Value Of Ki-67 Labeling Index Research Articles

Prognostic and Predictive Value of Centrally Reviewed Ki-67 Labeling Index in Postmenopausal Women With Endocrine-Responsive Breast Cancer: Results From Breast International Group Trial 1-98 Comparing Adjuvant Tamoxifen With Letrozole

To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

Ki‐67 proliferative index predicts clinical outcome in patients with atypical or anaplastic meningioma

Meningiomas represent the second most common central nervous system neoplasms in adults and account for 26% of all primary brain tumors. Although most are benign, between 5% and 15% of meningiomas are atypical (grade II) whereas 1-2% are anaplastic meningiomas (grade III). Although histological grade is the most relevant prognostic factor, there are some unusual cases in which establishing a diagnosis of high-grade meningioma following 2000 World Health Organization (WHO) histological criteria is extremely difficult. Therefore, the aim of the present study was to evaluate the predictive value of Ki-67 labeling index and its contribution to current WHO classification in predicting tumor recurrence and overall survival in patients with high-grade meningiomas. A total of 28 patients (with 16 atypical meningiomas and 12 anaplastic meningiomas) were evaluated for demographic, clinical, radiological and therapeutic variables, and for Ki-67 immunohistochemistry. Median Ki-67 labeling index in the whole series was 7.0 (0.5-31.5) with no differences with respect to the histological grade (P = 0.87). In the univariate analysis, Ki-67 labeling index and postoperative Karnofsky performance status were identified as significant prognostic factors of tumor recurrence and overall survival. The multivariate analysis demonstrated that Ki-67 labeling index is the only independent predictor of both tumor recurrence and overall survival. More importantly, this predictive value was maintained in both patients with atypical and patients with anaplastic meningioma.

Expression of c-FLIP in Gastric Cancer and its Relation to Tumor Cell Proliferation and Apoptosis

BackgroundThe expression of c-FLIP (cellular Fas-associated death domain-like interleukin-1 β-converting enzyme (FLICE)-inhibitory protein), which is a member of the family of inhibitors of apoptosis, has been associated with tumor development and progression. The aim of this study was to evaluate the expression of c-FLIP in gastric cancer and its correlation with tumor cell proliferation, apoptosis and the clinicopathologic features.MethodsImmunohistochemical staining with anti-c-FLIP antibody was performed in 98 tissue samples obtained from gastric cancer patients who underwent surgical treatment. The apoptotic cells were visualized by terminal deoxynucleotidyl transferase (TdT) mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL), and the proliferative cells were visualized by staining with Ki-67 antibody.ResultsThe positive expression of c-FLIP in the gastric cancer tissues was demonstrated in 57.1% of the cases. The expression of c-FLIP was increased in the gastric cancer tissues compared with the matched normal gastric mucosa. The expression of c-FLIP was significantly associated with histologic differentiation (p=0.038). However, there was no association between the c-FLIP expression and the other clinicopathological parameters, including patient survival. The Ki-67 labeling index (KI) for the 98 tumors ranged from 7.6 to 85.0 with a mean KI of 50.4±15.7. The mean KI value of the c-FLIP positive tumors was 54.1±15.3 and this was significantly higher than that of the c-FLIP negative tumors (p=0.005). The apoptotic index (AI) for the 98 tumors ranged from 0.0 to 10.0 with a mean AI of 7.4±2.3. There was no significant difference between the c-FLIP expression and the AI (p=0.347).ConclusionsThese results suggest that the c-FLIP expression may be associated with tumor cell proliferation of gastric cancer.

Prognostic impact of cholangiocellular and sarcomatous components in combined hepatocellular and cholangiocarcinoma

Combined hepatocellular and cholangiocarcinoma (cHC-CC) is a rare type of liver cancer displaying both hepatocellular and cholangiocellular components. The cholangiocellular carcinoma (CC) in these tumors ranges from focal to prominent. Those cHC-CCs with sarcomatous features are reported to have a poor prognosis. To clarify whether the CC and sarcomatous component affects the prognosis, we classified 40 patients with cHC-CCs into 4 groups according to the presence of a sarcomatous component and the extent of the CC component. Seven (17.5%) tumors showed areas with a sarcomatous component. The remaining tumors were divided into a low-CC group (CC occupying <30% of the tumor, n = 12), a middle-CC group (30%-60%, n = 15), and a high-CC group (>60%, n = 6). Vascular invasion was more frequently present in the high-CC and sarcomatous group than in the other groups (P = .0007). No lymph node metastasis occurred in either the low- or the middle-CC groups, but it was detected in 3 (50%) cases of the high-CC group and in 2 (29%) cases of the sarcomatous group (P < .0001). There was a tendency for tumor size to increase from the low- to the middle- to the high-CC group. The Ki-67 labeling index values for the hepatocellular carcinoma, CC, and sarcomatous components were 11.4% +/- 12.9%, 25.4% +/- 18.3%, and 46.0% +/- 23.6%, respectively. The overall survival of patients in the high-CC and sarcomatous group was significantly poorer than that of patients in the low- and middle-CC groups (P = .0048). By multivariate analysis of overall survival, lymph node metastasis, histological subgroup, and vascular invasion were significant independent prognostic factors. A cHC-CC with a large CC component is as aggressive as cHC-CC with sarcomatous features.

