Journal of Pathology and Translational Medicine

Original Articles

Correlation between Nuclear Grades and the Numbers of AgNORs and PCNA Labeling Indices in Renal Cell Carcinoma.: Hye Jin Lee, Young Im Han, Kang Suek Suh, Sun Kyung Lee; Korean J Pathol. 1996;30(2):132-139.

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Abstract PDF: The author examined the number of AgNORs and PCNA labeling indices by histochemical and immunohistochemical studies in 20 cases of renal cell carcinoma, composed of 5 cases according to the nuclear grades. The results obtained are summarized as follows; 1) Mean number of AgNORs according to the nuclear grades of renal cell carcinoma were 1.38+/-0.40 (mean+/-standard deviation) for Grade I, 2.53+/-0.33 for Grade II, 5.43+/-0.66 for Grade III, and 7.88+/-0.72 for Grade IV. The mean numbers of AgNORs according to the nuclear grades were significantly increased(p=0.0005). 2) PCNA labeling indices (positive nuclear ratio) according to the nuclear grades of renal cell carcinoma were 5.90+/-2.36 for Grade I, 19.30+/-6.71 for Grade II, 45.73+/-8.62 for Grade III, and 61.83+/-6.34 for Grade IV. Also, the PCNA labeling indices according to the nuclear grades were significantly increased(p=0.0008). 3) The mean numbers of AgNORs directly correlated with the PCNA labeling indices (r=0.9861, p<0.001). On the basis of the above results, it was considered that the numbers of AgNORs and PCNA labeling indices as markers of proliferative activity of tumor cells correlate well with the nuclear grades of renal cell carcinoma.

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.

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.

Prognostic Significance of PCNA Index and AgNORs Score in Transitional Cell Carcinoma of the Renal Pelvis.: Wan Seop Kim, Seung Sam Paik, Nam Hoon Kim, Moon Hyang Park, Jung Dal Lee; Korean J Pathol. 1998;32(7):521-530.

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Abstract: Proliferative activity of a malignant tumor is known to reflect its biological aggressiveness. Proliferating cell nuclear antigen (PCNA) is a marker of cellular proliferation, and silver-stained nucleolar organizer regions (AgNORs) have been shown to correlate with ploidy and proliferative activity of cells. In transitional cell carcinoma of the renal pelvis, the prognostic value of these markers has not been well defined. We studied PCNA expression and the AgNORs count in 22 transitional cell carcinoma of the renal pelvis to assess their prognostic significance compared with their cumulative survival rate, the stage of disease and histopathologic features of the tumors. An immunohistochemical method and a standard colloidal silver staining were used. The mean percentage of PCNA positivity (PCNA index) and the mean number of AgNORs per nucleus (AgNORs score) were determined. In a multivariable analysis, PCNA indexes were significantly associated with tumor stage (p=0.024), whereas AgNORs scores were not significantly associated with the stage or histopatholgic features of the tumors. Histologic grade was correlated to disease stage at a significant level (p=0.000). But there was a trend of low tumor PCNA-indices or AgNORs counts with survival advantage for patients, but this did not reach statistical significance. The results suggest that the fraction of PCNA positive nuclei would be useful for investigating the malignant potential of renal pelvic cancers, although their clinical use as markers of biologic behavior may be limited.

The Relationship of Ki-67, Proliferating Cell Nuclear Antigen, AgNORs and p53 Protein Expression in Astrocytoma.: Dong Ja Kim, Jae Weon Lim, Yoon Kyung Sohn; Korean J Pathol. 1999;33(1):25-31.

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Abstract PDF: The grading of astrocytoma has traditionally relied on histological assessment, but there are some differences in their parameters, application, and reproducibility. Recently, numerous studies have attempted to correlate biological aggresiveness with tumor proliferation index using new immunohistochemical methods. The purpose of this study is to correlate the histopathological grades of astrocytoma with the expression of Ki-67, PCNA, p53 protein and AgNORs. The paraffin sections of 41 consecutive cases of astrocytomas were examined. Histologically the tumors were graded as three groups under the St. Anne-Mayo system and showed 14 cases in grade II, 15 cases in grade III and 12 cases in grade IV (glioblastoma multiforme). As a result, the Ki-67 labelling index and p53 protein expression tended to increase with increasing grade of malignancy. But the univariate analysis showed that there was no significant difference between the tumor grades (p>0.05). The PCNA labelling index and number of AgNORs revealed striking differences between the grade II and grade III astrocytomas (p<0.05). We concluded that the PCNA labelling index and AgNORs counting are useful markers for differentiation between grade II and III astrocytomas.

