Journal of Pathology and Translational Medicine

Original Articles

The Study of p53 Expression and DNA Ploidy in Colorectal Carcinoma.: Ji Shin Lee, Kwang Soo Cheon, Chang Soo Park; Korean J Pathol. 1996;30(9):775-783.

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Abstract PDF: Mutation of the p53 gene frequently results in overexpression of the p53 protein and loss of its tumor-suppressing properties. The overexpression of the p53 gene could be an indicator of rapid proliferation, poor differentiation, advanced stages, or poor prognosis. The prognostic value of the overexpression of the p53 gene in colorectal carcinoma is equivocal. The presence of DNA aneuploidy has been described as a powerful adverse prognostic indicator in relation to survival. To investigate the prognostic significance of p53 expression, and the relationship with DNA ploidy, 92 cases of colorectal carcinomas were analyzed. The overexpression of p53 gene product was present in 50(54.4%) of 92 cases. p53 expression only correlated with recurrence or metastasis during the follow-up periods (p=0.045). DNA aneuploidy was observed in 32(39.1%) of 82 cases. DNA ploidy was strongly associated with lymph node invasion(p=0.005), Dukes' stage(p=0.003), TNM classification (p=0.003), and recurrence or metastasis during the follow-up periods (p=0.045). The frequency of DNA aneuploidy was higher in the p53-positive colorectal carcinomas(58.3%) than in the p53-negative colorectal carcinomas (21.6%) (p=0.003). p53-positive colorectal carcinomas had a higher rate of cell proliferation than p53-negative cases(p<0.001). These results suggest that checking the p53 expression and DNA ploidy could be useful prognostic indicators of colorectal carcinoma.

Flow Cytometric DNA Analysis in Papillary Carcinoma of Thyroid Gland: comparison with Ki-67 immunohistochemical staining.: Mee Joo, Hye Je Cho; Korean J Pathol. 1996;30(11):959-965.

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Abstract PDF: Nuclear DNA content was measured using a flow cytometric method to analyze 36 paraffin- embedded and 7 fresh tissues of 43 papillary carcinomas of thyroid gland. DNA aneuploidy was found in 3 cases(6.9%) and diploidy in 40 cases(93.1%). But there were no suggestive findings in clinical history, and cytological and morphological features for aneuploidy. In 40 diploid cases, S-phase fraction(SPF) were analyzed with regard to sex, age, tumor size, presence or absence of capsular invasion, lymph node involvement and ground glass nuclei. Among the multiple factors, only the tumor size, especially the larger sized-group(above 2cm in tumor diameter) was found to have a statistically significant higher SPF than the smaller sized-group (p<0.05). And high SPF groups relatively well corresponded to the high risk group. Thirty nine cases of papillary carcinoma have also been evaluated for proliferative activity with Ki-67 monoclonal antibody. The average Ki-67 labeling index was 0.36% in total cases, and that of the aneuploid cases was 0.73%, which was higher than that of the diploid cases(0.33%). So. We think that the low aneuploid rate and low Ki-67 labeling index relatively well represent the usual good clinical course of this tumor and the high SPF is a suggestive finding for a high risk group.

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.

The p53 Mutation and DNA Ploidy in Human Metastatic Breast Cancer.: Seong Jin Cho, Ae Ree Kim, Nam Hee Won; Korean J Pathol. 1997;31(2):135-144.

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Abstract PDF: The p53 gene, one of the tumor suppressor genes, is believed to play an important role through mutation and overexpression in the progression of various human malignant tumors. To compare the p53 mutation status between the primary and metastatic lesions of breast cancers and to investigate the mutational pattern of p53, immunohistochemistry (IHC) and polymerase chain reaction and single strand conformational polymorphism (PCR-SSCP) were performed in 25 cases of breast cancers with paraffin embedded tissue. Mutant protein products or point mutation were detected through IHC or PCR-SSCP method. And flow cytometrical (FCM) analysis were performed in the same paraffin blocks to correlate the DNA ploidy and p53 mutation. The following results are summarized. 1. The detection of the p53 gene mutation and overexpression of the p53 protein were measured in 40% and 48%, respectively, in 25 primary tumors, either or both methods was detected in 64%. 2. A concordance rate of the p53 protein expression between the primary and metastatic lesions of 25 breast cancers was 100%, but the concordance rate of the p53 gene mutation was 72%. 3. The correlation between the p53 mutation and the DNA aneuploidy was not statistically significant (p=0.38) 4. A p53 mutation by IHC or PCR-SSCP was more frequently detected in grade III breast cancers than in grade I or II. 5. Among 5 to 9 exons of the p53 gene, exon 7 was the most frequent mutation spot in this study. 6. Additional mutation of the p53 gene was developed in the three metastatic lesions. With the above results it is suggested that the p53 protein overexpression by immunohistochemistry is not correlated with the p53 mutation by PCR-SSCP. The p53 mutation pattern between the primary and metastatic lesions are not idenitical and an additional point mutation can occur in the metastatic lesion. The DNA aneuploidy is more frequently detected in the cases with the p53 protein overexpression than in the p53 protein negative, but it is not statistically significant.