Expression of Cyclooxygenase-2, p53 and Ki-67 in Gastric Cancer

It has been reported that p53 mutation may contribute to upregulate cyclooxygenase (COX)-2 expression that is observed in malignant tissues. These molecules are involved in carcinogenesis by affecting tumor cell proliferation. The aim of this study was to examine the relationship between COX-2 or p53 expression and clinico-pathological characteristics including tumor cell proliferation in gastric cancer. COX-2 and p53 expressions were investigated with immunostaining, in tissue specimens obtained from 119 patients who underwent surgery for gastric cancer. The Ki-67 labeling index (LI) was counted by Ki-67 immunostaining. COX-2 and p53 expressions correlated significantly with depth of tumor invasion. However, there was no association between COX-2 or p53 expression and survival. p53 expression did not correlate with COX-2 expression. There was no significant difference in various clinicopathological variables between Ki-67 LI subgroups. The mean Ki-67 LI value of COX-2 positive tumors was significantly higher than that of negative tumors. The mean Ki-67 LI value of p53 positive tumors was not significantly higher than that of negative tumors. The mean Ki-67 LI value of both COX-2 and p53 positive tumors was significantly higher than that of both negative tumors. These results imply that COX-2 expression is associated with tumor cell proliferation of gastric cancer.

Clinicopathologic study and Ki-67 proliferative marker evaluation in human osteosarcomas

BACKGROUND: Osteosarcoma is a relatively uncommon malignant neoplasm and little information has been reported on its cell proliferation using Ki-67. OBJECTIVES: Evaluate histological, clinical and immunohistochemical parameters using Ki-67 labeling index (LI), correlate one to another and with follow-up. MATERIAL AND METHOD: Fifty-seven patients with available clinicopathological data submitted to the study of cell proliferation as determined by Ki-67 expression measured by immunohistochemistry (IHC) staining using formalin-fixed paraffin embedded sections. In each sample, positive cells were quantified on at least a thousand nuclei and expressed as Ki-67 LI according to median value. RESULTS AND DISCUSSION: Non-significant correlations were observed in metastatic and non-metastatic cases when variables as surgery, tumor size, death and relapse were compared with Ki-67 LI values (cut-off of 45%). In the group of non-metastatic cases there was a direct correlation between higher values of Ki-67 index and better overall survival. Metastatic patients overall survival curve and LI high and low Ki-67 did not show significant differences. CONCLUSION: Based on our results the Ki-67 LI could be useful as a prognostic marker in patients without metastasis at diagnosis.

Biological features of bronchial squamous dysplasia followed up by autofluorescence bronchoscopy

Some dysplasias in the bronchial epithelium are thought to be precancerous lesions that can develop into squamous cell carcinomas. In this investigation, we assessed the biological behavior of bronchial squamous dysplasia in order to define which dysplasias have the potential to progress to squamous cell carcinoma. Using autofluorescence bronchoscopy, we followed up periodically localized dysplasias and examined for correlation between histological outcome and smoking status during the follow-up period, telomerase activity, Ki-67 labeling index, and p53 immunoreactivity of initial biopsy specimens. Ninety-nine dysplasias from 50 participants mainly with sputum cytology suspicious or positive for malignancy were followed up. Of 99 dysplasias, 3 dysplasias progressed to squamous cell carcinoma, 41 dysplasias remained as dysplasia, 6 dysplasias changed to metaplasia, 14 dysplasias changed to hyperplasia, and 35 dysplasias regressed to bronchitis or normal bronchial epithelium. There were no significant associations between histological outcome and smoking status. Mean initial telomerase activity and Ki-67 labeling index values in the dysplasias increased in proportion to the severity of the histological outcome at the second biopsy. There was also a significant difference between p53-positive and p53-negative dysplasia in terms of histological outcome at the second biopsy. Our results suggested that dysplasias with high telomerase activity, increased Ki-67 labeling index, and p53-positivity tended to remain as dysplasia and might have the potential to progress to squamous cell carcinoma. Patients with dysplastic lesions with these characteristics should be carefully followed up.

