Journal of Pathology and Translational Medicine

Original Articles

The Correlation between the Proliferative Activity in Biopsied Specimen of Gastric Adenocarcinoma and the Pathologic Findings of Resected Specimen.: Hye Sun Kim, Jae Bok Lee, Se Min Kim, Jong Sang Choi, Han Kyeom Kim; Korean J Pathol. 1997;31(3):211-218.

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Abstract PDF: Studies on the correlation between proliferative activity of biopsied specimen and pathologic findings of resected specimen have been carried out to find the prognostic factors. To estimate the proliferative activity, 100 cases of biopsied specimen of gastric adenocarcinoma were tested for the PCNA (proliferating cell nuclear antigen) and the AgNOR (argyrophilic nucleolar organizer region) by the immunohistochemical and histochemical stainings, respectively. The resected tumors classified by histologic type, differentiation, depth of invasion, and nodal metastatic status were followed by cell cycle analysis using flow cytometry. The PCNA LI (labelling index) were higher in well or moderately differentiated tumors (P<0.01) than the poorly differentiated ones and the aneuploid tumors (P<0.05) more than in diploid ones. However, there were no correlations among histologic types, depth of invasion, nodal metastatic status and PCNA LI. The AgNOR counts were higher in advanced tumor than in the EGC (early gastric cancer) (P<0.01). In cases with nodal metastasis, most of them showed the AgNOR counts higher than those without nodal metastasis. There were no correlations between the AgNOR counts and the DNA ploidy, histologic type, or differentiation. High PCNA LI and high AgNOR counts were shown in cases with advanced tumors (P=0.000) and nodal metastasis (P<0.05). No correlation was shown with the histologic type or differentiation. The results show that proliferative activity of the biopsied specimen of gastric adenocarcinoma is correlated with the differentiation and the invasion depth of resected specimen. Especially, better correlation is obtained by analyzing both the PCNA LI and the AgNOR counts than by analyzing each.

Flow Cytometric DNA Analysis of Gastrointestinal Stromal Tumors .: Mee Yon Cho, Soon Won Hong, Soon Hee Jung, Hogeun Kim, Chanil Park; Korean J Pathol. 1997;31(7):608-616.

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Abstract PDF: To evaluate the correlation between the histologic grade and DNA ploidy or proliferation index/S phase fraction (SPF) of gastrointestinal stromal tumors, we performed the DNA analysis using the flow cytometry. Paraffin embedded tissue samples of 57 gastrointestinal stromal tumors were used. The sites of the tumors were: stomach (28), small intestine (23), and large intestine(6). DNA index, proliferative index, and SPF by the flow cytomery were compared with histologic grade. The histologic grade of the gastric tumors were benign (12), borderline (10), and malignant (6). Those of the small intestinal timors were benign (2), borderline (13), and malignant(8). The large intestine were borderline (2), and malignant (4). In stomach, aneuploidy was found in 25.0% of benign, 40.0% of borderline, and 100% of malignant. And there was statistically significant correlation between the histologic grade and ploidy (p < 0.05). By contrast, small and large intestinal tumors showed more frequent aneuploidy in benign than in malignant. The proliferative index was correlated with the histologic grade in gastric tumors (p<0.05), but the SPF was not. In conclusion, the ploidy and proliferative index of gastric tumors are closely correlated to the histologic grade. However, aneuploidy in tumors of the small and large intestine were difficult to predict the malignancy.

Characteristics of the Immortalized Human B-cells by Epstein-Barr Virus.: Ho Jong Jeon, Bong Nam Choi, Yoon Kyeong Oh; Korean J Pathol. 1997;31(9):832-846.

