Is survivin expression prognostic or predictive in malignant pleural mesothelioma?

Malignant pleural mesothelioma is an incurable cancer strongly associated with asbestos exposure and characterised by poor response to treatment. The inhibitor-of-apoptosis protein family member survivin is involved in apoptosis and proliferation and is expressed in cancer cells only. The aims of the present study were to elucidate whether survivin expression is associated with tumour cell apoptosis and proliferation and to assess the prognostic and predictive value of survivin expression in malignant pleural mesothelioma. Archival pleural mesothelioma tissue samples from 101 patients were immunohistochemically analysed for nuclear expression of survivin, for proliferation with the use of Ki-67 as marker and for apoptosis using active caspase-3 as a marker. Staining results and clinical data were included in a survival analysis. Survivin was highly expressed in tumour cell nuclei in all samples and this correlated positively with both apoptosis and proliferation, but did not have a significant prognostic value. We found significantly higher survivin expression in patients who responded to chemotherapy compared to patients with progressive disease. Survivin expression might contribute to treatment response prediction, but survivin expression in malignant pleural mesothelioma did not have prognostic significance.     

Survivin expression in hepatocellular carcinoma: correlation with proliferation, prognostic parameters, and outcome.

Survivin is a novel inhibitor of apoptosis. It is detected in fetal and neoplastic adult tissue, but not in normal tissues. Several recent studies have shown that survivin not only inhibits apoptosis, but also accelerates cancer cell proliferative activity. Expression of the protein may be of prognostic significance and therapeutic relevance in many cancers. We investigated survivin expression in hepatocellular carcinoma, correlating results with proliferation (MIB-1), prognostic factors, and outcome. Paraffin-embedded sections of 72 hepatocellular carcinoma were immunostained for survivin and MIB-1 using tissue microarray technology. Expression was evaluated in nuclei and cytoplasm as intensity (0-3+), and percentage of positive cells scored on a four-tiered system with less than 10%=negative; 10-25%=1; 26-50%=2; 51-75%=3; and 76-100%=4. Frequency of nuclear survivin expression was 43%. There was a significant correlation between nuclear survivin expression and nuclear grade (P=0.0271), microvascular invasion (P=0.0064), mitotic rate (P=0.0017), and MIB-1 (P=0.0001), as well as local recurrence (P=0.0487), and disease-free survival (P=0.0098). Histologic grade (P=0.0544) and stage (P=0.0548) tended to correlate with survivin expression, which did not correlate with cirrhosis, tumor necrosis, multiple tumors, metastatic disease, or overall survival. Survivin expression correlates with poor prognostic parameters (high nuclear and histologic grade, microvascular invasion, increased proliferation (mitotic count, MIB-1)), local recurrence, and shorter disease-free survival, but does not correlate with overall survival. An important role is suggested for survivin in progression, recurrence, and treatment of hepatocellular carcinoma.     

Survivin and caspase-3 expression in breast cancer: correlation with prognostic parameters, proliferation, angiogenesis, and outcome.

BACKGROUND: Survivin is an inhibitor of apoptosis protein that is overexpressed in most human cancers, including breast, but is not expressed in normal tissue. Survivin is associated with more aggressive behavior and decreased survival in a variety of tumor types. It regulates the G2/M phase of the cell cycle by associating with mitotic spindle microtubules, and it directly inhibits caspase-3 and caspase-7 activity. We used a breast cancer tissue microarray to assess survivin and caspase-3 expression in breast cancer and to correlate both markers with proliferation (MIB-1), angiogenesis (CD31), and prognosis. DESIGN: A breast cancer tissue microarray with a total of 190 1-mm tissue samples (2 from each specimen) were immunostained for survivin, caspase-3, MIB-1, and CD31. The microarray contains 91 cases of breast carcinoma diagnosed at Emory University Hospital between 1992 and 2000, and 4 normal breast tissue controls. Follow-up information was obtained from hospital records and the Winship Cancer Center database. RESULTS: Eighty-four percent of breast carcinoma showed nuclear survivin expression. Normal breast tissue was immunonegative. Fifty-seven percent and 43% of breast cancer showed reduced and absent caspase-3 expression, respectively. Survivin (nuclear) and caspase (nuclear/cytoplasmic) expression showed significant correlation with histologic grade (P=0.008 and 0.041) and MIB-1 expression (P=0.033 and 0.012). Survivin nuclear expression also correlated significantly with tumor stage (P=0.012) and tended to correlate with estrogen receptor (P=0.050). There was no significant correlation between survivin and caspase expression. Furthermore, there was no correlation of both markers with other clinicopathologic parameters (age, tumor size, histologic type, progesterone receptor, Her-2 neu status, lymph node status), angiogenesis (CD31), or outcome (overall and disease-free survival). CONCLUSIONS: Survivin and caspase-3 expression correlate with poor prognostic parameters (higher histologic grade and high proliferation), but not with outcome, in breast carcinoma patients.     

