High Proliferating Cell Nuclear Antigen Research Articles

Immunohistochemical study on proliferating cell nuclear antigen expression in ameloblastomas.

The aim of this study is to evaluate the proliferating activity of ameloblastomas and its correlation to the biological behaviour according to each histological type. 38 cases of solid and unicystic ameloblastomas were reviewed including 1 case of ameloblastic carcinoma and 1 recurrent case. An anti-PCNA antibody, PC10(Dako), was applied for the detection of proliferating cell nuclear antigen (PCNA) in paraffin embedded tissue sections. Also 20 cases of dentigerous cysts were reviewed. In conclusion, we observed that there was no difference between the proliferating activities of the different histological types of solid ameloblastomas. Because 1 case of ameloblastic carcinoma and one recurrent case revealed remarkably high PCNA reactivity, we believe that PCNA would be useful in showing the differentiation between benign and malignant ameloblastomas. In unicystic ameloblastomas, plexiform intraluminal growth was considered to be an important feature in tumorous transformation of cystic epithelium.

Proliferating cell nuclear antigen in needle biopsy specimens of prostatic carcinoma.

The expression of proliferating cell nuclear antigen (PCNA) was immunohistochemically determined using a monoclonal antibody PC10 in 54 prostatic carcinoma samples. The samples were taken from needle biopsy specimens which had been paraffin-embedded after routine fixation with 10% formaldehyde solution (formalin) for less than 24 h. The PCNA index was calculated as the percentage of positive tumor cell nuclei. There was a significant difference in the PCNA index according to the growth pattern (p < 0.001), nuclear anaplasia (p < 0.001) and T stage (p < 0.01). Regarding the growth pattern, solid carcinomas showed a significantly higher PCNA index than did either separate gland carcinomas (p < 0.05) or trabecular/fused gland carcinomas (p < 0.05). The PCNA index correlated closely with either the nuclear anaplasia or T stage, and increased in conjunction with the increased nuclear anaplasia (rs = 0.641; p < 0.001) or T stage (rs = 0.435; p < 0.01). The patients in the high PCNA index (> or = 15%) group showed a significantly worse survival than did those in the lower PCNA index group (p < 0.01), and multivariate analyses indicated that the PCNA index had an independent prognostic significance. These results suggest that the PCNA index, as determined by PC 10 on needle biopsy specimens of prostatic carcinoma, can thus be an objective and quantitative means for evaluating the biological malignancy of prostatic carcinoma.

舌へん平上皮癌の増殖細胞核抗原（ＰＣＮＡ）による免疫組織化学的検討

We evaluated whether the degree of malignancy of tongue squamous cell carcinoma (SCC) is reflected in the distribution of proliferating cell nuclear antigen (PCNA). The PCNA labelling index (LI) was investigated in relation to the histological differentiation and the survival rate of tongue carcinoma patients.The initial biopsy specimens of tongue SCC from 38 cases were fixed with 10% formalin, processed conventionally, sectioned and immunohistochemically stained using anti-PCNA antibody, PC 10 (DAKO, Denmark). The cells positive for immunostaining were counted under a microscope to obtain the PCNA LI.The results were as follows. The PCNA LI was 11.8 ±6.9%(n=7) in normal epithelium of the tongue. In contrast, a high LI was noted in SCC of the tongue, being 30.2± 13.4%(n=38). With respect to histological differentiation, the PCNA LI immunostaining was high (M ± SD=35.2 ± 12.3) in moderately-poorly differentiated carcinomas (n=23), and low (M ± SD=22.5 ± 11.2) in well differentiated carcinomas (n=15). Concerning the prognosis, survival rate was high (86.8%) in cases with low PCNA LI (<30.0) and low (63.7%) in cases with high PCNA LI (≥30.0).These results indicated that the PCNA LI is closely associated with the differentiation of carcinomas, and the prognosis of patients with SCC of the tongue. In addition, the PCNA LI was helpful in assessing the degree of malignancy of tongue carcinomas.