E-Cadherin Expression and DNA Ploidy Analysis in Invasive Squamous Cell Carcinoma of the Uterine Cervix Comparison with those of CIN.: Yoo Jin Kim, Mee Young Sol, Man Ha Huh, Sun Kyung Lee; Korean J Pathol. 1997;31(6):557-565.

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Abstract PDF: Epithelial cadherin (E-cadherin) is a Ca2+ -dependent cell-cell adhesion molecule that connects cells via homotypic interactions. Its function is critical in the induction and maintenance of cell polarity and differentiation, and its loss is associated with an invasive and poorly differentiated phenotype in a wide range of tumors. Formalin-fixed, paraffin-embedded tissue sections from 36 cases of cervical intraepithelial neoplasia (CIN) and 14 cervical squamous cell carcinomas were investigated for the expression of E-cadherin immunohistochemically. While E-cadherin expression was usually restricted on the cell membrane of basal and parabasal cells in normal cervix, the presence of cytoplasmic E-cadherin was found to be associated with its grade in CIN lesions. Also, marked cytoplasmic staining was commonly revealed in poorly differentiated ones than well-differentiated squamous cell carcinomas. More intense reactivity of cytoplasmic E-cadherin was frequently seen in the foci of invasion than adjacent carcinoma in situ, and in its periphery than the center of tumor islands. In addition, DNA ploidy and S-phase fraction of squamous cell carcinomas were analyzed and compared with those of CIN lesion. We found that invasive squamous cell carcinomas more frequently disclosed DNA aneuploidy than CIN lesions, and there was correlation between cytoplasmic E-cadherin expression and DNA aneuploidy. Also, cytoplasmic E-cadherin-reactive cervical neoplasms had a higher rate of cell proliferation than that of membranous E-cadherin-reactive cases. These data suggest that the increased cytoplasmic E-cadherin expression may represent one of the abnormalities underlying the loss of polarity and invasiveness of cancer cells, and the abnormal E-cadherin expression combined with/without DNA ploidy or S-phase fraction may serve as a prognostic indicator.

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.

A Study on the Expression of p53 Oncogene Products, PCNA Index and DNA Ploidy in Renal Cell Carcinoma.: Jong Jae Jung, Ji Shin Lee, Chan Choi; Korean J Pathol. 1997;31(7):672-682.

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Abstract PDF: Mutant p53 is associated with the advanced stages of some human tumor but there is a wide variation in the reported incidence of p53 mutation in renal cell carcinoma and its prognostic significances. We designed this study to assess the expression of p53 in renal cell carcinomas and to compare with the established prognostic factors. Immunoreactivity for p53 protein and proliferating cell nuclear antigen (PCNA) were assessed in 44 cases of primary renal cell carcinoma, and flow cytometric analysis of DNA ploidy was perfon-ned in 37 of those cases. p53 protein was over-expressed in 16/44 (36.4%) renal cell carcinomas and 5 rumors had more than 10 immunoreactive tumor cells. The expression of p53 protein was positively related to nuclear grade (p=0.007) and PCNA index (p=0.002), but was independent of stage and DNA ploidy. In univariate survival analysis, stage (p<0.001), nuclear grade (p=0.017), DNA ploidy (p=0.045) and PCNA index (p<0.001) were significantly associated with patient survival. However, considering the stage, all of the last three factors had no prognostic influence. Cases showing strong positivity of p53 expression had worse prognosis than those with no or weak p53 expression, especially in early lesions (stage I,II) (p<0.001).

Correlation between p53 Immunohistochemical Expression, DNA Ploidy and Ki-67 Expression in Gastric Carcinoma.: Young Lyun Oh, Joung Ho Han, Young Hyeh Ko, Cheol Keun Park, Hwoe J Ree; Korean J Pathol. 1997;31(12):1264-1271.