Prognostic Significance of Ki-67 Antigen Immunostaining (MIB-1 Monoclonal Antibody) in Ovarian Cancer

To assess the potential usefulness of Ki-67 antigen expression as a predictor of outcome in ovarian cancer through the analysis of MIB-1 monoclonal antibody reactivity. Cell proliferation and clinicopathologic variables were assessed in 26 patients with primary epithelial ovarian cancer who had undergone exploratory laparotomy. The expression of primary tumor proliferation related to Ki-67 antigen was immunohistochemically evaluated by MIB-1 monoclonal antibody. The value of Ki-67 labeling index (LI) ranged between 0 and 92.6% with a mean of 48.9%. Ki-67 LI correlated well with the mitotic index, but not the histological subtype. Ki-67 LI of more than 40%was defined as a higher proliferating tumor by a receiver operating characteristic curve analysis. Higher proliferating tumors were identified in 14 patients (54% of all subjects). The patients with higher proliferating tumors had a statistically significantly worse prognosis compared with those with lower proliferating tumors (p<0.001). The present study demonstrates that the proliferating index detected by Ki-67 antigen immunostaining is a useful factor for predicting the survival of patients with ovarian cancer.

PCNA and Ki-67 in central nervous system tumors: correlation with the histological type and grade.

Determination of proteins in the control of proliferation in normal cells helps a better understanding of cellular transformation and proliferation mechanisms. Measurement of proliferative activity is important in determining the tumor grade, recurrence span and malignancy. Proliferating cell nuclear antigen (PCNA) and Ki-67 are two of the nuclear markers used to demonstrate the proliferative phase of the cell cycle. In the present study, 63 central nervous system (CNS) tumors of various histologic types, diagnosed in Cukurova University Medical Faculty. Department of Pathology and graded according to WHO grading system were examined for PCNA and Ki-67 monoclonal antibodies using immunohistochemistry. Results were analyzed with statistical methods. Distribution of PCNA and Ki-67 LI (labeling index) values were determined for different tumor types. The highest PCNA and Ki-67 LI values were detected in medulloblastoma, malignant meningioma, primitive neuroectodermal tumor (PNET) and glioblastoma (GBM) groups, while pilocytic astrocytoma, meningioma, craniopharyngioma and oligodendroglioma showed the lowest values. In such tumors, the correlation between the increasing grade and PCNA and Ki-67 LI values were statistically significant. A correlation between the clinical outcome and Ki-67 and PCNA LI values was also detected. Conclusively, both markers can be used to evaluate the tumor grade and to asses the possibility of recurrence and malignancy in CNS tumors.

Relationship of Ki-67 labeling index to DNA-ploidy, S-phase fraction, and outcome in prostate cancer treated with radiotherapy.

Our purpose was to evaluate the relationship of Ki-67 labeling index (Ki67-LI) to deoxyribonucleic acid (DNA) ploidy, S phase fraction (SPF), other clinical prognostic factors, and clinical outcome for patients with prostate cancer treated by external beam radiotherapy. Tissue was retrieved from 42 patients who underwent transurethral resection of the prostate before treatment with external beam radiotherapy between 1987-1993. DNA histogram profiles were classified as diploid (diploid + near-diploid) and nondiploid (tetraploid + aneuploid). Immunohistochemical staining of Ki-67 by the MIB-1 monoclonal antibody was used to calculate Ki67-LI. Median patient follow-up was 62 months. Treatment failure was defined as two consecutive rises in serum prostate-specific antigen (PSA) or clinical evidence of disease recurrence. The mean and median Ki67-LIs were 3.1 and 2.4, respectively (range, 0-12.4). Mean Ki67-LI values were significantly associated with higher stage, Gleason score, and pretreatment PSA. Nondiploid tumors had significantly higher Ki67-LIs, as did patients who failed radiotherapy over the follow-up period. SPF was not significantly correlated with Ki67-LI. As a categorical variable, the most significant relationships were seen when Ki67-LI was subdivided into thirds around the median (Ki67-LI </=1.5%, Ki67-LI >1.5-3.5%, and Ki67-LI >3.5%). This trichotomous variable correlated significantly with pretreatment PSA (P = 0.0008), tumor stage (P = 0.016), Gleason score (P = 0.024), and treatment failure (P = 0.0015), but not with DNA-ploidy (P = 0.15). In actuarial univariate analyses, Ki67-LI appeared to be a more significant predictor of patient outcome (P = 0.003) than DNA-ploidy (P = 0.035). The Ki67-LI correlated with known prognostic factors such as pretreatment PSA, tumor stage, and Gleason score, and was also weakly related to DNA-ploidy. In comparison to DNA-ploidy, Ki67 LI seems to be a better correlate of treatment outcome.

