Journal of Pathology and Translational Medicine

Original Articles

Expression Patterns of Bcl-2 and PCNA in Cervical Intraepithelial Neoplasia.: Mee Sook Roh, Gi Yeung Huh, Sook Hee Hong; Korean J Pathol. 1995;29(6):703-713.

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Abstract PDF: Immunohistochemical stains for bcl-2 oncoprotein and PCNA and examination of the mitosis level were perfon-ned in 76 cases of cervical intraepithelial neoplasia (CIN). We studied the expression pattern of bcl-2 protein according to histologic grades and the function of bcl-2 oncogene associated with cellular proliferation by comparing with PCNA expression and the mitosis level. The results were as follows: 1) Of 76 cervical intraepithelial neoplasias, 23 (30.3%) were CIN I, 23 (30.3%) were CIN II, and 30 (39.4%) were CIN III. 2) Of 23 CIN I cases, grade 0 and 1 mitosis level were seen in 20 (87.0%), PCNA in 16 (69.6%), and bcl-2 in 19 (82.6%) cases, respectively, which indicates that CIN I lesions have a low cellular proliferative activity. 3) Of 30 CIN III cases, grade 2 and 3 mitosis level were noted in 28 (93.3%), PCNA in 25 (83.3%) and bcl-2 in 19 (63.3%) cases, respectively, which indicates that CIN III lesions have a high cellular proliferative activity. The results suggest that progressive increase of dysfunctional proliferative activity and abnormal decrease of cell death result in increased number of neoplastic cells according to CIN grade. Also the expression rate of bcl-2, PCNA and mitosis level were significantly different between CIN I and 111, which suggest that they might be good parameters for classifying CIN into low and high grade and for prediction of the biologic behavior of the CIN lesion.

The Studies of bcl-2 Oncoprotein and Epstein-Barr Virus Expression in Malignant Lymphomas: Immunohistochemical and in situ hybridization analysis on 66 cases.: Hye Jae Cho, Yeon Mee Kim, Hyun Ju Yoo, Jong Eun Joo; Korean J Pathol. 1996;30(2):121-131.

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Abstract PDF: Bcl-2 oncoprotein is being localized to mitochondria and interfering with programmed cell death (apoptosis) independent of promoting cell division in the lymphoid and nonlymphoid cells. The bcl-2 oncoprotein expression has been reported in follicular lymphomas as well as in diffuse non-Hodgkin's lymphoma, leukemia and a variable propotion of Hodgkin's lymphoma cases. Recent evidence suggests that some lymphomas protected from apoptosis is conferred through expression of Epstein-Barr virus(EBV) latent membrane protein which turn to cause upregulation of bcl-2. To define the role of the bcl-2 oncoprotein and EBV in lymphoid malignancy, we tried immunohistochemical studies with anti-bcl-2 antibody and In situ hybridization (ISH) with EBV-encoded small nuclear RNAs(EBER) in the paraffin embedded sections of 46 non-Hodgkin's lymphoma (NHL) cases and 20 Hodgkin's lymphoma (HL) cases. Bcl-2 oncoprotein expression was found in 37 of 46 cases (80%) of NHL with relatively strong cytoplasmic staining, and in 14 of 20 cases (70%) of HL with weak cytoplasmic staining in limited small numbers of RS, Hodgkin and lacunar cells. The widespread presence of bcl-2 oncogene in many different types of both NHL and HL supports that the extended cell survival through overexpression of bcl-2 gene protein may be a growth advantage of neoplastic lymphoid cells. In the ISH analysis for EBV, the presence of EBV was detected in 17 of 20 cases (85%) of HL, compared to 6 of 44 cases(13.6%) of NHL. It appears to be no direct correlation between overexpression of bcl-2 oncoprotein by neoplastic lymphoid cells and the presence of EBV in NHL but it seems to be a definite association between EBV and HL.

c-erbB-2 Oncoprotein Expression in Ductal Carcinoma in situ and Paget's Disease of the Breast.: Jung Yeon Kim, Kyung Ja Cho, Seung Sook Lee, Shin Kwang Khang, Nam Sun Paik; Korean J Pathol. 1996;30(11):972-980.

