling method. The bcl-2 immunoreactivity was restricted to the basal epithelial cells of all normal colonic mucosa and they were expressed in all adenomas and 86% of adenocarcinomas, especially in the superficial lesion of some tumors. Mutations of p53 were not found in the normal colonic mucosa, but they were present in dysplastic cells of adenomas (52%) and in cancer cells of the adenocarcinomas (47%). Apoptosis was confined to the tips of the normal colonic mucosa. It was more easily detected in the p53-positive adenomas than in the p53-negative adenomas (p=0.010). In the adenocarcinomas, the findings of apoptotic process are not related with p53 mutation (p=0.3) and bcl-2 expression (p=0.187). p53 and bcl-2 are probably one step of several apoptotic processes in the adenocarcinomas.

Evaluation of Prognostic Significance of AgNORs and PCNA during 9,10-dimethyl-1,2-benzantracene(DMBA)-induced Hamster Buccal Pouch Carcinogenesis.: Sam Pyo Hong, Myong Soon Song, Seong Doo Hong, Jae Il Lee, Chang Yun Lim; Korean J Pathol. 1998;32(5):337-345.

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Abstract: The purpose of this study is to evaluate the prognostic significance of argyrophilic nucleoalr organizer regions (AgNORs) and proliferating cell nuclear antigen (PCNA) by using DMBA hamster buccal pouch carcinogenesis which provides a good experimental model in reproducing steps from precancerous lesions to invasive squamous cell carcinomas. The buccal pouches of 50 Syrian hamsters were applied with 0.5% DMBA in mineral oil three times a week to reproduce various lesions from precancerous ones such as hyperkeratosis or epithelial dysplasia to invasive squamous cell carcinomas. Their sections were stained with H & E, and silver colloid, and processed immunohistochemically by being applied with monoclonal antibody to PCNA. The histopathologic examainations were done and the counts of AgNORs were evaluated. The PCNA labelling indices on each lesions were evaluated. The correlation between histopathological grades and counts of AgNORs or PCNA labelling indices were evaluated. The number of AgNORs was 2.22+/-0.22 in control group, 3.46+/-0.72 in carcinoma in situ (CIS), 3.78+/-0.63 in squamous cell carcinoma (SCC), respectively. AgNORs significantly increased in severe epithelial dysplasia, CIS, and SCC compared with normal tissue (P<0.05). The PCNA Labeling Index (LI) was 39.47+/-6.68% in control group, 79.61+/-4.14% in CIS, and 85.43+/-6.25% in SCC, respectively. PCNA LI also significantly increased in epithelial dysplasia, CIS, and SCC compared with normal tissue (P<0.05). The number of AgNORs, AgNOR area, and PCNA LI slightly increased in the advancing front than in the center of SCC, but, it was not statistically significant. It appeared that there were a good correlation between the number of AgNORs and PCNA LI (Pierson correlation coefficient : 0.649, P<0.001). These results suggested that the number of AgNORs and the PCNA LI could be useful markers for evaluating the risk of malignant transformation and prognosis of SCC. It was thought that the clinical usefulness of these markers should be verified by using human tissue specimens.

Expression of CDK 4, Connexin 32, and PCNA in N-diethylnitrosamine-Induced Lesions of Rat Liver.: Bang Hur, Hung Jun Kim; Korean J Pathol. 1999;33(5):309-318.

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Abstract PDF: Cellular altered foci (CAF), hyperplastic nodules (HN) including regenerating and adenomatous nodules, and hepatocellular carcinomas (HCC) were induced in Sprague-Dawley rat liver by prolonged administration of N-diethylnitrosamine (DEN, 200 ppm). Immunohistochemical expression of connexin 32 (Cx 32), cyclin-dependent kinase 4 (CDK 4), and proliferating cell nuclear antigen (PCNA) was assessed for the evaluation of preneoplastic potential of CAF. Regardless the duration of DEN administration, basophilic cell foci were the most frequently observed lesion in both CAF and cellular expanding hyperplastic nodules. Eosinophilic cell foci, however, were concomitantly increased with adenomatous nodules in later experimental groups. Cx 32 showed perimembranous spot-like expression. Its number was 7.25 2.10 per cell in normal hepatocytes. CAF and adenomatous nodules showed markedly decreased Cx 32 spots. Moreover, its reduction was more prominent in HCC. PCNA-labelled hepatocytes were scattered in the most CAF, showing no significant difference between each CAF. PCNA labelling index (LI) in adenomatous nodule and HCC was markedly increased. CDK 4 was localized in the cytoplasm and/or nucleus of hepatocytes. Eosinophilic cell foci revealed more nuclear expression of CDK 4 than other types of CAF, of which expression incidence was comparable to that of adenomatous nodule. Nuclear CDK 4 expression in HN and HCC was increased, although significant difference between regenerating nodule and adenomatous nodule was not seen. In conclusion, the incidence of CDK 4 was concomitantly increased with PCNA LI, however, reciprocally decreased with Cx 32 in accordance with the advance of DEN-induced HCC in rat. Phenotypically altered foci manifested as CAF are early valuable preneoplastic marker lesion for evaluation. In addition, basophilic cell foci can be considered a discernible marker of cellular expansion within nodules. However, eosinophilic cell foci might be an indeterminate marker for the advance of DEN-induced HCC in rat.