AgNOR Counts in S-phase Human Cells.: Seung Il Kim, Eun Jung Lee; Korean J Pathol. 1999;33(2):103-107.

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Abstract: The nucleolus of human cell is a morphologically well recognizable nuclear organelle and the argyrophilic NORs (AgNORs) are nucleic acid-argyrophilic nonhistone protein complex in the nucleoli and the silver staining allows their identification and enumeration at the light microscopic level. The AgNOR counts are in parallel with mitotic activity and vary in different phase of cell cycle. It has been reported that human cells have one AgNOR during interphase and S-phase. However, the correlation between the number of AgNORs and S-phase markers is still controversial and they have never been studied simultaneously. In this study, AgNOR and PCNA were stained simultaneously to find out the relationship of AgNOR counts with cell cycle (S-phase) in human palatine tonsil, gastric carcinoma, liver and brain tissues. S-phase cells (PCNA-positive) were found predominantly in lymphoid follicles in palatine tonsil but gastric carcinoma showed diffuse immunoreactivity for PCNA. The AgNOR counts varied according to the type and locus of tissue. More than one AgNOR were identified in S-phase cells and some of hepatocytes and neurons in the brain which were not in S-phase contained two or more AgNORs. The above results suggest that the number of AgNOR is a characteristic feature of each type of cells and can be more than one even in S-phase.

Argyrophilic Nucleolar Organizer Region and Expression of Ki-67 in Malignant Lymphoma.: Hee Jung Lee, An Hi Lee, Kyo Young Lee, Chang Suk Kang, Sang In Shim, Byung Kee Kim; Korean J Pathol. 2000;34(4):257-263.

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Abstract PDF: Nucleolar organizer regions (NORs) are loops of DNA which occur in the nucleoli of cells which possess ribosomal RNA genes. The numbers and areas of NORs have been thought to be related to cellular activities. We aimed to investigate the direct relationship between the parameters of AgNORs and cellular proliferative activity using immunohistochemical method with the monoclonal antibody Ki-67, which demonstrates proliferating nuclei. The sequential technique for the simultaneous Ki-67 immunostaining and NOR staining was applied to the same slides of a series of non-Hodgkin's lymphomas (NHL) of the low, intermediate, and high grade type. The number of AgNOR per cell was counted and mean NOR percentage nuclear area (NPNA) was measured by morphometry in both the Ki-67 positive and Ki-67 negative nuclei. The increased immunoreactivity for Ki-67 was found in the high grade than in the low grade non-Hodgkin's lymphoma. This was reflected in the two areas of the palatine tonsils and lymph nodes, the positive cell counts being higher in the follicle center nuclei than in those in the interfollicular compartment. In general the numbers and NPNA of AgNORs were higher in the Ki-67 positive nuclei than in those lacking the antigen in malignant lymphomas as well as in control. The AgNORs numbers and NPNA in controls were the highest in the Ki-67 positive cells in the follicular area and the lowest in the Ki-67 negative cells in the perifollicular area. In malignant lymphomas the numbers and NPNA of AgNORs tended to increase in proportion to their grade in both the Ki-67 positive and negative cells. The numbers of AgNORs of the high grade and the NPNA of the intermediate and the high grade were significantly higher in Ki-67 positive cells than in Ki-67 negative ones. With this double staining method it was now possible to confirm that numbers and NPNA of AgNORs were directly related to the cellular proliferative activity. In maligant lymphoma, among the several parameters of the AgNORs, NPNA in Ki-67 positive cells is proposed to be the most useful marker in determining the prognosis of the patient.