乳腺癌组织Survivin和Ki-67的表达情况及其临床意义

目的：探讨乳腺癌与Survivin、Ki-67的相关性,以及Survivin、Ki-67检测的临床意义。方法：采用免疫组化法研究Survivin、Ki-67在乳腺癌中的表达情况。结果：36例乳腺癌患者有28例（77.8%）Survivin表达阳性,对照组30例中只有1例（3.3%）Survivin表达阳性,Survivin诊断乳腺癌的敏感性为77.8%,特异性为96.7%。36例乳腺癌患者有26例（72.2%）Ki-67表达阳性,对照组30例中无1例Ki-67表达阳性,Ki-67诊断乳腺癌的敏感性为72.2%,特异性为100%。36例乳腺癌患者中Survivin与Ki-67的表达密切相关（P〈0.05）。结论：Survivin、Ki-67在乳腺癌病例中均有较高表达,并且其特异性均很高,故临床检测Survivin、Ki-67对乳腺癌的病理诊断有较高的鉴别意义,具有临床推广价值。     

Survivin expression in pre-invasive lesions and non-small cell lung carcinoma

Survivin is an inhibitor of apoptosis protein, which is overexpressed in many carcinomas, including lung carcinoma. The aim of this immunohistochemical study was to investigate the role of survivin in the early steps of lung carcinogenesis and non-small cell lung carcinomas (NSCLC), and its relationship with expression of p53 protein, a tumor suppressor gene involved in cell cycle control. In the normal bronchial epithelium, low-grade atypical adenomatous hyperplasia (AAH) and non-neoplastic lung parenchyma adjacent to tumor, survivin was found completely negative. Expression of survivin was detected in the areas of squamous metaplasia and dysplasia as well as high-grade AAH lesions adjacent to tumor. Survivin was expressed in 50 (64%) and p53 in 41 (53%) NSCLC. Survivin expression was significantly correlated with lymph node metastasis (p=0.02). There was no correlation between survivin and p53 expression. The patients with expression of survivin had significantly worse prognosis (Log-rank test, p=0.003). Multivariate Cox regression analysis showed TNM stage (p<0.001) and survivin expression (p=0.003) as independent prognostic indicators. In conclusion, survivin expression might be an early step in lung carcinogenesis. Survivin expression might also be used as a prognostic indicator predicting the worse outcome in NSCLC, and might be a novel target for the treatment of patients with preinvasive lesions of lung and NSCLC.     

Expression of survivin is associated with malignant potential in epithelial ovarian carcinoma

Survivin is a new member of the inhibitor of apoptosis family of anti-apoptotic proteins. It has been reported that survivin is expressed during fetal development and in cancer tissues. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression of survivin in human endometrial carcinomas. We analyzed serial frozen sections for survivin protein expression in 26 patients with ovarian epithelial carcinoma and 10 patients with benign cystadenoma of the ovary by fluorescent immunohistochemistry. We analyzed the relationship between the percentages of survivin-stained cells and the characteristics of the patient including histological classification, clinical stage, histological grade, and clinical outcome. Survivin was weakly detected in some benign ovarian cystadenomas (0-12.1%). There was, however, abundant survivin immunoreactivity in the nucleus and/or cytoplasm of the epithelial ovarian carcinoma cells. Scoring on the basis of the percentage of positive cells indicated that survivin expression was significantly associated with PCNA-labeling index, clinical stage, histological grade, clinical outcome, and survival rate (p<0.01, respectively). We conclude that the survivin protein is a defining diagnostic marker for epithelial ovarian carcinomas that may also yield prognostic information.     