Immunohistochemical Analysis of Transforming Growth Factor (TGF)-beta1 and TGF-beta Receptor II and Quantitative Analysis of TGF-beta1 mRNA during Multistep Hepatocarcinogenesis Induced by Diethylnitrosamine in Sprague-Dawley Rats.: Mee Yon Cho, Ju Han Lee, Yong Koo Kang, Nam Hee Won; Korean J Pathol. 1999;33(11):1009-1023.

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Abstract PDF: Transforming growth factor (TGF)-beta1 plays an important role in hepatocarcinogenesis and has been described as a useful tumor marker and one of the poor prognostic indicators in patients with hepatocellular carcinoma (HCC). To investigate the role and cellular localization of TGF-beta1 during multistep hepatocarcinogenesis we performed a quantitative analysis of TGF-beta1 mRNA and immunohistochemical expression of TGF-beta1 and TGF-beta receptor II (TGF-betarII) in female Sprague-Dawley rats. The experimental groups included neoplastic lesions produced by Solt-Farber's protocol, regenerating liver after partial hepatectomy, and normal control. Quantitative change of TGF-beta1 mRNA was analysed by competitive reverse-transcription polymerase chain reaction (RT-PCR). TGF-beta1 protein and TGF-betarII expression were evaluated by immunohistochemical stain. The discrete tumor nodules were detected on 14th day and then increased in number and size. Three HCCs were induced on 8th or 9th month. RT-PCR demonstrated TGF-beta1 mRNA band in all examples of the normal and regenerating liver, nodules and HCCs. Competitive RT-PCR displayed higher TGF-beta1 mRNA in nodules, HCCs and regenerating liver than in normal controls. Hepatocytes from control and regenerating livers showed weak immunoreactivity for TGF-beta1. In contrast, the cytoplasm of hepatocytes of nodules in 7th, 8th and 9th month and HCCs were intensely stained for TGF-beta1. Some sinusoidal cells showed immunoreactivity for TGF-beta1 in all experimental groups. In early phase of carcinogenesis, the cytoplasm of hepatocytes in liver of 12h, 1d and 3d showed transiently increased immunoreactivity for TGF-beta1 and The immunoreactivity decreased thereafter. TGF-beta1 mRNA was also detected in the neoplastic hepatocytes by in-situ hybridization. Although TGF-betarII expression was correlated with TGF-beta1 immunoreactivity during early phase of carcinogenesis, hepatocytes in most nodules in 7th, 8th, 9th month and carcinomas showed decreased or little immunoreactivity for TGF-betarII. Based on the above results, it is concluded that TGF-beta1 expression increases not only in precancerous nodules but also in HCCs and its increase seems to be correlated with decrease or loss of TGF-betarII expression although its mechanism remains unclear. Hepatocytes may be a major cellular source of TGF-beta1 during hepatocarcinogenesis.

Aberrant Crypt Foci: Histopathologic Classification and Profiles of Mucin Secretion.: Aeree Kim, Jong Sang Choi, Won Jun Choi, Hong Young Moon; Korean J Pathol. 2000;34(1):50-55.

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Abstract PDF: Aberrant crypt foci (ACF) are grossly unidentifiable lesions of the colon and visible only with low-power microscopic examinations after methylene blue stain. To establish the role of ACF in colorectal carcinogenesis, we evaluated the distribution, frequency, histopathological classification, and patterns of mucin secretion of ACF in the colon. A total of 142 aberrant crypt foci were found in 41 colectomy specimen for adenocarcinoma (36 cases) and benign diseases of colon (5 cases). Ten of 142 ACFs were in the ascending and transverse colon, 39 in the descending and sigmoid colon, and 93 in the rectum. The mean number of ACFs in the rectum (0.13 0.11/cm2) was higher than in the ascending and transverse colons (0.019 0.018/ cm2) and descending and sigmoid colon (0.10 0.14/cm2). ACFs were found only in cancer patients. One hundred and twenty ACFs among 142 ACFs identified by topology, were identified on histological examination. We classified ACFs into simple (48.3%), hyperplastic (42.5%), and dysplastic (9.2%) types. All ACFs were infiltrated by the lymphocytes in the stroma and 18 of these accompanied the lymphoid follicles. ACFs have variable histopathologic features and mucin profiles. Some variants of ACFs are at the early stage of the spectrum between benign and malignant.