Relationship of Ki‐67 labeling index to DNA‐ploidy, S‐phase fraction, and outcome in prostate cancer treated with radiotherapy

BACKGROUND Our purpose was to evaluate the relationship of Ki-67 labeling index (Ki67-LI) to deoxyribonucleic acid (DNA) ploidy, S phase fraction (SPF), other clinical prognostic factors, and clinical outcome for patients with prostate cancer treated by external beam radiotherapy. METHODS Tissue was retrieved from 42 patients who underwent transurethral resection of the prostate before treatment with external beam radiotherapy between 1987–1993. DNA histogram profiles were classified as diploid (diploid + near-diploid) and nondiploid (tetraploid + aneuploid). Immunohistochemical staining of Ki-67 by the MIB-1 monoclonal antibody was used to calculate Ki67-LI. Median patient follow-up was 62 months. Treatment failure was defined as two consecutive rises in serum prostate-specific antigen (PSA) or clinical evidence of disease recurrence. RESULTS The mean and median Ki67-LIs were 3.1 and 2.4, respectively (range, 0–12.4). Mean Ki67-LI values were significantly associated with higher stage, Gleason score, and pretreatment PSA. Nondiploid tumors had significantly higher Ki67-LIs, as did patients who failed radiotherapy over the follow-up period. SPF was not significantly correlated with Ki67-LI. As a categorical variable, the most significant relationships were seen when Ki67-LI was subdivided into thirds around the median (Ki67-LI ≤1.5%, Ki67-LI >1.5–3.5%, and Ki67-LI >3.5%). This trichotomous variable correlated significantly with pretreatment PSA (P = 0.0008), tumor stage (P = 0.016), Gleason score (P = 0.024), and treatment failure (P = 0.0015), but not with DNA-ploidy (P = 0.15). In actuarial univariate analyses, Ki67-LI appeared to be a more significant predictor of patient outcome (P = 0.003) than DNA-ploidy (P = 0.035). CONCLUSIONS The Ki67-LI correlated with known prognostic factors such as pretreatment PSA, tumor stage, and Gleason score, and was also weakly related to DNA-ploidy. In comparison to DNA-ploidy, Ki67 LI seems to be a better correlate of treatment outcome. Prostate 41:166–172, 1999. © 1999 Wiley-Liss, Inc.

Accumulation of p53 and Ki-67 Expression Do Not Predict Survival in Patients with Fibrillary Astrocytomas or the Response of These Tumors to Radiotherapy

To the Editor: I enjoyed reading the article by Hilton et al. (1) regarding the relationship among the accumulation of p53, Ki-67 expression, survival, and response to radiotherapy of astrocytomas. The authors conclude that p53 accumulation and Ki-67 (MIB-1) expression do not help in predicting the survival of patients with astrocytomas or in predicting whether a patient is likely to benefit from radiotherapy. Recently, we concluded a study regarding the relationship between Ki-67 labeling index (LI) and survival in patients operated on for a high-grade gliomas and treated after surgery with tamoxifen (2). Using the MIB-1 antibody, the Ki-67 antigen staining of surgical specimens was obtained in 26 patients operated on for malignant cerebral gliomas. After undergoing surgery, nine patients (Group A) started to receive 40 mg per day, eight (Group B) 80 mg per day, and nine (Group C) 120 mg per day tamoxifen. All patients received radiotherapy (4500-6000 cGy). The overall mean survival rate was 19.8 months (median, 12 mo); the 12- and 24-month survival rates were 47 and 23%, respectively. The Ki-67 LI ranged from 2.3 to 62% (mean, 24.1%; median, 20.5%). Excluding 2 patients who died during the postoperative period, we analyzed the survival rates of the remaining 24 patients (8 in Group A, 7 in Group B, and 9 in Group C) in relation with the value of Ki-67 LI. The patients were divided into three groups, with different survival rates: Group L) Ki-67 LI A3 10%, with a mean survival rate of 30.7 months. (median, 31.5 mo); Group M) from 10.1% to 30%, with a mean survival rate of 15.8 months (median, 12 mo); and Group H) >30%, with a mean survival rate of 20.2 months (median, 15 mo). The 12-month survival rate was 60% in Group L, 43% in Group M, and 67% in Group H (p 3D0.08). To our knowledge, ours represents the first attempt to correlate the survival rate of patients with gliomas treated with tamoxifen with different levels of MIB-1 immunostaining and, thus, with different cell growth potential. Our preliminary observations seem to confirm the efficacy of tamoxifen in modifying the survival of malignant gliomas and seem to indicate that tumors with a lower LI and those with an LI of more than 30% could be associated with a better response than gliomas belonging to Group M, which could have a higher tumor proliferation rate in comparison with those of Group L and a lower sensitivity to protein kinase C antagonists than those of Group H. However, to confirm our preliminary observations and suggestions, larger studies are warranted. Luciano Mastronardi Fabrizio Puzzilli Rome, Italy Antonio Guiducci Terni, Italy