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Abstract PDF: Human lymphoblastoid B-cell lines immortalized by Epstein-Barr virus (EBV) were established from peripheral blood of patients with acute myeloblastic and chronic lymphocytic leukemia and chronic fatigue syndrome. The sera of patients with acute myeloblastic and chronic lymphocytic leukemia did not show antibodies to Epstein-Barr viral capsid antigen (VCA), but serum of a patient with chronic fatigue syndrome disclosed antibodies to VCA (IgG, IgM), and EBNA was demonstrated in peripheral blood mononuclear cells by polymerase chain reaction. The established cell lines were mature B-cell phenotypes with polyclonal proliferation in early passage and no evidence for commitment to other lineages. The immortalized cells by EBV were designated as CSUP-1 and CSUP-2 (from acute myeloblastic leukemia, FAB classification M2 and M1), CSUP-3 (from chronic lymphocytic leukemia) and CSUP-4 (from a patient with chronic fatigue syndrome). The CSUP-1, 2, 3, and 4 grew in suspension forming clumps with a doubling time of 38 to 49 hours. Colony formation was not recognized in plate. By light and electron microscopic examination, the immortalized cells showed features of lymphoblastoid to plasmacytoid lymphocytes, and multinucleated giant cells. The lymphoblastoid cells showed scanty cytoplasm with poorly developed organelles. Immunophenotypic analyses of CUSP-1, 2, 3, and 4 with monoclonal antibodies by flow cytometry showed B-cell phenotype with polyclonal proliferation in early passage. Epstein-Barr virus nuclear antigen was confirmed in the extracted DNAs from immortalized cells by polymerase chain reaction. DNA analysis showed a normodiploid stemline with a DNA index of 1.12. The established cells were strongly reactive for CD10, CD30 (Ki-1) in early passage, and bcl-2 and c-myc onco-protein in early and late passage. Karyotypic analysis of CSUP-1, 2, 3 and 4 showed 46, XY or 46, XX. No tumorigenesis in heterotransplanted SCID mouse was recognized. This immortalized cells by EBV should be a valuable cell lines to study the pathogenesis of EBV-related malignant lymphoma.

Correlation of Heregulin mRNA and Her-2/neu Protein Expression with Node Metastasis and DNA Ploidy Pattern in Human Invasive Breast Carcinoma.: Yee Jeong Kim, Woo Hee Jung, Hyde Lee, Sung Kong Lee, In Gul Moon, Kwang Gil Lee; Korean J Pathol. 1998;32(8):563-573.

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Abstract: The Her-2/neu protooncogene encodes a transmembrane tyrosine kinase that is structurally homologous to the receptor for epidermal growth factor. Its amplification and overexpression are associated with poor prognosis in breast cancer patients. Neu differentiation factor is a ligand for Her-2/neu protooncogene and was detected in ras-transformed rat fibroblasts. Heregulin (human homologue of neu differentiation factor) is a 44-kilodalton glycoprotein that stimulates tyrosine phosphorylation and induces growth arrest or stimulation and differentiation in human breast cancer cell lines. In this study we examined the expression of heregulin mRNA by nested reverse transcription (RT) PCR with fresh tissue, Her-2/neu protein, ICAM-1 and steroid receptors by immunohistochemistry, and DNA ploidy pattern by flow cytometry with paraffin-embedded tissue in invasive breast carcinoma. We compared the data with nodal status, lymphovascular invasion, steroid receptor status and DNA ploidy pattern. For RT-PCR to heregulin mRNA, 38 cases of fresh breast cancer tissue were obtained. Total 68 cases of invasive breast carcinoma tissue were fixed in formalin, which were used for routine histology, immunohistochemistry and flow cytometry. The results are as follows; 1) Heregulin mRNA was expressed in 86.1% of patients with invasive breast carcinoma and 100% of patients with benign breast lesion using nested RT-PCR analysis. 2) Her-2/neu protein was overexpressed in 50.0% of tumors using immunohistochemistry. The expression of Her-2/neu protein was significantly correlated with high counts of lymph nodes with metastasis (p<0.05), and high nuclear grade (p<0.05). 3) Her-2/neu protein overexpression was significantly correlated with a high DNA index(p<0.05). All of the tumors showing Her-2/neu protein overexpression and no heregulin mRNA expression revealed near tetraploid DNA content. However, both Her-2/neu overexpression and heregulin mRNA expressing tumors revealed near tetraploidy in 38.9% and diploidy in 50.0%. Based on these results, heregulin mRNA expression rate was 86.1% in human invasive breast carcinoma. Her-2/neu protein overexpression is associated with high positive lymph node number and DNA index. Statistically significant reverse correlation with lymph node metastasis is not present.

Flow Cytometric DNA Content Analysis in Breast Cancer Comparison study of fresh and paraffin-embedded tissues.: Jin Ye Yoo, Hye Jae Cho; Korean J Pathol. 1998;32(11):993-999.

