Shape analysis of tumor cell nuclei in ependymomas by means of Fourier analysis

OBJECTIVE: To study the prognostic significance of nuclear shape analysis in ependymomas. STUDY DESIGN: Tumor cell nuclei in surgical specimens of primary resected ependymomas from 30 patients were evaluated by means of Fourier analysis of nuclear contours, conventional morphometric features (nuclear area, shape factor) and the Ki-67 proliferation index. Fourier analysis can be used for decomposing an irregular nuclear contour by calculating "Fourier amplitudes." Tumors with different tumor grades according to the World Health Organization were compared, as were patients with and without recurrence of ependymomas. Planimetric data were further correlated with the Ki-67 index. RESULTS: t Test and multivariate analysis showed distinct differences between ependymomas with tumor grade 3 and the other tumor grades. Cross-validated, stepwise discriminant analysis with the event of recurrence as grouping variable revealed correct reclassification in 16/18 cases without recurrence and of 10/12 cases with recurrence. When considering just intracranial ependymomas with total surgical removal, Fourier amplitudes provided 100% correct reclassification concerning recurrence. Proliferation index, in contrast, showed considerable overlap between all tumor grades and between cases with and without recurrence. CONCLUSION: Quantification of the shape of tumor cell nuclei in ependymomas by means of Fourier analysis has prognostic significance and seems to be superior to the Ki-67 index.     

Topometric analysis of diffuse astrocytomas

OBJECTIVE: To investigate differences between astrocytomas of WHO grade 2 and anaplastic astrocytomas of WHO grade 3 in terms of topometric variables characterizing individual tumor cell nuclei. STUDY DESIGN: Paraffin sections from surgical specimens from 25 astrocytomas (grade 2, n = 11; grade 3, n = 14) were analyzed by means of an image analysis system. At least 300 tumor cell nuclei were measured in the region with the highest Ki-67 proliferation index. Three different kinds of topometric variables were determined for each tumor cell nucleus: (1) several distances; (2) the variable Angle 2/1, the angle between the straight lines representing the distance to the nearest and second-nearest nucleus; and (3) the number of neighbors according to our mathematical definition. RESULTS: Most topometric variables showed distinct differences between the 2 tumor grades (multivariate analysis of variance), with 88% cases correctly reclassified by means of cross-validated discriminant analysis. The variables with the highest discriminatory power were the SD of Angle 2/1 and the ratio between the distance to the second-nearest and nearest tumor cell nucleus, with lower values for these variables in anaplastic astrocytomas. Even variables concerning neighborhood relationships showed significant differences. CONCLUSION: The results of this pilot study show that this first set of topometric variables is sufficient to detect differences between topologic characteristics of tumor cell nuclei in astrocytomas grade 2 and grade 3. Topometry seems to be an important tool for grading astrocytomas.     

Correlation between preoperative magnetic resonance spectroscopic data on high grade gliomas and morphology of Ki-67-positive tumor cell nuclei

OBJECTIVE: To investigate possible statistical correlations between metabolic data from preoperative proton magnetic resonance spectroscopy (1HMRS) and morphology of proliferating tumor cell nuclei in anaplastic gliomas and glioblastomas. STUDY DESIGN: Ki-67-positive tumor cell nuclei in paraffin sections of surgical specimens from 36 patients (7 anaplastic gliomas, World Health Organization grade 3; 29 glioblastomas, World Health Organization grade 4) were investigated by means of a digital image analysis system. Stringent inclusion criteria were formulated for all cases with respect to histologic quality and spectroscopic examination. As morphometric variables, nuclear area, shape variables (roundness factor, size-invariate Fourier amplitudes) and density of Ki-67-positive tumor cell nuclei per reference area were determined. RESULTS: Correlation analysis according to Spearman revealed a significant positive correlation between the total creatine (TCR) peak and nuclear area (P = .005). This correlation was also found within the glioblastoma group (P = .019). There was also a significant negative correlation of nuclear area with the ratio between choline and TCR in all cases (P = .014) and within the glioblastoma group (P = .046). No significant correlation of spectroscopic data was found with nuclear shape or density of Ki-67-positive tumor cell nuclei. CONCLUSION: The results demonstrate a correlation between spectroscopic data and morphology of proliferating tumor cell nuclei (nuclear size) in high grade gliomas. This study is part of a detailed investigation of the interrelationship between preoperative 1HMRS and quantitative histomorphology of gliomas.     