The Significance of AgNOR Count in Body Fluid: Differential between reactive mesothelial cells & malignant cells.: Seung Sam Paik, Eun Kyung Hong, Se Jin Jang, Moon Hyang Park, Jung Dal Lee; Korean J Cytopathol. 1997;8(2):129-134.

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Abstract PDF: To distinguish reactive mesothelial cells from malignant cells in body fluid, we applied silver staining of nucleolar organizer regions(AgNORs) to ethanol fixed cytologic preparations. Fifty aspirated samples of benign(22 cases) and malignant(26 cases) body fluids were studied using the one step silver staining method. Two cytologically atypical samples were also included in the study. In malignant cases the mean AgNOR count was 3.56+/-0.81, while in benign cases the mean AgNOR count was 2.02+/-0.33. The difference of AgNOR counts between these two groups were statistically significant(p<0.001). The mean of atypical cases was 2.91. Both were diagnosed as malignant in follow-up cytology. In malignant effusions, there is statistically significant difference in AgNOR counts between cells forming complex papillae or clusters and singly scattered cells(p<0.05), 3.29+/-0.95 and 3.83+/-0.55, respectively. We concluded that AgNOR count appears to be useful as a diagnostic tool especially when the cytologic differentiation is difficult.

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.

PCNA Labelling index and AgNORs of Transitional Cell Carcinoma of the Urinary Bladder.: Byung Gon Park, Sang Yong Lee, Mee Sook Roh, Seo Hee Rha, Sook Hee Hong; Korean J Pathol. 1994;28(5):469-477.

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Abstract PDF: Proliferating cell nuclear antigen (PCNA, PC10), an auxillary protein of DNA polymerase, plays a main role in the early stage of DNA Synthesis and is synthesized from Gl phase to s phase of the cell cycle. Nucleolar organizer region (NORs) are DNA loops encoding RNA proteins(AgNORs). To evaluate correlation with PCNA labelling index (LI)and AgNORs according to histological grades and clinical stages of transitional cell carcinoma of the urinary bladder, the authors analysed 54 transitional cell carcinoma using immunohistochemical stain for PCNA and silver stain for AgNORs in paraffin sections. The comparison of PCNA (PC10) LI and clinical stage showed a significant correlation (p<0.05), where as PCNA (PC10) LI according to histologic grade showed no significant correlation. High grade tumors showed increase PCNA LI. Superficial tumors (Ta-Tl) showed significantly lower PCNA LI than muscle invasive tumors (T2-T4)(p<0.05). There was no significant correlation between AgNORs and clinical stage, bur higher stage and higher grade tumors showed increased noubers of AgNORs. These results suggest that PCNA LI has a significant correlation with clinical stages of transitional cell carcinoma of the urinary bladder.

Comparative Study

A Comparative Study of PCNA Immunostaining, AgNOR Scores Hormone Receptors and Histology in Human Breast Cancer.: Eun Sook Chang, Kwan Kyu Park; Korean J Pathol. 1993;27(6):605-617.

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Abstract PDF: This study was performed on 50 cases of primary breast cancer removed surgically during the period 1990~1991 and compared the results of four morphologic methods developed for the detection of estrogen receptors, progesterone receptors, monoclonal antibody PCNA immunoreactivity, and the mean number of argyrophilic nucleolar organizer regions(mAgNORs) to ascertain the prognostic significance and also to detect highly malignant heterogenous cancer. To determine the validity of these measurements, a variance analysis was done with Kruskal-Wallis 1-way ANOVA. The results showed that the significant correlation between histologic grade and ER/PR status(P=0.005/P=0.015), the borderline significant correlation between mAgNORs and ER/PR status(P=0.08), and between AgNORs and stage(P=0.07), PCNA has no correlation with ER/PR status(P=0.25), clinical stage and histologic grade. In follow up, four cases of invasive ductal carcinoma with ER/PR, developed early and rapid metastasis within 2 years, three of them were classified as histologic grade 3 and another case was grade 2, whereas two of them were classified ans stage III(+) and the rest were in stage IIB(+) and stage IIA(-). The mAgNOR count of these four cases were ranged from 3.32 to 4.29 which were in the aneuploid category most likely. One of them had rather stormy rapid course with multiple organ metastases resulting death within one year. These results indicated that ductal carcinoma(>2cm size) with ER-/PR- and high mAgNOR level or high PCNA grade, and hihg histologic grade had h highly malignant course, marked by rapidly developing metastases. Thus we concluded that the status of ER/PR alone in tumor tissue is an important information for selecting hormone treatment btu, for the ultimate prognosis, is a weak indicator. Therefore for early detection of such heterogenous tumor, besides ER/PR, AgNORs or PCNA, histologic grade and tumor size are very useful as biological indicators of prognosis. The status ER/PR in combination with these indicators are more accurate and provide better basis on which to base a decision for early implementation of chemotherapy from which to give probably benefit by inhibition of rapid progress.