Proliferating cell nuclear antigen in hepatocellular carcinoma and small cell liver dysplasia

Recently, proliferating cell nuclear antigen (PCNA) has been measured by using a monoclonal antibody in a variety of malignant neoplasms. The authors evaluated cell proliferative activity by immunostaining for PCNA in 92 hepatocellular carcinoma nodules and 14 lesions of small cell liver dysplasia. The average PCNA labeling indices (LI) in Grades I, II, III, and IV were 12.2%, 17.5%, 53.7%, and 83.9%, respectively. There were statistically significant differences in the PCNA LI between all the histologic grades, except for Grades I and II. The less differentiated the histologic grade, the higher the PCNA LI became. This finding was also recognized in a hepatocellular carcinoma showing a "nodule in a nodule" appearance, in which the less-differentiated inner nodule had a higher PCNA LI than did the well-differentiated outer lesion. For an analysis of the disease-free survival in 74 patients with clinical follow-up data, 2 groups of patients with a PCNA LI higher and lower than the average level (32.0%) were compared. The disease-free survival rate after surgery was significantly higher (P < 0.005), and the venous invasion was significantly less frequent (P = 0.0003) in the low PCNA LI group than in the high PCNA LI group. The average PCNA LI in small cell liver dysplasia was 13.9%, which was almost equal to that of Grades I and II hepatocellular carcinoma. The PCNA LI of hepatocellular carcinoma showed a close correlation with both the histologic findings and the biologic behavior. Small cell liver dysplasia was a small round focus having proliferative activity similar to that of Grades I and II hepatocellular carcinoma.

Proliferating cell nuclear antigen in endometrial adenocarcinomas of endometrioid type correlated with histologic grade, stage, previous hormonal treatment, and survival

Only a small number of endometrial carcinomas have been examined for proliferating cell nuclear antigen. The results indicate that a high proliferating cell nuclear antigen content correlates with a poor prognosis. One hundred eight endometrial carcinomas of endometrioid type were examined with the monoclonal antibody PC10 (48 tumors from postmenopausal estrogen users and 60 tumors from nonusers). The PC10 content was weakly but significantly correlated with mitotic count and architectural grade, but not with nuclear grade, stage, or survival. PC10 values in estrogen users were much lower (median, 14%) than in nonusers (median, 26%); the difference was independent of histologic grade and stage. After a median follow-up of 30 months (range, 12 to 66 months) 17 patients had died. The cause of death was established as cancer in only nine cases. No overall difference in PC10 values existed between survivors and nonsurvivors. However, if only the estrogen nonusers were examined the survivors showed a mean PC10 value of 27%, while the nonsurvivors showed a mean PC10 value of 45%. The present study indicates that carcinomas from patients with and without previous hormonal treatment are different with regard to their PC10 content. The quantitative and qualitative estimates of PC10 correlated well.

Proliferating cell nuclear antigen and nucleolar organizer regions in CNS tumors: correlation with histological type and tumor grade. A comparative study of 82 cases on paraffin sections.

We investigated the expression of proliferating cell nuclear antigen (PCNA) and the number of nucleolar organizer regions (NORs) in 82 cases of CNS tumors. PCNA is a nuclear protein maximally elevated in the S phase of the cell cycle and recognized immunohistochemically in paraffin sections by the monoclonal antibody PC-10. On the other hand, NORs are loops of DNA that carry the rRNA genes and can be demonstrated in paraffin sections using an argyrophilic method (AgNORs). The present study shows a significant correlation of PCNA index and of AgNOR number with the histological grade (PCNA: I versus II, p < 0.01; II versus III, p < 0.01; and III versus IV, p < 0.05; AgNORs: I versus II, p < 0.001; II versus III, p < 0.05; and III versus IV, p < 0.001). Higher values of PCNA index (0.01 < p < 0.05) were found in recurrent tumors. Metastatic carcinomas were characterized by high PCNA indices and AgNOR numbers, similar to grade IV tumors, whereas in CNS lymphomas the malignancy grade was reflected in PCNA indices and AgNOR numbers. A wide range of PCNA and AgNOR values has been observed within each histological type and grade, probably reflecting variations in the biological behavior, but little overlap in PCNA values was present between grades II and III. The latter finding might be of importance in distinguishing between low- and high-grade CNS tumors. The linear regression coefficient between PCNA index and AgNOR number was excellent (0.91). We suggest that PCNA and AgNORs may be successfully applied in routine material to assess the growth potential of CNS tumors. Their prognostic value, however, must be validated with clinical studies.