Survivin expression in non-small-cell lung carcinomas: correlation with apoptosis and other apoptosis-related proteins, clinicopathologic prognostic factors and prognosis.

The role of survivin that regulates the biological behavior of non-small-cell lung carcinoma (NSCLC) is still controversial. We aimed to investigate survivin expression in NSCLC and to define any correlation with expressions of p53, bcl-2, bax, apoptotic index (AI), tumor cell proliferation, clinicopathologic variables, and overall survival. Tumors of 63 patients with NSCLC were examined for expressions of survivin, p53, bcl-2, bax, and Ki-67 by immunohistochemistry. AI was also evaluated. Results for each antibody were correlated with each other, and with clinicopathologic variables including age, sex, histologic subtype, TNM (T: primary tumor, N: regional lymph node metastasis, M: distant metastasis) stage, lymph node status, smoking history, and prognosis. Nuclear survivin expression was inversely correlated with p53 expression (P = 0.04, r = - 0.367), and tumor stage (P = 0.03, r = - 0.273), and positively correlated with tumor cell proliferation (P = 0.009, r = 0.329). Cytoplasmic survivin expression positively correlated with smoking history (P = 0.02, r = 0.282). Survivin/bax ratio was inversely correlated with AI (r: - 0.004). By Kaplan-Meier analysis, TNM stage (P < or = 0.001), lymph node metastasis (P = 0.04), and Ki-67 index (P < or = 0.001) were associated with survival, whereas survivin was not. In multivariate analysis, only TNM stage was an independent predictor. Although survivin and other apoptosis-related protein expressions fail to predict the clinical outcome, the present findings suggest that survivin is involved in tumor cell apoptosis and proliferation and may play a role in critical steps of cancer progression in NSCLC.     

Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract

The members of the IAP (inhibitors of apoptosis) family, which includes survivin, have recently emerged as modulators of an evolutionarily conserved step in apoptosis. Survivin is present during embryonic and fetal development, but it is downregulated in normal adult tissues. However, it becomes re-expressed in a variety of cancers. We investigated the prognostic importance of the expression of survivin in transitional cell carcinoma of the upper urinary tract (TCC-UUT). In 126 cases of TCC-UUT, we examined its expression (using immunohistochemistry), and also its relationship with the expressions of bcl-2 oncoprotein, p53 oncoprotein, and proliferating cell nuclear antigen (PCNA) immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of survivin was recognized in 12.7% of samples, a granular pattern being apparent within the cytoplasm of tumor cells. Survivin expression did not correlate with clinicopathologic findings, bcl-2 oncoprotein expression, p53 oncoprotein expression, PCNA index, or prognosis. In the normal urothelium, its expression was not detected. In conclusion, the expression of survivin does not predict prognosis in TCC-UUT.     

The significance of Ki-67/MIB-1 labeling index in human meningiomas: a literature study

Histology alone does not always predict the clinical outcome of human meningiomas. Determination of proliferative activity has therefore become an important diagnostic and prognostic tool to identify more aggressive meningiomas, and the Ki-67/MIB-1 monoclonal antibody has become widely used. The aim of this study was to assess the prognostic value of the Ki-67/MIB-1 labeling index (LI) in human meningiomas by a search in the literature. In PubMed/Medline databases, 53 articles were found, and they all showed positive correlations between Ki-67/MIB-1 LI and histological malignancy grade. The average mean labeling indices were 3%, 8%, and 17% for grade I-III meningiomas, respectively. There was, however, considerable overlap of indices between the malignancy groups. Concerning recurrence, meningiomas with a labeling index beyond 4% may indicate an increased relapse rate. Consequently, Ki-67/MIB-1 LI represents a useful predictor of tumor grade and risk of recurrence, however, it must be interpreted cautiously in the individual tumor.     