EGFR gene amplification in glioblastomas. Is there a relationship with morphology of tumor cell nuclei and proliferative activity?

OBJECTIVE: To confirm a relationship between histomorphology of glioblastomas and amplification of the gene for the epidermal growth factor receptor (EGFR) as the most important molecular biologic alteration in these tumors. STUDY DESIGN: In paraffin sections of surgical specimens from 71 primary resected glioblastomas, tumor cell nuclei in the region with the highest proliferative activity (Ki-67 immunostaining) were investigated morphometrically. Shape variables (roundness factor, Fourier amplitudes) and nuclear area were measured. Additionally, the numerical density of Ki-67-positive tumor cell nuclei was estimated. Differential polymerase chain reaction (PCR) was performed from paraffin sections of the same tumor area. The signals for the EGFR gene and IFN gamma reference gene were quantified densitometrically. RESULTS: Cases with distinct EGFR gene amplification (EGFR/IFN ratios > 5) revealed significantly lower mean values for several Fourier amplitudes, indicating a more regular nuclear shape when compared with cases without evidence of EGFR gene amplification (EGFR/IFN-ratios < or = 1). The Ki-67 index and nuclear area showed no significant differences between these groups. Although a large variation in nuclear morphology was observed for cases without evidence of EGFR gene amplification, discriminant analysis based on morphometric variables provided a good separation of these cases from cases with distinct EGFR gene amplification, with a high percentage of statistically correct reclassified cases. CONCLUSION: Our results provide evidence of a relationship between genetic alterations and histomorphology of glioblastomas.     

Regional heterogeneity of EGFR gene amplification and nuclear morphology in glioblastomas. An investigation using laser microdissection and pressure catapulting

OBJECTIVE: To study the regional heterogeneity of epidermal growth factor receptor (EGFR) gene amplification (EGFR-GA) in glioblastomas, considering the relationship between this mutation and morphology of tumor cell nuclei. STUDY DESIGN: Tissue samples gained by laser microdissection and pressure catapulting were used for the performance of differential polymerase chain reaction in 32 morphologically different regions from 7 glioblastomas. Semiquantitative determination of EGFR expression and image analysis of tumor cell nuclei were performed in the same regions. RESULTS: Distinct regional differences concerning the degree of EGFR-GA were found in 2 tumor cases. When comparing regions with different degrees of gene amplification within these cases, morphologic differences in tumor cell nuclei were observed. The other tumor cases also showed distinct intratumoral heterogeneity concerning histomorphology but no regional heterogeneity in the degree of EGFR-GA. When comparing regions with a low densitometric EGFR/interferon (INF) band ratio (< 2.19, n = 18) and a high EGFR/IFN band ratio (> 4.39, n = 14), the latter type of region showed a significantly higher percentage of Ki-67--positive tumor cell nuclei and lower values for several shape variables (Fourier amplitudes), indicating a tendency toward a more regular nuclear shape in regions with distinct EGFR-GA. For the EGFR/IFN band ratio, a significant correlation was found with several morphometric variables, especially those of nuclear shape and distances between nuclei. CONCLUSION: In glioblastomas showing regional heterogeneity in the degree of EGFR-GA, morphology of tumor cell nuclei has been shown to be different when comparing regions with different degrees of EGFR-GA. Glioblastomas may also show distinct regional heterogeneity of histomorphology without evidence of regional heterogeneity of EGFR-GA. A significant statistical association has been confirmed between the degree of EGFR-GA and quantitative morphology of tumor cell nuclei.     