Original Articles

Application of Argyrophilic Nucleolar Organizer Regions(AgNORs) in the Diagnosi of Hepatocellular Carcinoma.: Cheol Hee Yun, Sang Sook Lee, Eun Sook Chang; Korean J Pathol. 1993;27(6):553-560.

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Abstract: Necleolar organizer regions(NORs) ARE LOOPS OF DNA which transcribe to ribosomal RNA by RNA polymerase I. Since NOR-associated proteins are argyrophilic, silver staining method has been used for demonstration of AgNORs. The numbers and/or configurations of NORs may reflect the activities of cells in hyperplastic and neoplastic conditions. To evaluated the applicability of AgNORs in the diagnosis of hepatocellular carcinoma, the author had performed silver staining on the routinely processed, formalin-fixed, paraffin-embedded sections of 14 cases of normal liver(control), 23 cirrhotic liver, and 21 hepatocellular carcinoma. The results are summarized as follows: 1) The mean number of AgNORs per nucleus(mAgNOR) of normal liver, cirrhotic liver and hepatocellular carcinoma was 1.45+/-0.07, 2.53+/-0.38 and 5.52+/-1.63, respectively. The difference of mAgNOR between normal and cirrhotic liver, and between cirrhotic liver and hepatocellular carcinoma was statistically significant, respectively(p<0.01). 2) The percentage of nuclei showing five or more AgNORs per nucleus(pAgNOR) was 0.07% in normal liver, 7.59% in cirrhotic liver, and 60.49% in hepatocellular carcinoma. 3) AgNORs in hepatocellular carcinoma were large, pleomorphic and irregularly clumped, in addition to increase of mAgNOR and high pAgNOR. In conclusion, the increase of mAgNOR, high pAgNOR and large, irregular AgNORs are regarded as an additional helpful finding for the histopathological diagnosis of hepatocellular carcinoma.

A Study of Nucleolar Organizer Regions in Normal and Neoplastic Epithelial Cells of Stomach.: Hee Jin Chang, Kyung Ha Kang, Jung Hee Park, Jin Hee Sohn, Jung Il Suh; Korean J Pathol. 1992;26(5):451-458.

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Abstract PDF: Nucleolar organizer regions are DNA loops encoding rihbosomal RNA production and detectable by the argyrophilia of their associated proteins(AgNORs). AgNOR numbers correlate with cellular proliferating activity. Many studies have shown a significnt difference in AgNOR counts between benign and malignant tumors. AgNOR counts were also helpful in differential diagnosis. For the evaluation of its diagnostic utility in gastric lesions, a silver staining technique was carried out in paraffin sections of 5 control cases, 5 benign peptic ulcers, 7 hyperplastic polyps, 10 tubular adenomas, 16 early gastric adenocarcinomas and 15 advanced gastric adenocarcinomas. The results were as follows. The mean numbers of AgNORs in early and advanced gastric adenocarcinomas(1.94 and 2.16) were significantly higher than those of normal foveolar epithelium(1.43) and epithelia of benign gastric ulcers(1.54), hyperplastic polyps(1.64) and tubular adenomas(1.79). In malignancy, there was increased variability in size and shape of AgNORs. There was little differences in mean AgNOR numbers between early and advanced gastric adenocarcinomas. Differentiation of the tumor made no difference in AgNOR numbers. From the above results, the AgNORs count, if its morphologic change are taken into consideration, is helpful in differentiation between malignant and non-malignant lesions.

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