p53 and Bcl-2 oncoprotein expression in placentas with hydropic changes and partial and complete moles

Forty molar and non-molar placentas with hydropic changes (14 complete moles, 14 partial moles, and 12 hydropic non-molar placentas) were examined immunohistochemically for expression of oncoproteins p53 and Bcl-2. The data were evaluated to determine if p53 and Bcl-2 expression could aid in differentiating molar from non-molar pregnancies on the one hand and complete mole from partial mole on the other. Thirteen out of fourteen complete moles showed p53 expression (93%), 8 of the 14 partial moles expressed p53 (57%), and none of the non-molar pregnancies expressed p53 in the extravillous intermediate trophoblasts. Regarding Bcl-2, the syncytiotrophoblasts of most molar and non-molar placentas showed strong and diffuse positivity. These results suggest that p53 expression can be used as a distinguishing parameter between complete moles and placentas with hydropic changes on the one hand and to a lesser extent between partial moles and placentas with hydropic changes on the other hand. Bcl-2 cannot be used in the same way as p53.     

Prognostic significance of Ki-67, p53, and Bcl-2 expression in prostate cancer patients with lymph node metastases: A retrospective immunohistochemical analysis

The prognostic significance of Ki-67, p53, and Bcl-2 expression was evaluated in prostate cancer patients with lymph node metastases. Immunohistochemical staining of archived material obtained from 56 patients was performed by the streptavldin-biotin method. Univariate survival analysis showed that a Ki-67 labeling index (Ki-67 LI) of ≥8.4 in the primary tumor identified a group of patients with a significantly poorer prognosis (P<0.001). Furthermore, a Ki-67 LI of ≥8.7 in the nodal metastatlc tumor was also associated with a poorer prognosis (P<0.01). Multivariate analysis showed that the Ki-67 LI of primary tumors (P<0.01) and lymph node metastases (P<0.01) had independent prognostic value. p53 and Bcl-2 expression had no prognostic value in patients with prostate cancer and lymph node involvement. The Ki-67 LI has more prognostic value than p53 and Bcl-2 expression for patients with prostate cancer that has spread to the lymph nodes.     

肺癌中P63与P53、E-cadherin、Ki-67表达的比较

目的　比较 p6 3及 p5 3、E cadherin(E cad)、Ki 6 7在肺癌中的表达 ,以了解在不同组织类型肺癌发生发展过程中 ,p6 3与抑癌基因 (p5 3)突变、上皮分化标志基因 (E cad)失活及细胞增殖标志基因 (Ki 6 7)激活有无相关性。方法　采用免疫组化S P法分别检测 6 1例原发性肺癌中 p6 3、p5 3、E cad和Ki 6 7的表达情况。 结果　p6 3在肺鳞癌中阳性率为 10 0 0 % ,而在其他组织类型肺癌中 p6 3基本不表达 ,差异有显著性 (P <0 0 5 ) ;在不同分化程度的肺鳞癌中 p6 3、p5 3的表达差异有显著性 (P<0 0 5 ) ,E cad、Ki 6 7的表达差异无显著性 (P >0 0 5 ) ;E cad的表达在小细胞肺癌与肺鳞癌和肺腺癌之间差异有显著性 (P <0 0 5 ) ;Ki 6 7的表达在各种组织类型肺癌之间差异有显著性 (P <0 0 5 ) ;在不同分化程度鳞癌中 p6 3与E cad的表达呈负相关(P <0 0 5 )。结论　p6 3可作为鳞状上皮源性肿瘤标记物 ,是判断鳞状细胞癌的增殖和分化有意义的指标 ,并可作为鉴别分化差的鳞癌和腺癌、小细胞癌的指标。     

Immunohistochemical analysis of bcl-2 and p53 expression in breast carcinomas: their correlation with Ki-67 growth fraction

We examined 59 breast cancers for p53 and bcl-2 protein expression by immunohistochemistry. The results were correlated with Ki-67 immunostaining. p53-negativity was noted in 40 cases and the remaining 19 tumours were p53-positive. Thirty-six tumours showed strong expression of bcl-2 and in 23 no staining for this protein was observed. We found statistically significant reverse correlation between expression of p53 and bcl-2 in majority of carcinomas: 31 cases were bcl-2 positive and p53-negative, and 14 tumours were bcl-2-negative and p53-positive. Six carcinomas showed no nuclear staining for Ki-67 and in the remaining 53 the percent of cancer cells positive for Ki-67 ranged from 1 to 60 (mean: 14.6). In these 53 cases we found that bcl-2-positive tumours were characterized by lower proliferation than bcl-2-negative tumours, the mean value of Ki-67 immunostaining being 10.7% and 23.0%, respectively. p53-negative tumours showed lower proliferation than p53-positive tumours: mean Ki-67 index was 10.2% and 23.9%, respectively.We conclude that immunohistochemically detected p53 and bcl-2 proteins show a significant inverse relationship in majority of breast carcinomas and their expression correlates with tumour proliferation (Ki-67 immunostaining).     