Prognostic biomarkers in renal cell carcinoma: relevance of DNA ploidy in predicting disease-related survival

OBJECTIVE: To investigate the prognostic value of DNA ploidy, Ki-67 index and p53 expression in relation to disease-related survival in a consecutive series of patients with renal cell carcinoma (RCC). MATERIAL AND METHODS: The study group consisted of 64 RCC patients treated by radical nephrectomy. Histological type, pathological staging and nuclear anaplasia were assessed according to the WHO classification, TNM system and Fuhrman grading criteria, respectively. Ploidy was determined by DNA flow cytometry using two sampling methods (frozen vs paraffin-embedded tissue). Ki-67 and p53 were evaluated by immunohistochemistry techniques using two cutoff points (10% vs mean value) for staining interpretation. Kaplan-Meier and Cox regression analyses were used for prognostic evaluation. RESULTS: Thirty-one tumors (48.4%) showed DNA diploidy and 33 (51.6%) were DNA aneuploid. Concordance between both ploidy measurement methods was found in 85.5% of cases (p=0.0455). The mean values for Ki-67 and p53 immunostaining were 3.65% (0-23.5%) and 5.90% (0-55.9%), respectively. DNA ploidy significantly correlated with staging, tumor size (pT), nuclear grading, and Ki-67 (mean value cutoff). Ki-67 (10% cutoff) correlated with staging and pT, while p53 (mean value cutoff) was associated with Ki-67 (mean value cutoff). There were significant differences between survival curves for pathological stage, pT, nuclear grade, ploidy, Ki-67 (both cutoffs), and p53 (10% cutoff). By univariate regression analysis, stage III and stage IV, pT3, aneuploidy, high Ki-67 (both cutoffs), and p53 overexpression (10% cutoff) showed significant correlations with worse disease-related survival. In addition, DNA aneuploidy significantly correlated with poor prognosis within stages I/II (p=0.0355) and stages III/IV (p=0.0138) of the disease. CONCLUSION: The results indicate that DNA ploidy has relevant prognostic value in RCC, adding useful information to the classic histopathological indicators of clinical outcome.     

Further testing of morphometric grading in T(A,1) urothelial carcinomas of the urinary bladder and the additional value of p53 immunoquantitation

OBJECTIVE: To analyze the value for grading of a previously developed quantitative morphometric/cytometric multivariate grading model (consisting of the mean nuclear area of the 10 largest nuclei (MNA-10, mitotic activity index = MAI and Ki-67 area% = Ki-67) in two new independent test sets of urothelial carcinomas (UCs) of the urinary bladder and to evaluate the additional value of p53 area% (p53) in this model. STUDY DESIGN: Ki-67 immunoquantitation, morphometric MAI and MNA-10 assessments using a previously described, strict protocol and matching of the resulting morphometric grade with subjective grade in two test sets of 154 T(A,1) UCs of the bladder (consensus grade between two independent observers). Further testing of this morphometric grading model was performed in 57 cases that lacked initial interobserver agreement on grade. Single and multivariate analysis of all features (including p53) was performed. RESULTS: With the previously developed morphometric/cytometric grading model, 93% (grade 1 vs. 2) and 91% (grade 2 vs. 3) of the consensus cases were correctly classified. These percentages were very similar to previous results, suggesting that the model is robust. Of the 57 cases that lacked initial interobserver agreement on grade, 53/57 (93%) were classified unambiguously as grade 1, 2 or 3 with the quantitative morphometric/ cytometric grading model. In the exploratory analysis, p53 was significant but with more overlap than the other features had. In multivariate analysis p53 did not improve the overall classification result of the original morphometric/cytometric model. CONCLUSION: The value of MNA-10, MAI and Ki-67 for grading in T(A,1) urothelial carcinomas of the urinary bladder was confirmed. p53 Did not improve overall grading classification of this combination.     

Cell kinetics analysis in stage I endometrial carcinoma as determined by image cytometry and immunohistochemistry. Correlation with clinicopathologic characteristics

OBJECTIVE: To test the significance of various proliferative indices in endometrial carcinoma (EC) since previous investigations failed to yield consistent results that would establish them as factors of clinical importance. STUDY DESIGN: Seventy patients with EC were evaluated for various proliferative indices (mitotic index, Ki-67 index, argyrophilic nucleolar organizer (AgNOR) number and area per nucleus, and p53 protein expression) in relation to image cytometry (nuclear area, diameter and roundness) and standard clinicopathologic features (age, histologic type and grade, and depth of invasion). We also tested the proliferation index (PI), which combines the Ki-67 index and AgNOR area in Ki-67-positive nuclei. Slides from each case were double stained for Ki-67 antigen and AgNOR proteins for this purpose. RESULTS: Mitotic counts were significantly higher in papillary-serous (vs. endometrioid) tumors (P = .0001), high grade (vs. low grade) tumors (P = .0001), deeply invasive (P = .017) and p53-positive tumors (P = .017). AgNOR counts correlated only with age (higher in older women, P = .002), while the PI correlated with mitotic counts (P = 0.28) and marginally with depth of invasion (P = .06). Morphometric variables were associated just with histologic type and grade. p53 Protein was expressed exclusively in invasive tumors and was related strongly to histologic type (P = .0029) and grade (P = .0001). CONCLUSION: Our data reestablish the value of classic histopathologic features (mitotic index, histologic type and grade) as the most important tools for EC evaluation. In addition, we suggest that p53 immunostaining may be used for predicting aggressive behavior in EC.     