The proliferation markers Ki-67/MIB-1, phosphohistone H3, and survivin may contribute in the identification of aggressive ovarian carcinomas

The identification of new proliferation markers could have clinical implications in ovarian carcinoma by stratifying patients for treatment and follow-up. The aim of this study was to evaluate the diagnostic and prognostic value of the proliferation markers Ki-67/MIB-1, phosphorylated histone H3 (PHH3), and survivin in epithelial ovarian tumors. Ninety women with a pelvic mass who underwent surgery at the Department of Gynecological Oncology were included: 68 ovarian carcinomas, 11 borderline tumors, and 11 ovarian cystadenomas. We performed mitotic count and immunohistochemical analyses of Ki-67/MIB-1, PHH3, and survivin, related to clinicopathological parameters. Uni- and multivariate analyses of five-year overall survival were performed. We found statistically significant correlations between mitotic count, Ki-67/MIB-1, PHH3, and survivin. The expression of all proliferation markers was significantly higher in the carcinomas than in the borderline and benign tumors (p<0.05). There was, however an overlap of indices between the different malignancy groups. Women with advanced stage cancers (FIGO stage III and IV) had significantly higher tumor expression of all markers compared to patients with early stage cancers (FIGO stage I and II). Women with advanced disease and complete chemotherapy response had higher Ki67/MIB-1 expression than women without complete chemotherapy response. All markers had an impact on survival in the univariate analyses. In the multivariate analysis, however, only age and stage of disease reached statistical significance as prognostic factors. In conclusion, the proliferation markers Ki-67/MIB-1, PHH3, and survivin are positively correlated with each other and with tumor grade, and may contribute in the identification of aggressive ovarian carcinomas.     

Survivin expression in ovarian carcinoma: correlation with apoptotic markers and prognosis.

Survivin is a novel inhibitor of apoptosis commonly detected in tissues during fetal development and in cancer, but not usually in normal tissues. Expression of this protein may be of prognostic significance and therapeutically relevant in many cancers. We assessed survivin expression in ovarian carcinoma, correlating results with expression of other anti-apoptotic (bcl-2, bcl-x, mutant p53) and pro-apoptotic (bax) markers, with prognostic parameters, and prognosis. Paraffin-embedded sections of 49 ovarian carcinoma were immunostained for survivin, bcl-2, bcl-x, bax, and p53. Expression was evaluated in nuclei and cytoplasm, as intensity (0-3+), and percentage of positive cells was scored on a four-tiered system with <10% as negative. Frequency of survivin, bcl-2, bcl-x, bax, and p53 was 73.5%, 36.7%, 93.9%, 77.6%, and 60.4%, respectively. There was significant correlation between nuclear survivin expression and grade (P =.0014), histologic type (P =.0376), and mutant p53 (P =.0414). Survivin expression did not correlate with bcl-2, bcl-x, or bax expression, stage, or overall or disease-free survival. The majority (74%) of ovarian carcinoma show survivin expression, which correlates with poor prognostic parameters (high grade, histologic type, p53 mutation) but not with survival. Therapeutic targeting of survivin in ovarian carcinoma is a future possibility.     

Survivin在反应性和肿瘤性星形胶质细胞中的表达及意义

目的探讨survivin、bc l-2和K i-67在星形胶质细胞反应性增生与低级别星形胶质细胞瘤中表达的区别及意义。方法利用组织芯片和免疫组化PV6000通用型二步法检测正常脑组织、星形胶质细胞反应性增生、低级别(Ⅰ~Ⅱ级)和高级别(Ⅲ~Ⅳ级)星形胶质细胞瘤中survivin、bc l-2和K i-67蛋白的表达情况。结果正常脑组织中三者均为阴性表达;survivin、bc l-2和K i-67在星形胶质细胞反应性增生组中阳性率分别为26.7%、26.7%和22.2%;在低级别星形胶质细胞瘤组中阳性率分别为53.2%、50.0%和70.2%;在高级别星形胶质细胞瘤组中阳性率分别为88.1%、79.2%和95.2%。survivin、bc l-2和K i-67在增生组与低级别组之间差异均具有显著性(P<0.01)。结论survivin和bc l-2在星形胶质细胞反应性增生及星形胶质细胞瘤的发生、发展中起重要作用;survivin、bc l-2和K i-67联合应用在两者的鉴别诊断中可能有一定的意义。     