The significance of immunohistochemical expression of Ki-67, p53, p21, and p16 in meningiomas tissue arrays

Although histologic grading of meningiomas has prognostic and clinical implications, it is difficult in some cases to predict the outcome of patients. There have been several efforts to evaluate the use of different immunohistochemical markers for predicting meningioma prognosis. We analyzed the immunohistochemical expression of Ki-67, p53, p21, p16, and PTEN proteins in 130 meningiomas (64 benign, 39 atypical, and 27 malignant meningiomas) using tissue microarray. The tumors were graded according to the World Health Organization classification. There was a statistically significant correlation between the expression of Ki-67, p53, p21, p16, and the grade of meningiomas (p0.001). By ordinal logistic regression, p53 and Ki-67 were significantly associated with grade, and an increase of 1% in the labeling index of these markers resulted in an increase in the risk of raising the grade by 2.17 and 1.49, respectively. Histological grade, p53, Ki-67 labeling indices, and overexpression of p16 were strongly associated with decreased event-free survival in univariate analysis. In contrast, multivariate analysis revealed that only tumor grade is an independent factor for predicting meningioma recurrence. We conclude that the Ki-67 and p53 labeling indices are useful additional tools in discriminating atypical from benign or anaplastic meningiomas, especially in histological borderline cases.     

Clinicopathological and prognostic significance of p53, Ki-67, and Bcl-2 expression in Tunisian gastric adenocarcinomas

Gastric carcinoma (GC) is a highly aggressive malignancy with poor prognosis. It is widely accepted that malignancy results from abnormal cell growth due to dysregulation of the balance between cell proliferation and apoptosis. Our study aimed to investigate the clinicopathological and prognostic significance of p53, Ki-67, and Bcl-2 in Tunisian GC patients by immunohistochemistry. It was observed that the older patients showed p53 overexpression compared with the younger patients (p < 0.05). There was higher p53 expression in the intestinal-type compared with the diffuse-type (p < 0.05), and in well/moderate differentiated than in poor differentiated tumors. The expression of Ki-67 was positively associated with tumor size and venous invasion (p < 0.05). Bcl2 expression occurred in male patients and correlated with depth of invasion (p = 0.02). A Kaplan–Meier analysis indicated an inverse correlation between p53 and Ki-67 expression and the overall survival. Multivariate analysis revealed that the tumor site, Ki-67 and p53 expression were independent prognostic factors for gastric carcinomas (p < 0.05). Finally, combined expression of p53, Ki-67 and Bcl-2 showed that the group of patients with tumors p53+/Ki-67+/Bcl2− had aggressive behavior and poor prognosis (p log rank = 0.000). In summary, our data indicated that the expression of p53, Ki-67, and Bcl-2 may provide useful information for identifying patients with aggressive behavior and poor prognosis of GC.     

P16、Ki-67和Bcl-2在宫颈上皮内瘤变中的表达及应用

目的探讨P16、Ki-67、Bcl-2抗体在宫颈上皮内瘤变(CIN)中的表达及应用价值。方法用快捷免疫组化染色法检测30例正常宫颈组织和66例CIN中p16、Ki-67和Bcl-2的表达,分析比较两组的标记结果。结果 CIN中p16、Ki-67、Bcl-2的阳性率显著高于正常宫颈(﹤0.05),CINⅡ-Ⅲ的表达率显著高于CINⅠ(﹤0.05)。结论 P16、Ki-67和BCL-2抗体联合标记可作为病理诊断CIN和区分级别的重要参考指标。     

Enhanced expression of Ki-67, topoisomerase IIα, PCNA, p53 and p21 reflecting proliferation and repair activity in UV-irradiated melanocytic nevi