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Abstract: DNA content of 25 cases of breast carcinoma was analyzed by flow cytometry in both fresh and formalin-fixed, paraffin-embedded tissue. Aneuploidy in fresh tissue and paraffin-embedded tissues was 72% and 32%, respectively. There was a 52% agreement in analysis of DNA ploidy between fresh and paraffin-embedded tissues. Most of the discrepancies resulted from loss of aneuploid peaks on the histograms of paraffin-embedded tissue. Mean S-phase fraction was slightly higher in a paraffin-embedded tissue than that in the fresh tissue; 19.2 9.1% versus 16.1 8.8% and there was no significant correlation between the S-phase fractions. In statistical analysis, the histologic and nuclear grades were not correlated with ploidy or mean S-phase fraction. Therefore it is strongly recommended to use the fresh tissue in flow cytometric DNA content analysis of breast cancer.

DNA Ploidy Analysis as a Prognostic Indicator in Phyllodes Tumor of the Breast.: Hee Jung Kim, Jae Ho Han, Woo Hee Jung, Hy De Lee; Korean J Pathol. 1999;33(7):507-516.

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Abstract PDF: DNA ploidy analysis using flow cytometry was performed on sixty six cases of phyllodes tumor of the breast including benign, low grade and high grade malignant phyllodes tumor. The rate of aneuploidy was 41.2% in high grade malignant phyllodes tumor and 4.8% in benign phyllodes tumor. No aneuploidy was noted in low grade malignant phyllodes tumor. The recurrence rate according to DNA ploidy pattern revealed 16.7% of aneuploidy and 7.7% of diploidy. In the aneuploid cases, the DNA index of high grade malignant phyllodes tumor was higher than benign phyllodes tumor. Morever, in diploid cases, %SG2M were significantly higher in high grade malignant phyllodes tumor. Therefore, we conclude that DNA ploidy analysis as well as histologic characteristics such as cellularity, pleomorphism of stromal cells and mitoses is useful parameters in the diagnosis, recurrence and prognostic predictors of phyllodes tumor.

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.

Diagnostic Value of Flow Cytometric DNA Analysis in the Evaluation of Effusions .: Ji Shin Lee, Sang Woo Juhng; Korean J Cytopathol. 1997;8(1):20-26.

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Abstract PDF: The specificity of cytologic examination in effusions is high but the sensitivity is low. Therefore, various ancillary methods for the detection of malignant cells in effusions have been proposed. The presence of an aneuploid cell population is generally considered diagnostic of malignancy. The purpose of this study is to determine whether the routine use of flow cytometry adds to standard cytologic evaluation in effusions. We did flow cytometric DNA analysis in 76 effusions(28 malignant and 48 benign fluids). All the 48 benign effusions were diploid. There were 12(42.9%) aneuploid and 16(67.1%) diploid malignant effusions. Based on these results flow cytometric DNA analysis had a sensitivity of 42.9% and a specificity of 100%. These results suggest that flow cytometric DNA analysis may be a useful adjunct to conventional cytology, but its principal limitation is its relatively low sensitivity.

Congenital Mesoblastic Nephromas with lmmunohistochemical and Flow Cytometric Analysis.: Woo Hee Jung, Yee Jeong Kim, Jee Young Han, Woo Ick Yang, Dae Young Kang; Korean J Pathol. 1995;29(3):303-310.

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Abstract PDF: We reviewed 7 cases of congenital mesoblastic nephroma (4 cases of classical mesoblastic nephroma (CMN) and 3 cases of atypical mesoblastic nephroma (AMN)) using immuno-histochemical and flow cytometric study. Results are as follows. 1) The mean tumor size was 5 (3 to 7cm)cm in CMN and 9 (7 to 10cm)cm in AMN. The AMN revealed hemorrhage and necrosis in two Of three cases. A case of AMN showed cystic change without hemorrhage and necrosis. Mitotic count ranged in 0~4/10HPF in CMN and 20-35/10HPF in AMN. 2) Immunohistochemistry for vimentin was all positive. Actin, desmin were weakly positive in CMN, but negative in AMN. The findings were consistent with myofibroblastic differentiation in CMN and AMN was considered to be the less differentiated form of CMN. 3) Flow cytometiic analysis showed diploidy in two of two CMNs and two of three AMNs. Only one AMN showed aneuploidy with DNA index of 1.41. %SG2M were 8.1 and 15.9 (mean 12.0) in CMN and 16.9, 32.9 and 19.3 (mean 22.9) in AMN, respectively. We concluded that AMN should be distinguished from CMN, clinicopathologically.

Flow Cytometric DNA Analysis in Thyroid Neoplasms: With Emphasis on the Correlation between Ploidy Level and Pathologic Features.: Young Tae Kim, Jin Man Kim, Kwang Sun Suh, Jin Sun Bae; Korean J Pathol. 1995;29(2):127-135.