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.

Expression of Glutathione S-Transferase, E-Cadherin, and Catenins during N,N-Diethylnitrosamine-Induced Hepatocarcinogenesis in Rat Liver.: Hyoung Joong Kim, Yon Sik Yoo, Tae Jin Lee, Mi Kyung Kim, Eon Sub Park, Jae Hyung Yoo; Korean J Pathol. 2000;34(12):982-993.

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Abstract PDF: N,N-Diethylnitrosamine (DEN) has been proved to have carcinogenic potential in the initiation or promotion stage and the transformed cells proliferate to form preneoplastic nodules which are positive for placental form of glutathione S-transferase (GST-P). E-Cadherin, a member of the cadherin family, is expressed in epithelial cells. To evaluate the role of adhesion molecules (E-Cadherin, alpha-catenin, and beta-catenin), which have not been well understood in carcinogenesis, we investigated the changes of E-cadherin, alpha-Catenin and beta-Catenins by immunohistochemistry and immunoblotting in DEN-induced hepatocarcinogenesis of rat liver. In addition, the sequential analysis of histopathology and the expression of GST-P were also examined. Immunoreactive areas for GST-P were gradually increased from early period of carcinogenesis and strong GST-P positive foci were noted in various lesions, especially in the clear cell and eosinophilic cell nodules. Immunohistochemically, the E-Cadherin expression was increased in DEN-treated preneoplastic nodules in 4 and 10 weeks and hepatocellular carcinomas displayed relatively reduced expression compared with the hyperplastic nodules. But alpha- and beta-catenin expression was increased in hyperplastic nodules and hepatocellular carcinomas. Immunoblotting studies revealed that the level of alpha-catenin (cytosol and membranous fraction) was overexpressed in hyperplastic nodules as well as hepatocellular carcinomas, which showed markedly increased expression. The membranous fraction of beta-catenin was markedly increased in 10 weeks of DEN treatment and slightly reduced in hepatocellular carcinomas. These findings suggest that during DEN-induced hepatocarcinogenesis, the clear cell and eosinophilic cell nodules expressing GST-P in their cytoplasm are early transformed cell nodules. The altered expression of E-Cadherin and catenins is closely related with tumor propagation. Loss or reduced expression of E-cadherin may play a role in the progression of late hyperplastic nodule to hepatocellular carcinoma in DEN-induced rat hepato carcinogenesis.

Expression of Survivin, HSP90, Bcl-2 and Bax Proteins in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced Rat Bladder Carcinogenesis.: Sang Dae Lee, Sung Woong Park, Soon Auck Hong, Gui Young Kwon, Tae Jin Lee; Korean J Pathol. 2006;40(5):333-338.

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Abstract PDF: BACKGROUND
Survivin belongs to the inhibitor of apoptosis family, and it has recently been found to be expressed in most solid tumors. Therefore, its expression is suggested to have prognostic significance. However, no data are available concerning the significance of survivin for the carcinogenesis of bladder cancer.
METHODS
In order to induce urothelial tumor in the rat urinary bladder, 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was administered to male Sprague-Dawley rats for 30 weeks. We used immunohistochemistry to investigate the expressions of survivin, HSP90, Bcl-2 and Bax in rat bladder carcinogenesis.
RESULTS
Urothelial cell hyperplasia, papilloma, non-invasive urothelial carcinoma and invasive urothelial carcinoma appeared at 5, 10, 20 and 30 weeks, respectively. The expressions of survivin and HSP90 increased sequentially from normal mucosa, hyperplasia, papilloma, non-invasive urothelial carcinoma to invasive urothelial carcinoma. The expressions of Bcl-2 and Bax did not increase, however the number of cases with more than 1 of Bcl-2/Bax expression ratio increased sequentially during the progression of urothelial lesion. The expression of survivin showed a statistically significant correlation with the expression of HSP90 and the Bcl-2/Bax expression ratio.
CONCLUSIONS
Our findings suggest that survivin may be involved in the carcinogenesis of rat bladder and its expression is correlated with the expression of HSP90 and the Bcl-2/Bax expression ratio.

Expression of Cyclins (D1, A, E, and B1) in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced Rat Bladder Carcinogenesis.: Gui Young Kwon, Eon Sub Park, Sung Geun Bong, Tae Jin Lee, Mi Kyung Kim, Jae Hyung Yoo, Kye Yong Song; Korean J Pathol. 2003;37(4):255-262.