To investigate the effect of ultraviolet (UV) irradiation on the expression of cell cycle-associated proteins, melanocytic nevi from healthy volunteers were partially covered, irradiated with a defined UV dose, and excised 1 week thereafter. The irradiated and the protected parts were examined separately by conventional microscopy and immunohistochemistry using the antibodies Ki-S11 (Ki-67), Ki-S7 (topoisomerase IIα), PC10 (proliferating cell nuclear antigen [PCna]), DO-7 (p53), 6B6 (p21^WAF1/Cip1), and the melanocytic marker HMB-45. DNA nick-end labeling was used as a marker of apoptosis. Irradiation resulted in morphological changes and increased HMB-45 reactivity. Proliferation, as assessed by Ki-67 and topoisomerase IIα expression, was also clearly enhanced in the UV-exposed areas. This was confirmed by the appearance of occasional mitotic figures. PCNA expression levels markedly exceeded those of the proliferation markers and did not correlate with the latter in most cases. p21 immunolabeling indices were also consistently augmented after UV exposure; hence it is likely that growth-inhibitory mechanisms partly compensate for the proliferative impulse, and the disproportional rise in PCNA expression probably reflects DNA repair activity. Enhanced p53 immunostaining in four cases suggests that the induction of p21 after irradiation may be p53 mediated, whereas no concomitant apoptotic events were observed. We conclude that UV light can stimulate the proliferative activity of melanocytes in melanocytic nevi, but that simultaneously cell cycle inhibitors are activated to permit DNA repair.     

乳腺癌复发转移灶与原发灶中ER、PR、HER-2、p53、Ki-67的表达差异

目的 探讨ER、PR、HER-2、p53、Ki-67在乳腺癌复发转移灶与原发灶中的表达差异。方法 采用免疫组化En Vision两步法检测156例乳腺癌原发病灶及对应的复发或转移灶中ER、PR、HER-2、p53及Ki-67的表达,比较各指标的表达差异,并分析发生局部复发或远处转移的乳腺癌临床病理特征及与原发癌相比与各指标表达的一致性。结果 乳腺癌局部复发组和远处转移组与肿瘤分期(P=0.015)、肿瘤直径(P=0.005)差异有显著性;与患者年龄、组织学分级和腋窝淋巴结状态的差异无显著性(P0.05)。复发转移灶ER、PR阳性率比原发灶均有所下降,但差异无显著性;ER、PR表达不一致(分别为18.6%、19.2%),差异有显著性(P=0.024,P=0.043);原发灶与复发转移灶HER-2表达有较高的一致性,表达不一致占5.1%;原发灶与复发转移灶p53的阳性率差异不大,p53表达不一致占14.1%;复发转移灶Ki-67高表达者比原发灶多,Ki-67表达不一致占30.8%,差异有显著性(P0.001)。局部复发组和远处转移组各指标表达不一致的差异无显著性。结论 乳腺癌原发灶与复发转移灶ER、PR和Ki-67表达存在不一致性,HER-2表达有较高一致性。因此,检测乳腺癌复发转移灶中各指标表达对治疗方案选择和预后有重要意义。     

P53, bcl-2 and Ki-67 expression in adenoid cystic carcinoma of the palate. A clinico-pathologic study of 21 cases with long-term follow-up

Adenoid cystic carcinoma (ACC) is an indolent tumor that pursues a protracted clinical course with recurrences and late metastases. The aim of this study was to investigate immunohistochemically the expression of p53, bcl-2 protein, and Ki-67 in 21 cases of ACC of the palate, all with a minimum of 10 years and a maximum of 22 years of clinical follow-up. These results were also analyzed with regard to different clinical prognoses of the histologic subtypes of ACC. High expression of p53 and bcl-2 was noted in 19 out of 21 ACC cases (90%), in which most tumor cells (from 66% to 99%) proved to be immunopositive. A relation to the histologic types, clinical staging, and survival was not found. Therefore, the high immunoreactivity against these oncoproteins in the same tumor cells suggests that these two oncogenes may be involved since the early stage of carcinogenesis. Loss of function of the p53 protein combined with bcl-2 upregulation might give the tumor cells a double growth advantage, because uncontrolled proliferation is combined with a reduced cell death rate. The interaction with other oncogenes may then trigger a multistep process able to promote tumor progression. The low labeling index Ki-67 was detected in nine out of 21 cases (42%), with a low percentage of tumor cells (from 3% to 15%) being positive, whereas the remaining 12 cases were negative. We found no relation to the histologic types, clinical staging, and survival; however, the low proliferation rate could explain the natural course of tumor.     