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Abstract PDF: A clinico-pathologic study with an immunohistochemical examination for c-erbB-2 expression in 54 cases of ductal carcinoma in situ and 16 cases of Paget's disease of the breast was performed. c-erbB-2 oncoprotein overexpression was observed in 45% (24/54) and 88% (14/16) of ductal carcinoma in situ and Paget's disease, respectively. The overexpression of c-erbB-2 oncoprotein was significantly correlated with the nuclear grade of tumors and inversely with the status of the estrogen receptor. c-erbB-2 was positive in 4 out of 5 patients with metastasis to axillary lymph nodes and 3 out of 4 patients who died of the disease. Prognostic significance of c-erbB-2 oncoprotein in ductal carcinoma in situ was highly suggested. The expression of c-erbB-2 oncoprotein in Paget's disease was well correlated with coexisting infiltrating or in situ ductal carcinoma. The high positive rate of c-erbB-2 oncoprotein in ductal carcinoma with Paget's disease could be understood with a recent hypothesis that c-erbB-2 oncoprotein is involved in promotion of cell motility and the spread of carcinoma cells.

Polymerase Chain Reaction Analysis of Human Papillomavirus in Esophageal Squamous Cell Carcinoma with its Correlation to p53 mutation.: Wan Seop Kim, Eun Kyung Hong, In Kyu Kim, Moon Hyang Park, Jung Dal Lee; Korean J Pathol. 1996;30(11):1018-1026.

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Abstract PDF: HPV infection has been implicated strongly in the pathogenesis of human squamous cell carcinoma(SCC). We analysed a series of 28 surgically removed, invasive squamous cell carcinoma of the esophagus by polymerase chain reaction to detect HPV DNA using consensus primers and 8 type-specific primers of HPV (6, 11, 16, 18, 31, 33, 35, 51). HPV 6, 31, 35 or 51 DNA were detected in 20 out of 28 cases (71.4%) of the esophageal SCCs. HPV 51 was the most frequently detected type, occuring in 13 out of 28 cases (46.4%). p53 immunohistochemical staining was also performed to demonstrate any relationship to HPV DNA positivity. It showed positivity in 16 out of 28(57.1%) esophageal SCCs, and HPV DNA and p53 positivity were concurrently detected in 11 out of 28 cases of SCCs. There was no significant inverse relation between HPV DNA positivity and p53 expression(p>0.05). Our results supported HPV involvement in esophageal squamous cell carcinoma, and suggested there may be another pathway not related to the p53-binding pathway in the carcinogenesis of esophageal SCCs by HPV.

Establishment and Characterization of a Small Cell Lung Cancer Cell Line(JePa-1).: Mi Ja Lee, Ho Jong Jeon, Jong Hoon Chung; Korean J Pathol. 1997;31(8):695-710.

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Abstract PDF: Lung cancer is the most common malignant tumor worldwide and its incidence continues to rise each year. Recent development of molecular biologic method has led to advances in determining the etiologic factors of lung cancer and the establishment of cell lines has provided a lot of information on the through chemosensitivity, radiation biology studies, cytogenetics, and molecular biologic studies, which permits improved treatment for lung cancer. We established a small cell lung cancer cell line, designated JePa-1, obtained from malignant pericardial effusion of small cell lung cancer patient and characterized its morphologic and molecular biologic features. the JePa-1 cell line grew relatively slowly (doubling time 45hrs) as very loosely adherent floating aggregates growing in small clumps with distinct cell outlines and intertwined cords. Also JePa-1 cell line secreted antidiuretic hormones. Electronmicroscopic examination revealed that JePa-1 cell line and xenografts contained electron dense core granules, characteristic of being of neuroendocrine origin. To investigate the tumorigenic capacity, the JePa-1 cell line was injected into SCID and nude mice. Tumors taken from xenografts were observed in 3 out of 4 of the SCID mice and 2 out of 4 of the nude mice. The histologic characteristics of the xenografts were similar to those of the cell line and the original cytologic finding of the pericardial fluid, suggesting small cell carcinoma. The results of immunohistochemical markers showed reactivity for Rb protein, c-myc, TGF-alpha, TGF-beta , EGFR, keratin, NSE, chromogranin, and EMA. The DNA ploidy and the index of the JePa-1 cells was tetraploid and 2.13, respectively. The positive rate for the Rb, c-myc and K-ras proteins of the JePa-1 cell line were 98.9%, 99.3%, and 99.7% respectively as determined by flow cytometry. Cytogenetic analysis using the G-banding technique showed 65 chromosomes with various numerical and structural abnormalities. On examination of the expression of TGF-alpha, TGF-beta , and EGFR by PCR, only the EGFR was positive Through the establishment of JePa-1 cell line, we report in this paper the characterization of a small cell lung cancer such as morphologic and immunocytochemical features, growth characteristics in culture, hormone production, expression of oncoprotein and several growth factors, tumorigenicity, chromosomal abnormalities, and DNA ploidy and index. The JePa-1 cell line will be valuable in vitro studies for the etiology, treatment and the prognostic factors in small cell lung cancer.