The prognostic value of immunohistochemical staining for proliferating cell nuclear antigen in synovial sarcoma.

The biologic behavior of synovial sarcoma remains a matter of controversy. Some investigators considered proliferative activity to be an important prognostic factor in this tumor. Fifty-six patients with synovial sarcoma were immunohistochemically studied with PC10, a monoclonal antibody to proliferating cell nuclear antigen (PCNA). The percentage of nuclear areas with positive staining for PCNA (PCNA score), quantified by using an image analyzer, was compared with nuclear atypia, tumor necrosis, mitoses, and survival. Fifty-one patients were available for survival analysis. DNA flow cytometry was performed on 30 patients and compared with PCNA score and survival. The prognostic variables were analyzed with a multivariate technique using the Cox hazard model. Nuclear atypia (mild, 14; moderate, 23; severe, 14), mitosis (low, 34; high, 17), and tumor necrosis (< 50%, 37; > 50%, 14) were found to highly affect survival in the log-rank test (P < 0.01). Sixteen patients with a high (> or = 12.5) PCNA score had a worse survival (P < 0.01) than did the 35 patients with a low (< 12.5) PCNA score. In patients in whom DNA flow cytometry was performed, the S+G2M-phase fraction showed no correlation with the clinical outcome. However, there was a significant relationship between the extent of PCNA staining and S+G2M fraction (correlation coefficient [CC] = 0.54; P = 0.002), although the CC between PCNA staining and the mitotic count was only 0.38. However, the ploidy pattern was not related to PCNA scores or prognosis. In a multivariate analysis, a high PCNA score (P = 0.017) and severe nuclear atypia (P = 0.0003) were strong prognostic factors. The results suggest that a high PCNA score is one of the poor prognostic factors in synovial sarcoma.

Dna analysis of head and neck squamous cell carcinoma by flow cytometry

The use of flow cytometry to measure the DNA content from tumors has evolved over the years. In squamous cell carcinoma arising in the head and neck, there has not been uniform agreement in the literature, and decisions regarding patient treatment cannot be made using this parameter. The use of proliferating cell nuclear antigen (PCNA), a newly available marker of a cell's proliferative activity (S-phase fraction) is also discussed. In a prospective series of patients, the findings of diploidy, aneuploidy, low (PCNA) positivity, and high PCNA positivity are compared to known biological parameters. Strong trends are shown demonstrating biological aggressiveness associated with aneuploidy, high PCNA fraction, and the combination of aneuploidy and high PCNA fraction. The potential use of whole-cell preparation to determine ploidy and PCNA fraction as a predictor of metastatic potential are discussed. The whole-cell preparation technique allows accurate DNA ploidy measurements and, with the use of PCNA, a measure of proliferative activity. These parameters combined with known TNM staging may 1. allow alteration in treatment and ultimately affect patient survival, and 2. allow comparison of treatment modalities between biologically similar tumors.

PREDICTION OF THE PROGNOSIS OF PATIENTS WITH GASTRIC-CANCER BY ERBB-2 TISSUE STATUS AND EXPRESSION OF PROLIFERATING CELL NUCLEAR ANTIGEN

Correlation between erbB-2 tissue status and expression of proliferating cell nuclear antigen (PCNA) was studied in 164 gastric carcinomas, and these results were compared with the risk of metastasis and prognosis. Thirty-one (19%) tumors showe evidence of erbB-2 protein expression, and the PCNA index ranged from 8.2% to 77.2% (mean; 40%). erbB-2 protein positive tumors were most often encountered in the following clinicopathological groups: tumors with serosal invasion, lymph node metastasis, and venous invasion. There was a significant correlation between PCNA index and lymph node metastasis. In addition, erbB-2 positive tumors showed significantly higher PCNA index than erbB-2 negative tumors. Cox prortional hazard model identified lymph node metastasis. In invasion, liver metastasis, and erbB-2 tissue status as independent prognostic factors, but PCNA index was not an independent prognostic factor. However, by combining erbB-2 tissue status and PCNA index, PCNA index. was a good prognostic factor particularly in patients with erbB-2 negative tumors. These results indicate that the determination of erbB-2 tissue status, when combined with PCNA index, may be useful in the prediction of the prognosis and in deciding the therapeutic schedule of patients with gastric cancer.

Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence

The recurrence rate of pituitary adenomas has been reported to be as high as 10% to 35% despite their generally benign nature. A monoclonal antibody directed against proliferating cell nuclear antigen (PCNA) was used to investigate whether the proliferative index might help to predict adenoma recurrence. This antigen is a nuclear protein identified as the auxiliary protein of deoxyribonucleic acid polymerase delta, and its gene expression correlates with cell proliferation. The authors studied 30 patients with recurrent pituitary adenomas, 32 with nonrecurrent adenomas, and seven normal pituitary tissue samples. The mean interval to recurrence ( +/- standard error of the mean) was 5.3 +/- 0.7 years. The age- and sex-matched nonrecurrent group had a mean follow-up period of 6.6 +/- 0.3 years without clinical recurrence. Mean percentages of PCNA-positive tumor nuclei in both the initial and the second surgical specimens of the recurrent adenomas (13.45% +/- 3.02% and 19.56% +/- 3.66%, respectively) were significantly higher than that of the nonrecurrent group (2.49% +/- 1.21%). In addition, recurrent tumors had a higher PCNA index than the initial tumors in the same patients. Normal anterior pituitary gland tissue had a significantly lower mean PCNA index (0.12% +/- 0.11%) than either patient group. Stepwise multivariate regression analysis indicated that factors which collectively correlated significantly with recurrence were: high PCNA index, large tumor size, extrasellar extension, and incomplete surgical excision. The PCNA nuclear count was not associated with age, sex, or hormone hypersecretion, but was higher in macro- than in microadenomas, in tumors with extrasellar extension, and in those incompletely excised. A higher PCNA index also correlated with a shorter disease-free interval. The authors conclude that evaluation of the PCNA index assists in predicting the likelihood of pituitary adenoma recurrence.

Analysis of proliferative activity using anti-proliferating cell nuclear antigen antibody in gastric cancer tissue specimens obtained by endoscopic biopsy

Proliferative activities of tumors are thought to be prognostic features of malignant tumors, but their value as measured by proliferating cell nuclear antigen (PCNA) labeling remains unclear in gastric cancer. PCNA labeling rates (LR) were quantified in 121 paraffin-embedded biopsy specimens from primary tumors by immunocytochemistry. Immunohistochemical analyses have demonstrated that PCNA presents an intense staining in the nuclei of tumor cells and mucous neck cells of gastric glands. The PCNA LR ranged from 12% to 79% (mean +/- standard deviation), and a significant correlation was found between bromodeoxyuridine labeling indices and PCNA LR: PCNA LR were closely associated with tumor size, serosal invasion, and nodal involvement. The patients with tumors with high PCNA LR (greater than 40%) were dead significantly earlier than were those with tumors with low PCNA LR: When the PCNA LR and all the clinicopathologic parameters were entered into a Cox regression model, PCNA LR emerged as an independent prognostic factor. These results indicate that PCNA LR may be a potentially useful prognostic factor for gastric cancer.

Assessment of proliferating cell nuclear antigen expression in precursor stages of gastric carcinoma using the PC10 antibody to PCNA

Immunohistochemistry using the PC10 antibody to proliferating cell nuclear antigen (PCNA) was applied to archival material from mucosa adjacent to gastric carcinoma ('normal', hyperplasia, complete and incomplete intestinal metaplasia and dysplasia) and non-cancer controls (normal and complete intestinal metaplasia). Overall, increased PCNA indices, with expansion and altered location of the proliferative zones, were observed in carcinoma fields and compared with controls (P < 0.001). These differences were particularly significant in 'normal' mucosa far from carcinoma as compared with normal in controls (P < 0.001). In carcinoma 'fields' distinct patterns of PCNA expression were noted in complete and incomplete intestinal metaplasia. Similarly, in dysplastic lesions high PCNA indices were present either throughout the gland or found predominantly in the upper compartment. We conclude that these differences in PCNA index and staining patterns might prove useful in monitoring the evolution of the disease in the follow-up of patients at risk of developing gastric cancer.