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Abstract PDF: We examined the p53 protein overexpression and evaluated its correlation with pathobiological variables, including: (1) patient age, sex, tumor size, histological type and grade, invasion depth, vascular invasion, perineural invasion and lymph node status; (2) the Ki-67 labeling index in 100 gastric carcinomas; and (3) the DNA ploidy pattern, S phase fraction (SPF), and the proliferation index (PI) in 84 cases using flow cytometry. The positive rate of p53 staining was 48% and the p53 immunoreactivity was independent of variable clinicopathologic factors. No correlation was made between the Ki-67 labeling index with p53 immunostaining and DNA ploidy parameters. Aneuploidy rate was slightly higher in the p53 positive group (55.6%) than the p53 negative group (44.4%)(p=0.097). The mean values of SPF and PI were significantly higher in the p53 protein positive group. Aneuploidy was more often observed in the intestinal type (p=0.038), advanced gastric carcinoma (p=0.015) and lymph node positive group(p=0.039). The above results suggest that although the p53 protein overexpression has no significant correlation with pathological factors and the Ki-67 labeling index, it may play an important role in tumor cell proliferation. Since p53 protein overexpression was slightly higher in the aneuploidy group showing significant correlation with poor prognostic parameters, it is thought that re-evaluation of the p53 mutation by molecular biological study is needed.

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.

Expression of Biologic Markers and DNA Ploidy Analysis in Atypical Ductal Hyperplasia and Ductal Carcinoma in Situ of the Breast.: Hee Jung Kim, Woo Hee Jung, Hyeon Joo Jeong, Hy De Lee; Korean J Pathol. 1999;33(11):1076-1089.

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Abstract PDF: Status of margins and the size of the lesion are independent prognostic factors of ductal carcinoma in situ (DCIS). Histologic grading of DCIS and expression of biologic marker also appear to act as prognostic factors. However, DNA ploidy analysis using flow cytometry in the DCIS and atypical ductal hyperplasia (ADH) has been rarely reported, and the biologic behavior of ADH is unknown. We performed immunohistochemical staining and DNA ploidy analysis using flow cytometry on 45 cases of pure DCIS without microinvasion and 34 cases of ADH to compare the expression of biologic markers and DNA ploidy patterns according to the histologic grade of DCIS, to evaluate the usefulness of the Van Nuys classification, and to investigate the biologic behavior of ADH and low grade DCIS. A total of 41.9% of DCIS and 32.1% of ADH were detected mammographically in asymptomatic patients. The most common subtype of the high grade DCIS was comedo type (56.3%), while the low and intermediate grade DCIS were cribriform type. Expression of ER, c-erbB-2 and Ki-67 proliferative index (PI) was significantly associated with nuclear grade and histologic grade of DCIS. Expression of c-erbB-2 was also significantly correlated with presence of necrosis. In low grade DCIS, Ki-67 PI was significantly higher than ADH. A total of 63.6% of DCIS and 70% of ADH were diploidy and 15.9% of DCIS was aneuploidy. There was no aneuploidy in ADH. No significant association was noted between DNA ploidy and histologic grade or nuclear grade. However, in high grade DCIS, the frequency of aneuploidy was high. In conclusion, histologic grading of DCIS employing nuclear grade and necrosis is a useful tool accounting for biologic behavior. High grade DCIS and comedo DCIS impart aggressive biologic behavior and suggest a higher possibility of local recurrence or progression to invasive carcinoma. In the differential diagnosis of ADH and low grade DCIS, the use of Ki-67 PI and DNA ploidy analysis by flow cytometry will be helpful for accurate diagnosis and prediction of biologic behavior.

DNA Ploidy in Anaplastic Carcinoma of the Thyroid Gland by Image Analysis.: Ji Shin Lee, Min Cheol Lee, Chang Soo Park, Sang Woo Juhng; Korean J Cytopathol. 1995;6(1):10-17.

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Abstract PDF: Anaplastic carcinoma of the thyroid gland is one of the most malignant tumors. Recently, DNA ploidy measured by flow cytometry and image analysis has been suggested as an additional useful indicator of tumor behavior. Studies on the occurrence and clinical significance of DNA aneuploidy in anaplastic carcinoma of the thyroid are rare. In this study, the pattern of DNA ploidy was measured by image analysis on Papanicolaou stained slides in four cases of anaplastic carcinoma and also measured by flow cytometry using paraffin blocks in two cases. In all cases of anaplastic carcinoma. DNA aneuploidy was found by image analaysis. By flow cytometry, one case had a diploid peak and the other case had an arieuploid peak. According to the above results, we conclude that anaplastic carcinoma of the thyroid glands have a high incidence of DNA aneuploidy and image analysis using Papanicolaou stained slides is a useful method in detecting DNA aneuploidy.