Prognostic significance of augmented metallothionein (MT) expression correlated with Ki-67 antigen expression in selected soft tissue sarcomas

In soft tissue sarcomas, the most important prognostic criteria include extent of malignancy (G), size of the tumour and intensity of Ki-67 antigen expression. In recent times expression of metallothionein (MT) in cells of some malignant processes of epithelial origin was found to correlate with intensity of Ki-67 antigen expression and to carry a possible prognostic significance. The present study aimed at a demonstration of prognostic value of MT expression and at comparing it with Ki-67 antigen expression and G grade in selected soft tissue sarcomas. Immunohistochemical studies were performed on paraffin sections in 54 cases of malignant fibrous histiocytoma (MFH), 18 cases of liposarcoma and 20 cases of synovial sarcoma. The extent of MT and Ki-67 antigen expression was evaluated and an attempt was made to correlate the results with each other and with grade of the tumour. Expression of MT was evident both in the cytoplasm and in cell nuclei of all studied sarcomas. The most pronounced MT expression was noted in MFH-type tumours. The extent of Ki-67 antigen expression was similar in MFH and liposarcoma and was the lowest in synovial sarcoma. In MFH, liposarcoma and synovial sarcoma a pronounced positive correlation was documented between expression of MT and Ki-67 antigen (r=0.85; p<0.001; r=0.93, p<0.0001; r=0.79, p<0.0001). In all types of the tumours a positive relation was detected between MT expression, expression of Ki-67 and G grade of malignancy in the tumour. Moreover, patients with higher MT expression in the studied tumours demonstrated a shorter survival. MT expression in soft tissue tumours of MFH, liposarcoma and synovial sarcoma type strongly correlated with intensity of proliferation (Ki-67) and G grade and could be useful in defining the extent of malignancy and in prognostic appraisal in the tumours.     

Comparison of cell proliferation in breast carcinoma using image analysis (Ki-67) and flow cytometric systems.

Cellular proliferation has been implicated as an important predictor of biologic behavior in breast cancer. Cellular proliferation of 95 breast carcinomas was evaluated by comparing Ki-67 immunoreactivity in frozen sections quantitated by image analysis with S-phase and S + G2/M phase fraction determined by flow cytometry on nuclei extracted from fixed, paraffin-embedded sections (modified Hedley's technique). These parameters were correlated with traditional morphologic features of histologic grade, including mitotic count. Ki-67 immunoreactivity correlated with S-phase fraction determined by flow cytometry (r = .41, P = .001) and with S + G2/M phase fraction determined by flow cytometry (r = .29, P = .008). There was also a correlation between histologic grade and Ki-67 immunoreactivity (r = .30, P = .004) and between histologic grade and S-phase fraction (r = .42, P = .0001). Mitotic count correlated with Ki-67 immunoreactivity (r = .25, P = .015) and with S-phase fraction (r = .35, P = .001). Image and flow cytometric analysis systems provide comparable measurements of cellular proliferation; their measurements correlate with histologic grade and mitotic count in breast cancer.     