Proliferating cell nuclear antigen (PCNA): expression in samples of human astrocytic gliomas.

In this retrospective study, 55 astrocytic tumours were stained with monoclonal antibody PC10 which recognizes the proliferating cell nuclear antigen (PCNA) in formalin fixed, paraffin-wax embedded sections. All the cases were graded using the Daumas-Duport system and the PCNA labelling indices (LIs) were correlated with tumour grades. Mean PCNA LI was 4.1% in the grade II, 8.1% in the grade III and 26.1% in the grade IV group. Six juvenile and cerebellar (grade I) astrocytomas had a mean PCNA LI of 5.6%. In general PCNA LI increased with tumour grade, but there was considerable variation of LIs especially in grade IV tumours which often had very high PCNA LIs (up to 72.7%). PC10 may be a useful complementary technique in surgical neuropathology, but the significance of the high LIs, seen in a proportion of glioblastomas, needs to be further determined.

Intratumor variation in cell proliferation in breast carcinoma as determined by antiproliferating cell nuclear antigen monoclonal antibody and automated image analysis.

Immunohistochemical detection of the proliferating cell nuclear antigen (PCNA) represents a potentially useful tool for the study of tumor proliferative activity. To study the intratumor heterogeneity of tumor growth, 88 breast carcinomas were immunostained with the anti-PCNA antibody 19F4 and analyzed with the CAS 200 image analysis system (Cell Analysis System, Inc., Lombard, IL). For each sample, 12 fields from both the central and the peripheral areas of the tumor were measured. The proportion of PCNA-positive nuclear area in the whole tumor (PCNAt score) varied from 0.7% to 45.2% (median, 14.4%). There was considerable intratumor heterogeneity in the staining for PCNA. In 79% of the specimens, the PCNA score was higher in peripheral areas than in the center of the tumor, the average difference being +3.4% (range, -9.2- +15.1%; P < 0.0001, Student's t-test). The S-phase fraction, determined by DNA flow cytometry of the same tumors, varied from 2.0% to 32.6% (median, 10.0%). The PCNA score showed a significant correlation with the S-phase fraction (r = 0.469, P < 0.001). Most divergent results were those with high PCNA scores and low S-phase fraction; possible explanations for this are discussed. The PCNA score also was related to the histologic grade of the tumors (P = 0.03, analysis of variance). In conclusion, proliferation indices obtained from different areas of a tumor can differ significantly because of intratumor heterogeneity in growth fractions. The PCNA immunostaining correlates with well-known prognostic factors (S-phase fraction and histologic tumor grade) in breast carcinoma.

Cell proliferation in breast carcinoma assessed by a PCNA grading system and its relation to other prognostic variables

This study was undertaken to relate the expression of the proliferating cell nuclear antigen (PCNA), a proliferation marker of putative prognostic significance, to some more established prognostic factors in a series of 60 consecutive breast cancer surgical specimens. PCNA was detected by the PC10 monoclonal antibody (MAb) using an immunohistochemical method and PCNA immunostaining was estimated on a semi-quantitative basis, a cut-off value of 50% of positively stained tumour cells discriminating between the high (> 50%) and low (< 50%) PCNA grade. The PCNA grade did not correlate with tumour size and axillary node status. However, a high PCNA grade tended to be associated with a poor histological grade and there was an inverse relationship with oestrogen-receptor status, as determined by means of the immunohistochemical staining for the oestrogen-induced pS2 protein. These conflicting results suggest that the possible prognostic usefulness of PCNA immunostaining, as a measure of cell proliferation rate, in breast cancer is yet to be demonstrated and can be validated only by direct relation to survival data.