Ki-67 immunoreactivity in human central nervous system tumors: a study with MIB 1 monoclonal antibody on archival material.

Paraffin-embedded surgical specimens from 136 primary human central nervous system (CNS) tumors, including 50 meningiomas, 24 astrocytomas, 26 anaplastic astrocytomas, 9 glioblastomas, 8 oligodendrogliomas, 4 ependymomas, 1 anaplastic ependymoma, 2 subependymomas, 9 medulloblastomas, and 3 paragangliomas, were immunostained, following microwave processing, using a streptavidin/peroxidase method and the MIB 1 monoclonal antibody (mAb) against the Ki-67 antigen. The following mean Ki-67 labeling index (LI) values +/- SD were found: meningiomas, 2.47 +/- 1.83; astrocytomas, 2.03 +/- 2.03; anaplastic astrocytomas, 12.80 +/- 6.29; glioblastomas, 14.57 +/- 6.77; oligodendrogliomas, 5.06 +/- 4.78; ependymomas, 2.63 +/- 2.58; anaplastic ependymoma, 6.89; subependymomas, 1.79 +/- 1.54; medulloblastomas, 18.77 +/- 9.65; and paragangliomas, 2.19 +/- 2.51. Our findings indicate that while malignant CNS tumors always exhibited high Ki-67 LI values, and benign CNS tumors generally displayed lower values, increased immunoreactivity for Ki-67 epitopes (Ki-67 LI higher than 4) was noted in a number of meningiomas, astrocytomas, ependymomas, oligodendrogliomas and paragangliomas, contrasting with their benign histological features. Further investigations of the Ki-67 immunoreactivity in CNS tumors and systematic correlation with the postoperative follow-up of patients are necessary to determine the value of Ki-67 LI in predicting the biological behavior of CNS neoplasms.

P53 and c-erbB-2 protein expression in breast carcinomas. An immunohistochemical study including correlations with receptor status, proliferation markers, and clinical stage in human breast cancer.

Receptor status, proliferative activity, loss of differentiation, inactivation of tumor suppressor genes, and overexpression of oncogenes are related events that may affect the prognosis of patients with breast cancer. Ninety-seven unselected breast carcinomas were immunostained for estrogen and progesterone receptors, Ki-67 proliferation-associated antigen, p53 tumor suppressor gene product (p53), and c-erbB-2 protein. Immunohistochemical results and clinical data were compared. Altered p53 expression (regarded as indirect indication of inactivating gene alterations) was found in 25.8% of cases and was associated with a high Ki-67 labeling index, high mitotic count, and high histologic grade, with c-erbB-2 overexpression, and with negative estrogen and progesterone receptor status. p53 immunostaining could be found also in cytologic samples and correlated with p53 immunoreactivity on frozen sections of the corresponding tumors. c-erbB-2 protein overexpression was seen in 24.7% of cases and was associated with p53 altered expression and negative receptor status. Double immunohistochemical staining showed p53 and c-erbB-2 immunoreactivity in the same cells. Median and mean +/- standard deviation Ki-67 labeling index values were 15 and 16.32 +/- 10.05, respectively. Ki-67 labeling index was correlated with high mitotic count and was positively associated with histologic grade, negative progesterone receptor status, and p53 expression. Estrogen receptor status was not associated with any histologic or clinical parameters, whereas progesterone receptor status was associated with grading. The direct relation of p53 protein alterations with c-erbB-2 overexpression may be interpreted in light of the multistep model of tumor progression. Cases with altered expression of both p53 and c-erbB-2 proteins could be interpreted as having lost one inhibitory control mechanism of cell proliferation and having gained one activator of the malignant potential. However, in comparing cases with the p53 + c-erbB-2 + phenotype with cases showing positivity for only one of these gene products, no association with higher stages was seen. Detection of p53 altered expression on cytologic samples of malignant tumors may have diagnostic relevance, and p53 immunostaining may prove to be an additional diagnostic criterion in cytologic diagnosis.