Expression of cyclin D1, Ki-67 and PCNA in non-small cell lung cancer: prognostic significance and comparison with p53 and bcl-2

Uncontrolled cell proliferation is the hallmark of malignant tumours. Thus, the proliferative potential of tumour cells is an important prognostic factor. However, evaluation of the prognostic significance of the expression of proteins involved in regulation of cell proliferation remains controversial. In the present study, expression of Ki-67, PCNA and cyclin D1 was estimated in a group of 89 surgically resected non-small cell lung carcinomas using immunohistochemistry. The results were compared with expression of bcl-2 and p53 and with clinicopathological parameters including patients' survival. Ki-67 and PCNA were found to be moderately and highly expressed in 39% and 44% of the tumours, respectively. There was a strong correlation between Ki67 and PCNA expression. Forty five of 88 tumours (51%) showed overexpression of cyclin D1. Surprisingly, cyclin D1 was mainly localized in the cytoplasm and only a small group of tumours (9/88, 10%) showed nuclear staining as well. Bcl-2 and p53 expression was observed in 69% and 30% of the tumours, respectively. All these markers were found to be independent of clinicopathological parameters, except for Ki-67 and bcl-2 expression, which was associated with squamous cell carcinomas. It is concluded that none of the markers that were studied can be used as an independent prognostic factor, whereas the following combinations of markers may have favourable prognostic value: p53 positivity and low Ki-67 expression, p53 positivity and lack of cyclin D1 expression, bcl-2 positivity and low Ki-67 expression, and lack of cyclin D1 expression and low Ki-67 expression.     

Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas

Tumour growth is regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis). Until recently, the majority of the studies dealing with oncogenesis has been focused on the regulation of cell proliferation. There is now growing understanding that control of growth arrest and apoptosis play key roles in the development of human cancer and in cancer treatment. Some of the more heavily studied proteins of importance for the control of growth arrest and apoptosis are p53, p21, bcl-2 and bax. Alterations in the p53 protein may lead to malignant transformation and defect therapy response, most likely as a result of defective p53-dependent apoptosis. In addition, p21 (WAF1/CIP1) is involved in cell-cycle arrest and probably in induction of p53-dependent apoptosis. Proteins belonging to the bcl-2 family are also important for normal apoptosis. Overexpression of bcl-2 protein is thought to reduce the apoptotic capacity, while bax protein seems to be necessary for induction of apoptosis. In this study, we have immunostained tissues from 93 primary colon carcinomas and have examined the expression of p53, p21 (WAF1/CIP1), bcl-2 bax, pRb and cyclin D1 for evaluation of their roles in colon-cancer progression. A highly significant association between p53 accumulation and downregulation of p21 (WAF1/CIP1) was seen. We also found a strong association between reduced/absent p21 and the development of metastases and death due to cancer disease. Cyclin D1, bcl-2 and bax protein failed to have independent prognostic impacts. Bcl-2 and bax protein levels showed an inverse relationship. The results of the present study indicate that reduced p21 protein levels play an important role in progression of colon cancer. We concluded that evaluation of p21 expression in primary colon carcinomas at the time of surgery might be a valuable tool in defining patients with a high risk of developing metastases. Received: 22 June 1999 / Accepted: 24 September 1999     

Human papillomavirus infection in actinic keratosis and bowen's disease: comparative study with expression of cell-cycle regulatory proteins p21(Waf1/Cip1), p53, PCNA, Ki-67, and Bcl-2 in positive and negative lesions

We examined the presence of human papillomavirus (HPV) DNA in tissues of premalignant skin lesions, i.e., actinic keratosis (n = 13) and Bowen's disease (n = 62), taken from 69 Japanese immunocompetent and renal transplant recipient patients. Detection and typing of HPV DNA were performed using polymerase chain reaction (PCR) and sequence analysis or restriction fragment length polymorphism (RFLP) analysis, respectively. The positivity rates of HPV DNA in tissues of actinic keratosis and Bowen's disease were 77% and 65%, respectively. Twenty-seven HPV types were detected in 50 (67%) premalignant skin lesions, in which Z95963 (accession no. in the EMBL Databank), Z95968, AJ010823, and AJ000151 have been described as partial sequences of unknown HPV types. Furthermore, 2 unknown types, HPVX1 and HPVX2, were found in specimens of actinic keratosis. Sequence analysis showed that HPVX1 is related to HPV-37 (86.1% sequence homology) and that HPVX2 is related to HPV-38 (79.7%). These results indicate that various mucosal and epidermodysplasia verruciformis-related HPV types are associated with the pathogenesis of actinic keratosis and Bowen's disease. In addition, 24 specimens of HPV-positive or HPV-negative premalignant skin lesions were examined immunohistochemically for proliferating cells to determine biological differences between HPV-positive and HPV-negative lesions. Immunohistochemistry for p21(Waf1/Cip1), p53, proliferating cell nuclear antigen (PCNA), Ki-67, and Bcl-2 revealed that there was no significant difference in the cell proliferation activity between HPV-positive and HPV-negative lesions, suggesting that HPV infection alone does not induce cell proliferation in those lesions.