PCNA and total nuclear protein content as markers of cell proliferation in pea tissue

ABSTRACT The identification of cell proliferation markers has been shown to be a useful tool with which to study basic mechanisms of cell cycle progression. The use of immunofluorescence techniques revealed the presence of the proliferating cell nuclear antigen (PCNA) in pea tissue, where we observed a high PCNA expression in proliferating cells of the root meristem compared to noncycling cells of the differentiated leaf. The presence of PCNA was monitored also during the time-course of seed germination, before, during and after the cell cycle resumption of the embryo cells. PCNA is present in embryo cells not only during and after resumption of the cell cycle but also before, when cells have not yet begun replicating their genome. A bivariate flow cytometric analysis of DNA and nuclear protein content was used to localize precisely the cells of the examined pea tissues in different cell cycle phase subcompartments. A high correlation was found between the degree of cell proliferation and the protein content of G1 nuclei, on the one hand, and the percentage of PCNA positive cells on the other.

Proliferating cell nuclear antigen (PCNA) expression in formalin-fixed tissue of non-small cell lung carcinoma.

An immunohistochemical study of non-small cell lung carcinoma using PC10, a monoclonal antibody against PCNA, was performed on tissues routinely processed with formalin fixation and paraffin embedding. The PCNA labelling index and mitotic index were determined from sections of these tissues. Tumours showed a high mean PCNA labelling index of 53.3%. The mean mitotic index was 10.3/1000 cells. Inter-examiner agreement of mitotic counting was good. A linear correlation between the PCNA labelling index and mitotic index was demonstrated (r = 0.71, P less than 0.00001). It is concluded that immunohistochemical nuclear labelling with anti-PCNA on routinely processed tissue is a simple technique for the assessment of proliferation in non-small cell lung carcinoma.

Prognostic significance of proliferating cell nuclear antigen-positive growth fraction in gastric adenomas.

The proliferative activity of gastric adenomas from 18 patients (42 endoscopic procedures) was compared with follow-up results. These cases were gastric adenomas proven by follow-up with repeated endoscopic procedures for more than 2 years, or were confirmed as gastric adenocarcinoma thereafter by histopathologic examination. Among the eighteen cases, nine showed carcinoma in the subsequent biopsies (group 1) and the remaining nine did not result in carcinoma (group 2). The proliferating cell nuclear antigen (PCNA) positivity rates of the two groups were significantly different (P < 0.01). The average PCNA positivity in group 1 was 33.1%, while it was 10.0% in group 2. The risk of developing carcinoma increased as the PCNA positivity increased: 0% in the low PCNA positivity group, 41% in the mid-positivity group and 89% in the high positivity group. We concluded that growth fraction could be taken into account as one of the most important prognostic factors for gastric adenoma, and accordingly repeated endoscopic biopsies with close follow-up should be carried out especially in the high PCNA positivity group.

Proliferating cell nuclear antigen and Ki-67 immunohistochemistry in brain tumors: A comparative study

Proliferating cell nuclear antigen (PCNA) is a 36-kDa DNA polymerase-delta auxiliary protein which accumulates in the nucleus during S phase of the cell cycle. Immunohistochemical labeling indices (LI) of PCNA and Ki-67 were compared using an avidin-biotin complex method on frozen sections of 27 nervous system tumors. 3 normal cerebral cortices, and 3 peripheral nerves. In glial tumors, PCNA and Ki-67 LI increased with increasing tumor grade (Daumas-Duport system). In 5 low-grade glial tumors, PCNA and Ki-67 LI were less than or equal to 1%, except for one optic nerve glioma (Ki-67 LI = 6%). In 7 grade 3 astrocytomas and 1 mixed glioma, PCNA LI were less than or equal to 1-1.5%, while Ki-67 LI were 2%-10%. In 7 grade 4 astrocytomas and 1 metastatic carcinoma, PCNA LI ranged from 6%-15% while Ki-67 LI ranged from 17%-30%. In 5 of 6 schwannomas, focally high PCNA LI (4%-65%) were noted, despite low LI with Ki-67 (less than or equal to 1.6%). Scattered normal schwann cell nuclei also stained with PCNA, but normal cerebral cortex did not.(ABSTRACT TRUNCATED AT 250 WORDS)