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Abstract PDF: BACKGROUND
Cell cycle deregulation plays a major role in chemical multistage carcinogenesis.Therefore, the evaluation of cell cycle proteins is important.
METHODS
In order to induce carcinogenesis in the rat urinary bladder, 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)was administered to male Sprague-Dawley rats for 30 weeks. Expressions of cyclin D1, A, E, and B1 were examined by immunohistochemical stainings.
RESULTS
Urothelial cell hyperplasia appeared at 5 weeks, followed by papilloma at 10 weeks. Superficial carcinoma was observed at 20 weeks, and invasive carcinoma developed in 40% (4/10) of the rats at 30 weeks. Expressions of cyclin D1 and A increased sequentially from normal mucosa throughhyperplasia, papilloma, and carcinoma (p<0.01). Expressions of cyclin D1, B1 and cyclin Ewere higher in invasive carcinomas than in superficial carcinomas (p<0.01). In contrast, therewas no significant difference in the expression of cyclin B1 between hyperplasia, papillomaand superficial carcinoma.
CONCLUSIONS
The present results indicate the important roles of cyclin D1 and A in the development of BBN-induced urothelial carcinoma of rats. Aberrantexpression of cyclin B1 and E may contribute to the progression from superficial to invasivebladder cancer rather than tumorigenesis.

The Effect of Dehydroepiandrosterone on Inhibition of Carcinogenesis and Induction of Apoptosis in Murine Hepatoma Model.: Kye Yong Song, Eun Sup Park, Jee young Choi, Sang Chul Park; Korean J Pathol. 1995;29(1):24-32.

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Abstract PDF: Tumor suppressive effect of dehydroepiandrosterone (DHEA) on the experimentally induced hepatocellular carcinoma was investigated, especially focusing on glutatione transferase and transglutaminase with aptosis in the carcinogenesis. The chemical hepatocarcinogenic procedure of Solt-Farber method was used on Sprague-Dawley rats. Experimental groups were divided into AA group treated by the standard Solt-Farber regimen of diethylnitrosamine (DEN) and 2-acetamidofluorene (AAF) and AD group treated with DHEA simultaneously with AAF and the AAD group treated by DHEA after treatment with AAF. Each group was divided by time sequence further into four subgroups, GI (8wk), G2 (16wk), G3 (28wk), and G4 (36wk). For neoplastic lesion, the immuno histochemical study with anti GSTP antibody was carried out, while the activity and expression of TGase was compared at the same time. The results were summarized as follows; GST-P positive foci detected in AD groups were significantly more suppressed by DHEA treatment than AA groups (P<0.05). AD groups. AD group showed higher activities of TGase than AA groups (P<0.05), which was confirmed by Western and Northern blot analysis. But the number of apoptotic bodies was not correlated with activity and expression of TGase in the nodule. These results suggest that the suppressive effect of DHEA on the murine hepatocellular carcinogenesis might be operating on the promotion process of carcinogenesis rather than regression process of transformed hyperplastic nodules.

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.

Short-term Effect of Iron on the Hyperplastic Lesions of Chemical Hepatocarcinogenesis.: Young Nyun Park, Woo Hee Jung, Soon Hee Jung, Chan Il Park; Korean J Pathol. 1994;28(6):569-583.

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Abstract PDF: This study was undertaken to elucidate the short-term effect of iron on the hyperplastic lesions of experimental hepatocarcinogenesis. The Solt-Farber's resistant hepatocyte model was chosen for the experiment, and Sprague-Dawley rats wee divided into six groups: normal control, iron-rich diet administration with or without hydroxyquinoline. The iron content, microscopic changes, bromodeoxyuridine(BrdU) labelling index and the DNA polidy were studied. In the carcinogen administered group, oval cell proliferation and consecutive hyperplastic lesions of hepatocyte developed regardless of iron administration. The hepatic iron content was increased rimarkably by iron administration, but gradually decreased as the hyperplastic lesions developed in carcinogen administered groups. Although the administration of iron without carcinogen induced hepatic accumulation of stainable iron, the hyperplastic lesions appeared to be lack of it. BrdU labelling indices of the oval cells and the hyperplastic lesions of hepatocyte were very high and were not significantly altered by iron administration. Most liver cells had diploid or tetraploid DNA content, but there was an increase of diploidy as the development of hyperplastic lesions regardless of iron administration. The results indicate that the chemical carcinogen-induced hyperplastic lesions of hepatocyte do not accumulate iron, and that short-term iron administration does not affect the development of hyperplastic lesions and their proliferative activity and DNA ploidy.

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