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Abstract PDF: Nuclear DNA content in 31 cases of thyroid neoplasm was determined by flow cytometry with the use of paraffin-embedded archival tissue. DNA aneuploidy was found in 6 cases (19.4%) of the 31 thyroid neoplasms; such as 2 of 8 (DI=1.16, 1.56) follicular adenomas, 1 of 6 (DI=1.10) follicular carcinomas, 1 of 15 (DI=1.18) papillary carcinomas and 2 of 2 (DI=1.76, 2.07) medullary carcinomas. The remaining tumors were diploid. No significant difference between follicular adenomas and carcinomas was detected with respect to the S phase fraction(SPF). In the papillary carcinoma group the SPF was higher than in the follicular neoplasm group, but it was statistically insignificant. Regional lymph node metastasis was present in 8 of 15( 53.3%) papillary carcinomas but absent in all of the 14 follicular neoplasms. In the medullary carcinoma group one case showed regional node metastasis at the time of resection and the other developed metastasis 11 months after surgical removal of the primary lesion. In this study tumors predominantly composed of Hurthle cells were found to have a significantly higher D.I. than those with few or no Hurthle cells. No significant difference was found between tumors with metastasis and those without metastasis.

Comparative Studys

A Comparative Study of DNA Quantitation by Image Cytometry and Flow Cytometry.: In Sun Kim, Eun Sook Nam; Korean J Pathol. 1994;28(4):399-404.

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Abstract PDF: There are substantial evidences suggesting that DNA content of tumors may provide the prognostic information with independent significances. In this study, the results of DNA ploidy analyzed by image cytometry on touch imprint and by flow cytometry on fresh cell suspension of 78 solid tumors were compared. For 68 cases, there was an excellent correlation between two methods. For 6 cases, an aneuploid population was found by image, but not by flow cytometry one case had an aneuploid peak by flow cytometry. Two methods may use in a complementary fashion m identify as many aneuploid cell population as possible.

Interpretation of DNA Histogram in Flow Cytometry: A Comparative Study of DNA Ploidy in Fresh and Paraffin-embedded Tissues of Colorectal Adenocarcinomas.: Eun Sook Nam, Soon Hee Jung, Yeon Lim Suh, Woo Hee Jung, Keung Min Kim, In Sun Kim; Korean J Pathol. 1994;28(4):341-349.

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Abstract PDF: As flow cytometric analysis using paraffin-embedded tissue was developed by Hedley et al in 1983, retrospective study with large amount of archival material was possible. Many literatures reported that the result of paraffin embedded tissue was compatible with that of fresh tissue. We compared the DNA histograms of 26 cases of colorectal adenocarcinoma in which the analysis was done in both fresh and paraffin-embedded tissues. Aneuploidy in fresh and paraffin-embed-ded tissues was 73.0% and 50.0%, respectively. The concordance rate of fresh and paraffin-em-bedded tissues was 76.8% and six interpreters were agreed in 73.0% of the cases. Because flow cytometric DNA analysis using fresh tissues can detect more aneuploid population than in paraffin-embedded tissue, the former is strongly recommeded in DNA ploidy study. Also careful observation using standard criteria may improve the interpretation of DNA histogram.

Case Report

Leukemic Infiltration of Acute Hybrid Leukemia with CD7 CD13+ and CD19+ Immunophenotype in the Lymph Node: A case report.: Mi Ja Lee, Ho Jong Jeok, Sang Woo Juhng; Korean J Pathol. 1994;28(2):191-199.

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Abstract PDF: Acute hybrid leukemia is an uncommon disease that demonstrates malignant transformation expressing lymphoid and myeloid cell lineage. We experienced a case of 25-year-old man with acute leukemia with unusual characteristics: unclassifiable morphology and undifferentiated cytochemistry by French-American-British (FAB) criteria. Microscopically, it disclosed monotonous tumor cell population in lymph node with vascular plugging and perivascular infiltration, and indian file appearance in capsule and surroun ng adipose tissue. Results of flow cytometry and immunohistochemical studies of frozen sections, cytospins, and formalin fixed lymphoid tissues disclosed hybrid form characterized by myeloid and lymphoid cell lineage. The immunophenotype analysis showed both anti-T cell, anti-B cell and anti-myeloid cell monoclonal antibody reactivity; blast cells were consistently CD7+(94.6%), CD13+(97.1%), and CD19+(85.22%). The normal hematopoietic cells were almost replaced by tumor cells in PB and bone marrow. In preparation of cytospin of peripheral blood(PB) cells separated by a Ficoll-hypaque gradients, blast cells were negative for Sudan black B, myeloperoxidase, periodic acid Schiff, and nonspecific esterase.