Morphohistometric Investigation and bcl-2 Expression in the Placenta of Chromosomally Abnormal Pregnancy.: Joung ho Han, Kyu Rae Kim, Yeon Lim Suh, Mi Kyung Kim, Young Hyeh Ko, Dae Shick Kim, Howe Jung Ree; Korean J Pathol. 1999;33(5):353-360.

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Abstract PDF: To evaluate the significance of placental histology, a collaborative histological and cytogenetic study was performed on the products of 88 spontaneous abortions, and subsequently bcl-2 immunostaining was performed on 62 cases. The morphometric parameters included were DCIRCLE, FORMSHAPE, CPRATIO, and the expression of bcl-2 immunostainig was graded in four categories (I to IV). The results were as follows: 1) 40% (n=35) were chromosomally abnormal: trisomies predominated (57%, n=20) and was followed by triploidy (14%, n=5), double trisomy (6%, n=2), monosomy X (6%, n=2), inversion (9) (6%, n=2). 2) mean of DCIRCLE in chromosomally abnormal pregnancy was 40 micrometer larger than that in chromosomally normal pregnancy (p=0.012, one side t-test), while no difference was found in FORMSHAPE and CPRATIO between chromosomally abnormal and normal pregnancy. 3) bcl-2 expression was found in syncytiotrophoblast and cytotrophoblast. bcl-2 expression was weaker in chromosomally abnormal pregnancy with intensity I and II of 59% than chromosomally normal pregnancy with intensity I and II of 24%. 4) In comparison bcl-2 expression with DCIRCLE, in chromosomally normal abortion one (10%) in I & II and one (3%) in III & IV showed large DCIRCLE (above 360 micrometer), while 11 (85%) in I & II and 3 (33%) in III & IV in chromosomally abnormal pregnancy. It would mean that bcl-2 protein is necessary in preservation of pregnancy and placental morphology. Abnormal villous diameter and weak bcl-2 expression may be suggestive of chromosomal anomaly. Besides other histologic parameters, application of bcl-2 immunostaining and morphometric analysis probably give more sensitive and specific results in identifying chromosomally abnormal abortion.

A Study of the Correlation between Expression of c-erbB-2 Oncoprotein and Various Clinicopathological Prognostic Factors in Breast Carcinoma.: Jong Hee Nam, Kyung Soo Kim, Chang Soo Park, Sang Woo Juhng; Korean J Pathol. 1995;29(2):136-144.