DTI定量参数对脑胶质瘤的诊断价值及其与血管内皮生长因子、细胞核增殖相关抗原的关系

目的:探讨扩散张量成像(DTI)定量参数对脑胶质瘤的诊断价值及其与血管内皮生长因子(VEGF)、细胞核增殖相关抗原(Ki-67)的关系。方法:选取2014年6月到2017年6月期间在我院接受治疗的90例脑胶质瘤患者,根据病理分级的不同分为中低级别组(n=46)和高级别组(n=44),比较两组患者表观扩散系数(ADC)值、各向异性分数(FA)值、相对表观扩散系数(rADC)值、相对各向异性分数(rFA)值、VEGF和Ki-67的阳性率,分析ADC值、FA值、rADC值、rFA值与VEGF、Ki-67表达的相关性。结果:高级别组的ADC值、FA值、rADC值和rFA值低于中低级别组(P0.05)。高级别组病理组织中VEGF、Ki-67的阳性表达率高于中低级别组(P0.05)。经Spearman相关分析显示,ADC值、FA值、rADC值和rFA值与VEGF、Ki-67的表达水平均呈负相关(P0.05)。结论:DTI定量参数与脑胶质瘤病理分级和VEGF、Ki-67的表达水平密切相关。     

Washless double staining of unfixed nuclei for flow cytometric analysis of DNA and a nuclear antigen (Ki-67 or bromodeoxyuridine).

Washless methods for double staining of nuclear antigen and DNA in unfixed nuclei were compared with established methods for staining of fixed cells. The methods were tested on phytohemagglutinin (PHA)-stimulated normal human blood lymphocytes for the double staining of 1) Ki-67 antigen and DNA and 2) bromodeoxyuridine (BrdUrd) and DNA, in continuously BrdUrd-labeled cells. With respect to the discrimination between antigen-positive and -negative subpopulations, there was no statistically significant differences between the results from direct (Ki-67) or indirect (Ki-67 or BrdUrd) washless staining of unfixed nuclei and the results from staining of fixed cells. Washless staining of unfixed nuclei was found to be rapid and simple and resulted in greater precision of the DNA analysis and in less aggregation and loss of cells.     

Histogram Profiling of Postcontrast T1-Weighted MRI Gives Valuable Insights into Tumor Biology and Enables Prediction of Growth Kinetics and Prognosis in Meningiomas

BACKGROUND: Meningiomas are the most frequently diagnosed intracranial masses, oftentimes requiring surgery. Especially procedure-related morbidity can be substantial, particularly in elderly patients. Hence, reliable imaging modalities enabling pretherapeutic prediction of tumor grade, growth kinetic, realistic prognosis, and—as a consequence—necessity of surgery are of great value. In this context, a promising diagnostic approach is advanced analysis of magnetic resonance imaging data. Therefore, our study investigated whether histogram profiling of routinely acquired postcontrast T1-weighted images is capable of separating low-grade from high-grade lesions and whether histogram parameters reflect Ki-67 expression in meningiomas. MATERIAL AND METHODS: Pretreatment T1-weighted postcontrast volumes of 44 meningioma patients were used for signal intensity histogram profiling. WHO grade, tumor volume, and Ki-67 expression were evaluated. Comparative and correlative statistics investigating the association between histogram profile parameters and neuropathology were performed. RESULTS: None of the investigated histogram parameters revealed significant differences between low-grade and high-grade meningiomas. However, significant correlations were identified between Ki-67 and the histogram parameters skewness and entropy as well as between entropy and tumor volume. CONCLUSIONS: Contrary to previously reported findings, pretherapeutic postcontrast T1-weighted images can be used to predict growth kinetics in meningiomas if whole tumor histogram analysis is employed. However, no differences between distinct WHO grades were identifiable in out cohort. As a consequence, histogram analysis of postcontrast T1-weighted images is a promising approach to obtain quantitative in vivo biomarkers reflecting the proliferative potential in meningiomas.     

Correlation between amplification of the gene for the epidermal growth factor receptor (EGFR), data from preoperative proton-MR-spectroscopy (1HMRS) and histomorphometric data of glioblastomas

OBJECTIVE: To investigate a correlation between preoperative data from proton-MR-spectroscopy (1HMRS), genomic alterations (epidermal growth growth factor receptor [EGFR] gene amplification) and histomorphometric data from glioblastomas. STUDY DESIGN: In surgical specimens from 18 patients with glioblastomas, the degree of amplification of the gene for EGFR was determined in the region with the largest Ki-67 proliferation index by differential polymerase chain reaction. RESULTS: Correlation analysis showed significant positive correlation between degree of EGFR gene amplification and choline and total creatine (CHO/TCR) ratio, indicating increased membrane turnover. Cases with a high EGFR/interferon ratio showed a tendency toward a low lipid peak, whereas cases with a low EGFR/interferon ratio showed a large variation of the lipid peak. Differences were observed regarding quantitative histomorphologic data of tumor cell nuclei, especially nuclear size and shape. Together with the EGFR/interferon ratio, these morphometric data provided a good reclassification of cases with low and with high values for both spectroscopic variables by means of cross-validated linear discriminant analysis. CONCLUSION: The results provide further evidence for the biologic significance of metabolic data from preoperative 1HMRS, because these metabolic data showed a significant statistical relationship with histomorphology and a frequently occurring molecular biologic alteration (EGFR gene amplification) in glioblastomas.     