间变性大细胞淋巴瘤组织间变性淋巴瘤激酶及survivin蛋白表达及其临床意义

目的研究间变性大细胞淋巴瘤（ALCL）中间变性淋巴瘤激酶（ALK）蛋白及survivin蛋白的表达特点及其临床意义。方法应用免疫组织化学LSAB法检测ALK蛋白及survivin蛋白的表达。结果ALK蛋白在81例ALCL中有51例（63％）阳性,30例（37％）阴性。ALK阳性患者预后优于阴性患者（P〈0．05）。survivin蛋白在77例ALCL中均有不同程度的表达,其中高表达33例（42．9％）,低表达44例（57．1％）。survivin的表达与ALK蛋白表达无关（P〉0．05）。预后：Survivin高表达患者较低表达者差（P〈0．05）。在ALK蛋白阳性病例中,survivin高表达患者较低表达者差（P〈0．05）;ALK阴性病例中,survivin的表达状况与预后无关（P〉0．05）。Cox比例风险回归分析表明ALK的表达、体质性症状及survivin的不同表达状况对存活的影响有统计学意义（P〈0．05）,其中ALK的表达对生存的影响最大,survivin表达的影响最小。结论survivin蛋白在ALCL中的表达与ALK蛋白的表达不相关,是一个独立的指标,可有助于判断ALK阳性ALCL病例的预后。     

Prognostic value of the proliferative index determined by Ki-67 immunostaining in superficial bladder tumors

The biological behavior of urothelial carcinomas remains unpredictable. The objective of this study was to determine the prognostic value of Ki-67 index in superficial papillary bladder tumors and to correlate it with the S-phase fraction (SPF) measured by flow cytometry. Three hundred nineteen patients with newly diagnosed superficial (pTa, pT1) bladder tumors were included between September 1990 and April 1992. Patients with bladder carcinoma in situ alone were excluded. We observed 255 pTa tumors and 64 pT1 tumors, whereas 111 lesions were classified as grade G1 and 208 as grade G2-G3. Ki-67 immunostaining was performed on paraffin-embedded material using a 3-step immunoperoxidase procedure with the murine monoclonal antibody MiB1. The relation between Ki-67 expression and prognostic variables (stage, grade, tumor size, multifocality, age, and sex) was investigated by the chi-square test. Cox regression was used to describe the association between Ki-67 and tumor recurrence in 308 patients with follow-up while adjusting for potentially confounding prognostic variables. The frequency of high Ki-67 expression (> or =10%) increased with stage (P = .005) and grade (P = .001), but not with tumor size or multifocality. Two hundred one patients experienced tumor recurrence in a median follow-up of 68 months. Stage, grade, tumor size, and multifocality were all independent predictors of recurrence. Ki-67 index greater than 10% was found to be an independent predictor of tumor recurrence among patients with tumors larger than 3 cm in diameter (HR = 2.05, CI = 1.18-3.55), but not those with smaller size tumors. With regards to the DNA index, a significant but weak correlation was observed between Ki-67 expression and the SPF (Spearman's correlation coefficient = 0.23, P = .004). In addition, aneuploid tumors had significantly higher expression of Ki-67 (22.5%) than diploid tumors (10.1%) (P = .0006). Moreover, patients with DNA aneuploid bladder tumors were more likely to have more than 10% Ki-67-positive cells than those with diploid tumors. In patients with newly diagnosed pTa or pT1 bladder tumors, a Ki-67 index above 10% is an independent predictor of shorter time to recurrence only in those with tumors larger than 3 cm.     

Analysis of survivin expression in a spectrum of benign to malignant lesions of the breast.

Survivin, a novel inhibitor of apoptosis, is expressed in a variety of human cancers, with reports of prognostic significance in some neoplasms. The authors' aim was to evaluate survivin expression in a spectrum of breast lesions to determine differential expression in malignant versus benign lesions and its potential role as a diagnostic or prognostic marker. The authors found that survivin is expressed in breast tissue in the full spectrum of normal to invasive carcinoma. It is predominantly nuclear with a faint cytoplasmic blush. Survivin expression was independent of patient age and tumor size. Benign breast tissue showed survivin expression in a lower percentage of cells (45%) than malignant lesions. The median values for the percentage of cells that stained for survivin were statistically different among the categories of invasive carcinoma, DCIS, LCIS, and benign breast tissue (P < or = 0.001). The highest percentage of positive-staining cells was seen in high-grade DCIS (95%). The authors found a trend toward a higher percentage of cells staining for survivin in breast carcinoma cases that were ER negative, PR negative, or Her2/neu positive, although this was not statistically significant. Survivin expression was preserved in biopsies from recurrent tumors without loss of nuclear survivin expression. In conclusion, survivin is overexpressed in malignant breast lesions relative to benign lesions or normal breast tissue and in high-grade DCIS relative to nonhigh-grade DCIS. Therefore, survivin may have a role, albeit a limited one, as a prognostic marker in breast lesions.     