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Abstract PDF: Immunohistochemical study for c-erbB-2 oncoprotein was performed on paraffin sections of 76 primary breast carcinomas to determine the relationship between expression of c-erbB-2 and various clinicopathological prognostic indicators, including the expression of epidermal growth factor receptor (EGFR). Positive reaction for c-erbB-2 oncoprotein revealed an intense red granular staining predominantly located at the tumor cell membrane, with some cells exhibiting a weak cytoplasmic staining as well. The epithelial cells of the normal lobule and duct showed a negative reaction. Positive reaction for EGFR revealed a granular staining in the cytoplasm and the cell membrane of the tumor cells. Some tumors showed a positive EGFR staining in the epithelial cells of normal duct and lobule. Twenty six of 76 cases (34.2%) of primary breast carcinomas revealed a positive reaction for c-erbB-2 oncoprotein, and 28 cases (36.8%) were positive for EGFR. Expression of c-erbB-2 oncoprotein and EGFR was evident in 37.7% and 40.6% of 69 classic invasive ductal carcinomas, respectively. None of the other histological types showed a positive reaction. Expression of c-erbB-2 oncoprotein was strongly associated with tumor size(p=0.0015), histologic grade(.p=0.0175), vascular invasion(p=0.0043), and lymph node metastasis(p=0.0024), but not with age at diagnosis(p=0.1836). No significant association was found between expression of c-erbB-2 oncoprotein and EGFR. Co-expression of c-erbB-2 oncoprotein and EGFR was also strongly associated with tumor size (p=0.0029). These results suggest that c-erbB-2 oncoprotein is biologically distinct from EGFR, and may be used as a prognostic indicator of breast carcinoma due to its strong association with various clinicopathological prognostic factors.

Assessment of DNA Ploidy, Estrogen and Progesterone Recetor Status and Her-2/neu Oneoprotein Expression in Breast Carcinoma by Image Analysis.: Ae Ree Kim, In Sun Kim, Kap No Lee; Korean J Pathol. 1994;28(3):246-259.

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Abstract: In 41 cases of breast cancers, the aneuploidy measured by Image Analyzer was compared with that of flow cytometric analysis, and estrogen and progesterone receptor(ER/PR) and Her-2/neu oncoprotein were immunohistochemically stained and measured by Image Analyzer. In ER/PR, the positive nuclear area(PNA, %) was measured, and in Her-2/neu, the content of oncoprotein was expressed as pg/cell. To assess the usefulness of these parameters as a prognostic factor, the author evaluated the results in relation with tumor size, nuclear grade and lymph node metastasis. The obtained results are summarized as follows: 1) The detection rate (90%) of aneuploidy by image analysis was higher than that (70%) of flow cytometric analysis. The concordance rate of both method was 80%. 2) The positivity of ER was 73% and PR was 34%, and the high PNA of ER and PR was related with high nuclear grade. There was an inverse correlation of the ER PNA with tumor size and PR PNA with negative lymph node. 3) Her-2/neu oncoprotein overexpression was found in only 2 cases and another two showed borderline overexpression. All four cases had DNA tetraploidy. From the above results, it was concluded that the image analyzer could be used in DNA analysis and in quantitation of immunostained ER/PR and Her-2/neu oncoprotein, providing the important information in the management of the breast cancer patients.

c-erbB-2 Oncoprotein Overexpression in Breast Cancer.: Tae Sook Hwang, Kyung Ja Cho, Young Bae Kim, Joo Ryung Huh, Ja June Jang; Korean J Pathol. 1994;28(1):1-7.

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Abstract PDF: c-erbB-2 oncogene is a normal cellular proto-oncogene coding transmembrane glycoprotein structurally similar to the epidermal growth factor receptor. Amplification of this oncogene in a variety of human adenocarcinomas has been reported and is particularly well documented in breast carcinoma. It has been suggested that amplification of this oncogene is indicative of poor prognosis and is valuable only second to the lymph node status. Using immunohistochemical staining for the c-erbB-2 protein, overexpression of this protein was analysed in 228 primary breast cancer specimens and the frequency of overexpression and the relationship between overexpression and the other established prognostic variables are evaluated. Ninty three cases out of 228 cases(40.8%) show postive oncoprotein overexpression and using the chi-squared test for a trend, a significant correlation was found between c-erbB-2 protein staining and the histological grade, lymph node status, and estrogen receptor status(P<0.05). No significant association was found between staining and the patient's age and tumor size. Most of the tumors with histological types known to have good prognosis showed negative expression. Above findings strongly suggest that expression of c-erbB-2 oncogene is another independent indicator of poor prognosis in breast carcinoma.

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