Original Articles

Histologic Grading of Astrocytic Neoplasms in Conjunction with Evaluation of Proliferative Activity Using Ag-NORs Count PCNA Expression, and Flow CYtometric DNA Analysis.: Mee Yon Cho, Soon Hee Jung, Tal Seung Kim, Yong Pyo Han; Korean J Pathol. 1994;28(1):49-55.

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Abstract PDF: Although the histologic grade of astrocytic neoplasms of the brain have been used as a prognostic factor, the lack of an objective criteria is possible to create the disagreement of classification. We evaluated 25 cases of astrocytic neoplasms of brain to document the usefulness of prolifera-tive potential of tumor as a prognostic indicator and the correlation with histologic grade by Nils Ringertz. The Ringertz's classification was relatively simple in an application among the variable systems and easy to define the differentiate from grade to grade. The examined cases were com-prised of 7 astrocytomas, 9 anaplastic astrocytomas and 9 glioblastoma multif6rmes. The prolife-rative potential of tumors were measured by Ag-NORs count, PCNA labeling index and flow cytometric analysis. The mean numbers of Ag-NORs per cell and PCNA labeling index were sig-nificantly differ among each histologic grade. In addition, abnormal DNA content and high prolif-erative index were frequently identified in anaplastic astrocytoma and glioblastoma multiforme. Therefore, the Ag-NORs counts, PCNA labeling index, DNA index and proliferative index were well correlated with the histologic grade.

The Epidermal Proliferation and the Number of Langerhans Cells in 7, 12-dimethylbenzanthracene Induced Epidermal Changes.: Chang Soon Han, Young Nyun Park, Kwang Gil Lee, In Joon Choi; Korean J Pathol. 1993;27(6):590-604.

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Abstract PDF: Chemically induced epiderml carcinogenesis is usually divided into two stages, the initiation and promotion. The initiation involves conversion of some epidermal cells into latent neoplastic cells and the promotion is proliferation of the transformed cells. As immunosurveillence is thought to be a host defense against tumors, Langerhans cells, being essential in initiation of local cutaneous immunologic reaction, is suggested to be important in the carcingenesis of the epidermis. This study is attempted to investigate the epidermal proliferative changes in mice induced by application of 12-0-tetradecanoy1-phorbol-13-acetate(TPA) on the skin initiated with 7, 12-dimethylbenzanthracene(DMBA) and its relationship with Langerhans cell. Ninty five male inbred BALB/c mice weighing 20~25 g were divided into five groups; the 33 week-group, the 21 week-group, the 12 week-group and the 4 week-group according to the duration of carcinogen application, and the control group. The carcingen was applied with a brush on the dorsal skin of mice after depilation. Ten days after application of 800 nmole DMBA in 0.4 cc acetone, 20 nmole TPA in 0.4 cc acetone was applied twice per week and the control group was applied with the same amount of acetone for 4 weeks. Animals were sacrificed 3 days after the last application of TPA. One hour before sacrifice, bromodeoxyuridine(BrdU) (1 mg/g) was injected via the tail artert for BrdU stain of S phase cells. A strip of dorsal skin was used for hematoxylineosin stain, immunohistochemical stain for BrdU and la antigen of Langerhans cell, and flow cytometry. The results are as follows: 1. Cellular proliferation, hyperkeratosis and dysplasia of the epidermis were increased in relation to duration of carcingen application. Papillomas were developed 12 weeks after application of the carcingen. 2. BrdU labelling and proliferative indices of the 20 weeks' application group were significantly higher than those of the 12 weeks' application group. The number of Langerhans cell was decreased markedly ater 4 week' application of the carcinogen. 3. All epiedrmal lesions including a case of squamous cell carcinoma were diploidy in flow cytometry. It is thought that disturbance of immunosurveillence, caused by depletion of Langerhans cell, may permit proliferation of epidermal cells. Although abnormal quantitative change of nuclear DNA has not occurred even when the epidermal proliferative activity and dysplastic change were increased markedly, it is thought that the occurrence of structural change of chromosome is remained to be clarified.

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