Risk Factors Associated with Discordant Ki-67 Levels between Preoperative Biopsy and Postoperative Surgical Specimens in Breast Cancers

Purpose

The Ki-67 labelling index is significant for the management of breast cancer. However, the concordance of Ki-67 expression between preoperative biopsy and postoperative surgical specimens has not been well evaluated. This study aimed to find the correlation in Ki-67 expression between biopsy and surgical specimens and to determine the clinicopathological risk factors associated with discordant values.

Patients and Methods

Ki-67 levels were immunohistochemically measured using paired biopsy and surgical specimens in 310 breast cancer patients between 2008 and 2013. ΔKi-67 was calculated by postoperative Ki-67 minus preoperative levels. The outliers of ΔKi-67 were defined as [lower quartile of ΔKi-67–1.5 × interquartile range (IQR)] or (upper quartile + 1.5 × IQR) and were evaluated according to clinicopathological parameters by logistic regression analysis.

Results

The median preoperative and postoperative Ki-67 levels were 10 (IQR, 15) and 10 (IQR, 25), respectively. Correlation of Ki-67 levels between the two specimens indicated a moderately positive relationship (coefficient = 0.676). Of 310 patients, 44 (14.2%) showed outliers of ΔKi-67 (range, ≤-20 or ≥28). A significant association with poor prognostic factors was found among these patients. Multivariate analysis determined that significant risk factors for outliers of ΔKi-67 were tumor size >1 cm, negative progesterone receptor (PR) expression, grade III cancer, and age ≤35 years. Among 171 patients with luminal human epidermal growth factor receptor 2-negative tumors, breast cancer subtype according to preoperative or postoperative Ki-67 levels discordantly changed in 46 (26.9%) patients and a significant proportion of patients with discordant cases had ≥1 risk factor.

Conclusion

Ki-67 expression showed a substantial concordance between biopsy and surgical specimens. Extremely discordant Ki-67 levels may be associated with aggressive tumor biology. In patients with luminal subtype disease, clinical application of Ki-67 values should be cautious considering types of specimens and clinicopathological risk factors.     

神经胶质瘤中PTEN、Ki-67和HIF-1α的表达及临床意义

目的:抑癌基因PTEN、癌基因Ki-67及HIF-1α对多种人类肿瘤的恶性进展均起重要的调控作用。本研究主要探讨PTEN、Ki-67及HIF-1α在人脑胶质瘤中的表达及临床意义,为胶质瘤患者预后的判定、分子病理学的诊断、基因靶向的治疗奠定理论基础。方法:在83例原发性人脑胶质瘤组织样本中,通过免疫组化的方法检测PTEN、Ki-67及HIF-1α的表达情况,并分析其表达相互间及其表达与肿瘤恶性级别之间的相关性。结果:在正常脑组织中,PTEN的表达均为阳性,Ki-67的表达均为阴性,10%(1/10)的样本HIF-1α的表达为阳性。在胶质细胞瘤中,PTEN的表达显著降低(P=0.001),而Ki-67(P0.001)和HIF-1α(P=0.001)的表达明显增高。随肿瘤恶性级别的增高,PTEN的表达呈降低趋势(P0.001),而Ki-67和HIF-1α的表达呈升高趋势(两者P均0.001)。相关性分析表明,PTEN的表达与Ki-67和HIF-1α的表达呈负相关(r值分别为-0.289和-0.304;P值分别为0.008和0.005),Ki-67的表达与HIF-1α的表达呈正相关(r=0.833;P0.001)。结论:胶质瘤组织缺乏抑癌基因PTEN蛋白的表达,而高度表达癌基因Ki-67和HIF-1α。抑癌基因PTEN表达减少或失活,癌基因Ki-67和HIF-1α的过表达对胶质瘤恶性进展可能起到至关重要的作用。PTEN、Ki-67和HIF-1α蛋白的联合检测对胶质瘤恶性程度和预后的判定有十分重要的临床意义。     