Proliferation, ploidy and prognosis in uterine smooth muscle tumours

DNA ploidy, mitotic rate (per 10 high power fields), mitotic index (per 1000 tumour nuclei), Ki-67 labelling index and S phase fraction were measured in 23 uterine leiomyosarcomas and 10 tumours of uncertain malignant potential. Correlations were calculated by Spearmann rank correlation. Univariate survival analysis was performed by log rank analysis and multivariate analysis performed by the Cox linear regression method. Ki-67 index and S phase fraction were significantly higher in leiomyosarcomas than in tumours of uncertain malignant potential. There was significant correlation between mitotic rate, mitotic index, Ki-67 index and S phase fraction in cases of leiomyosarcoma. Fifteen of 22 leiomyosarcomas and one of 10 tumours of uncertain malignant potential were DNA aneuploid. On univariate analysis of all the smooth muscle tumours, DNA ploidy, presence of significant nuclear atypia and presence of coagulative tumour cell necrosis were associated with outcome. Only DNA ploidy was associated with outcome in the group of leiomyosarcomas. On multivariate analysis of all of the smooth muscle tumours. DNA ploidy, age and grade of atypia were independently associated with outcome. No single factor was independently predicitive of outcome in the group of leiomyosarcomas. Alternative indices of cell proliferation correlate with mitotic rate in uterine leiomyosarcoma and do not provide additional useful prognostic information. DNA ploidy, age and grade of atypia are independently associated with outcome in uterine smooth muscle tumours and measurement of DNA ploidy may be useful in identification of cases with an adverse prognosis.     

Overexpression of the myc target gene Mina53 in advanced renal cell carcinoma

The myc target gene Mina53 was reported to be overexpressed in esophageal cancer with a poor prognosis. The purpose of the present study was to examined Mina53 expression and its relationship to clinicopathological parameters in human renal cell carcinoma (RCC). Mina53 and Ki-67 expression was examined on immunohistochemistry for 64 surgically resected RCC and non-cancerous tissue. In addition, the relationship between Mina53 expression and clinicopathological prognostic factors of RCC such as age, stage, microvenous invasion (MVI), histological subtype, Ki-67 labeling index (LI), and prognosis, was examined. Mina53 was expressed in the nuclei of tumor cells and tubular nuclei of normal renal tissue. The expression level of Mina53 was significantly higher in patients with poor prognostic factors (stage IV, MVI-positive, and sarcomatoid RCC, and high Ki-67 LI). The prognosis of high Mina53-expressing tumors was significantly poorer than that of non-Mina53-high tumors (P < 0.0001). In conclusion, Mina53 is overexpressed in RCC tissue from patients with poor prognostic factors, suggesting that Mina53 overexpression is one of the factors for poor prognosis in RCC.     

Standardizing evaluation of sarcoma proliferation- higher Ki-67 expression in the tumor periphery than the center

Soft tissue sarcomas often present as large and histopathologically heterogenous tumors. Proliferation has repeatedly been identified as a prognostic factor and immunostaining for Ki-67 represents the most commonly used proliferation marker. There is, however, a lack of consensus on how to evaluate Ki-67 staining regarding optimal cut-off levels, selection of tumor areas, and the number of tumor cells to evaluate. We assessed the impact of targeting peripheral versus central tumor areas using tissue microarray-based staining for Ki-67 throughout the tumor diameter in 25 leiomyosarcomas. In 18/25 tumors, Ki-67 expression was higher in the tumor periphery. If 10% staining tumor nuclei was used as cut-off and the maximal Ki-67 staining section in the tumor periphery was considered, 21/25 tumors would have been classified as highly proliferative compared to 14/25 if the tumor center had been analyzed. Similar results were obtained also when higher cut-off levels were used and if the mean expression rather than the maximal expression was considered and the differences were neither caused by necrosis nor by hypoxia (assessed as HIF-1alpha expression). Our findings suggest that the determination of proliferation in soft tissue sarcomas should be standardized for clinical application of Ki-67 as a prognostic marker.