Prognostic Implications of DNA Ploidy and S-phase Fraction Comparing with Other Prognostic Factors in Advanced Coloretal Adenocarcinomas .: Young Il Yang, Jong Eun Joo; Korean J Pathol. 1995;29(2):170-180.

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Abstract PDF: Dukes' stage of colorectal carcinoma has proven to be the most reliable and conventional prognostic indicator, followed by histological grade, lymph node metastases, tumor size, vascular and neural invasion. Flow cytometric analysis of DNA ploidy and S-phase fraciion (SPF) was examined to elucidate the correlations between sex, age, preoperative serum carcinoembryonic antigen (CEA) value, Dukes' stage, tumor site, size, gross features, histologic grade, and survival rate in 117 paraffin-embedded tissues of 68 cases of colorectal adenocarcinoma in Dukes' stage and 39 cases of colorectal adenoma and 10 cases of normal colonic mucosa. DNA aneuploidy was detected in 30 cases(44%) in adenocarcinomas and 6 cases (15%) in adenomas. Although the DNA ploidy and SPF did not show any correlation with sex, age, preoperative serum CEA level, Dukes' stage, tumor size, site and gross features, the incidence of DNA aneuploidy in the moderately differentiated adenocarcinomas was significantly higher than that of the well differentiated adenocarcinomas (p=0.0127) An apparent correlation was found between survival rate and DNA ploidy, Dukes' stage, histologic grade and preoperative serum CEA value. Dukes' stage was the most reliable prognostic indicator (p=0.0106), followed by histologic grade (p=0.0230), DNA aneuploidy (p=0.0251) and preoperative serum CEA level. (p=0.0369) In the patients with Dukes' stage C, DNA aneuploidy was more important than histologic grade as a prognostic indicator (p=0.0202). Although high SPF, greater than 21% in adenocarcinoma, was associated with the lower 5-year survival rate (12.0%), it was not statistically significant. These results suggest that DNA aneuploidy is regarded as biologic aggressiveness and considered as independent and/or dependent prognostic indicator along with Dukes' stage. However, prognostic utility of the SPF was not significant.

A Study of the Correlation between Cellular Proliferating Activities and Prognosis in Gastrointestinal Stromal Tumors .: Hee Jin Chang, Duck Hwan Kim, Sung Sook Pang, Jin Hee Sohn, Jung Il Suh, In Sun Kim, Jong Sang Choi; Korean J Pathol. 1995;29(2):152-169.

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Abstract PDF: Gastrointestinal stromal tumors are notorious for their unpredictable clinical behavior. To assess the cellular proliferating activities, four different methods were used: mitotic count, nucleolar organizer region(AgNOR) staining, immunostaining of proliferating cell nuclear antigen (PCNA) and DNA ploidy were used on 39 cases of gastrointestinal stromal tumors. Additionally, we analysed cellularity, cellular atypism and necrosis. Among 39 cases of gastrointestinal stromal tumors, 11 cases were diagnosed as benign lesions according to clinicopathologic findings. Malignant lesions were arbitrarily classified into low grade(n=ll) and high grade(n=17) on the basis of absence or presence of recurrence, metastasis or tumor-related death during the follow-up period. Numbers of mitosis, AgNORs, PCNA index and DNA ploidy were correlated with grades of tumor and prognosis. Among them, AgNORs counting appeared to be the most useful in predicting prognosis. Numbers of mitosis, PCNA index and DNA ploidy showed varying degrees of overlap among the 3 groups. Among the histological parameters, cellular atypia showed some relationship with the prognosis that others did not reveal.

Case Report

Pleomorphic Xanthoastrocytoma in a 58-year-old Woman: A case report.: Joo Heon Kim, Myoung Jae Kang, Dong Geun Lee, Ho Yeul Choi, Sang Ho Kim, Min Cheol Lee; Korean J Pathol. 1995;29(1):122-125.

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Abstract: A case of left parietal pleomorphic xanthoastrocytoma that occurred in a 58-year-old woman is reported clinicopathologically. Histopathologic diagnosis of pleomorphic xanthoastrocytoma was made because of the unique pleomorphic histologic features, positive glial fibrillary acidic protein in immunohistochemical staining. The flow cytometric analysis reveals DNA aneuploidy and relatively high S-phase fraction. The pleomorphic xanthoastrocytoma is considered as a special subgroup of glioma on the basis of superficial cortical location, GFAP expression, marked cellular atypia, xanthomatous cells, and relatively favorable prognosis.

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