Expression of p53, bcl-2 and Ki-67 in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix

OBJECTIVE: To assess the expression of p53, bcl-2 and Ki-67 in the progression of cervical neoplasia. STUDY DESIGN: A total of 131 cervical specimens, consisting of normal cervical epithelium (n = 43), cervical intraepithelial neoplasia (CIN) lesions (n =40) and cervical squamous cell carcinomas (SCCs) (n = 48) were examined immunohistochemically in paraffin sections for expression of p53, bcl-2 and Ki-67. RESULTS: Immunoreactivity of p53 was found in 27% of SCC cases, but it had no significant relationship with SCC staging (p = 0.791). Immunoreactivity of bcl-2 was observed in 33% of CIN 3 cases. We found a significant relationship (chi2 test: p = 0.009) between the expression of bcl-2 and CIN grading. Ki-67 index was higher in high grade CIN (HGCIN: CIN 2 and 3) and SCC lesions compared to normal cervices. Ki-67 index showed a correlation with bcl-2 protein expression (p = 0.030), but not with p53 protein expression (p = 0.239). CONCLUSION: HGCIN is an early stage to demonstrate the alteration of bcl-2 and Ki-67 expressions. Progression of neoplasia in the uterine cervix is accompanied by an increase of antiapoptotic protein, bcl-2 as well as cellular proliferation.     

Signal Intensities in Preoperative MRI Do Not Reflect Proliferative Activity in Meningioma

BACKGROUND: Identification of high-grade meningiomas in preoperative magnetic resonance imaging (MRI) is important for optimized surgical strategy and best possible resection. Numerous studies investigated subjectively determined morphological features as predictors of tumor biology in meningiomas. The aim of this study was to identify the predictive value of more reliable, quantitatively measured signal intensities in MRI for differentiation of high- and low-grade meningiomas and identification of meningiomas with high proliferation rates, respectively. PATIENTS AND METHODS: Sixty-six patients (56 World Health Organization [WHO] grade I, 9 WHO grade II, and 1 WHO grade I) were included in the study. Preoperative MRI signal intensities (fluid-attenuated inversion recovery [FLAIR], T1 precontrast, and T1 postcontrast as genuine and normalized values) were correlated with Ki-67 expression in tissue sections of resected meningiomas. Differences between the groups (analysis of variance) and Spearman rho correlation were computed using SPSS 22. RESULTS: Mean values of genuine signal intensities of meningiomas in FLAIR, T1 native, and T1 postcontrast were 323.9 ± 59, 332.8 ± 67.9, and 768.5 ± 165.3. Mean values of normalized (to the contralateral white matter) signal intensities of meningiomas in FLAIR, T1 native, and T1 postcontrast were 1.5 ± 0.3, 0.8 ± 0.1, and 1.9 ± 0.4. There was no significant correlation between MRI signal intensities and WHO grade or Ki-67 expression. Signal intensities did not differ significantly between WHO grade I and II/III meningiomas. Ki-67 expression was significantly increased in high-grade meningiomas compared with low-grade meningiomas (P < 0.01). Objectively measured values of MRI signal intensities (FLAIR, T1 precontrast, and T1 postcontrast enhancement) did not distinguish between high-grade and low-grade meningiomas. Furthermore, there was no association between MRI signal intensities and Ki-67 expression representing proliferative activity.Meningiomas are among the most common brain tumors. Their incidence is about 1%, and they account for almost one third of all primary intracranial masses. The majority of meningiomas are very slowly growing and nonsymptomatic or minimally symptomatic entities, discovered as incidental findings on neuroimaging [1]. The World Health Organization (WHO) classification system distinguishes 3 histological grades and 15 subtypes and is a well-accepted tool for prediction of prognosis. Although most meningiomas are benign masses, certain histological subtypes reveal very high recurrence rates despite the tumors’ seemingly total removal. Grade II (atypical) and grade III (anaplastic) meningiomas are associated with an increased risk of recurrence, are more aggressive, and show invasive behavior [2]. Grade I meningiomas are generally considered as benign tumors, but recent studies indicate substantial neurological deficits and impaired long-term survival due to tumor recurrence and stroke despite their low histopathological grading in a considerable proportion of cases [3], [4]. Increased mitotic activity (more than 4 mitoses per 10 high-power fields) and elevated Ki-67 expression (Ki-67 index of more than 5% of nuclei) are reliable histopathological markers for tumor recurrence [2].Because histopathological grading alone does not predict outcome satisfyingly, numerous studies investigated the value of preoperative magnetic resonance imaging (MRI) for prognostics. For example, Liu et al. demonstrated that hyperintensity on diffusion-weighted imaging, heterogeneous gadolinium enhancement, disruption of the arachnoid at brain tumor interface, T2 hyperintense peritumoral edema, and irregular tumor shape were independent predictors of non–grade I meningioma [5]. Other works produced comparable results, although some of these studies underline the importance of positive capsular enhancement [6], [7], whereas others emphasize the predictive value of peritumoral edema [5], [8]. All the above-cited works investigated morphological features of meningiomas summarized in subjective scoring systems, but not one of the studies objectively analyzed values of SIs in commonly used preoperative MRI sequences.Therefore, the aim of this study was to investigate the predictive value of genuine and normalized SIs of standardized preoperative MRI (T1 pre- and postcontrast, T2, and fluid-attenuated inversion recovery [FLAIR]) as in vivo predictors of proliferative activity of meningiomas.     

p53 protein expression and proliferative activity in imprints of superficial transitional cell carcinoma of the bladder

OBJECTIVE: To investigate p53 protein expression and proliferative activity in imprints of tumor biopsies from superficial transitional cell carcinoma of the bladder in relation to the histologic grade of malignancy and recurrence status. STUDY DESIGN: The study group consisted of 70 cases of superficial transitional cell carcinoma of the bladder. In order to investigate p53 protein expression and Ki-67 expression, an immunocytochemical avidin-extravidin complex technique was performed using monoclonal antibodies p53 D0-7 and proliferating cells correspondingly. RESULTS: Thirty-seven percent of superficial transitional cell carcinoma cases showed positive expression of p53 protein. No correlation was found between p53 protein expression and grade of malignancy (P = .45). p53 Protein expression was statistically correlated with a high Ki-67 labeling index (LI) (P < .001) and recurrence status (P < .001). Forty-seven percent of cases showed a Ki-67 LI > 25%. No correlation was found between a high Ki-67 LI and grade of malignancy (P = .703). A significant difference in high Ki-67 LI between recurrent and nonrecurrent tumors of the same grade (P < .001) and between recurrent and nonrecurrent tumors was found independently of grade (P < .001). CONCLUSION: These results on cytologic material could provide useful information on the biologic behavior of superficial transitional cell carcinoma of the bladder at the time of diagnosis.     

Progesterone Receptor Status and Ki-67 Index May Predict Early Relapse in Luminal B/HER2 Negative Breast Cancer Patients: A Retrospective Study

Purpose

Few studies has documented early relapse in luminal B/HER2-negative breast cancer. We examined prognostic factors for early relapse among these patients to improve treatment decision-making.

Patients and Methods

A total 398 patients with luminal B/HER2-negative breast cancer were included. Kaplan-Meier curves were applied to estimate disease-free survival and Cox regression to identify prognostic factors.

Results

Progesterone receptor (PR) negative expression was associated with higher tumor grade (p<.001) and higher Ki-67 index (p = .010). PR-negative patients received more chemotherapy than the PR-positive group (p = .009). After a median follow-up of 28 months, 17 patients (4.3%) had early relapses and 8 patients (2.0%) died of breast cancer. The 2-year disease-free survival was 97.7% in the PR-positive and 90.4% in the PR-negative groups (Log-rank p = .002). Also, patients with a high Ki-67 index (defined as >30%) had a reduced disease-free survival (DFS) when compared with low Ki-67 index group (≤30%) (98.0% vs 92.4%, respectively, Log-rank p = .013). In multivariate analysis, PR negativity was significantly associated with a reduced DFS (HR = 3.91, 95% CI 1.29–11.88, p = .016).

Conclusion

In this study, PR negativity was a prognostic factor for early relapse in luminal B/HER2-negative breast cancer, while a high Ki-67 index suggested a higher risk of early relapse.