Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (> or =5 cm), mitotic counts (> or =5/50 high-power fields), Ki-67 LI (> or =4.92%), cyclin A LI (> or =1.61%), and cdc2 LI (> or =1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.     

p53 but not erbB-2 expression is associated with rapid tumor proliferation in urinary bladder cancer

Tumor proliferation in bladder cancer is associated with tumor behavior. To assess the association between Ki-67 labeling index (LI), p53, and c-erbB-2 overexpression, formalin-fixed tissue samples of 160 patients with transitional cell carcinoma (TCC) of the urinary bladder were studied by immunohistochemistry. Ki-67 LI was strongly associated with tumor stage (P < .0001), tumor grade (P < .0001), and p53 status (P = .0014) but not with erbB-2 overexpression (P > .2). Ki-67 LI was higher in p53-positive tumors (19%) than in p53-negative tumors (14%) when all stages were compared. Ki-67 LI was independent of p53 expression in pTa tumors (p53-positive, 9%; p53-negative, 11%), showing that p53 overexpression alone is not sufficient to induce rapid tumor cell proliferation in pTa tumors. Ki-67 LI also was independent of p53 expression in pT2 to pT4 tumors (p53-positive, 20%; p53-negative, 23%), indicating that p53 expression is not necessary for rapid tumor cell proliferation in advanced stages. However, there was a striking difference in Ki-67 LI between p53-positive pT1 tumors (22.0% ± 8.8 standard deviation [SD]; n = 20) and p53-negative pT1 tumors (9.7 ± 8.3 SD; n = 22; P = .0001). These results suggest that increased proliferation in p53-positive pT1 tumors is caused by additional alterations that occur during tumor progression.     

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.     

Prognostic significance of a novel proliferation marker, anti-repp 86, for endometrial carcinoma: a multivariate study.

Traditional prognostic factors often fail to identify a subgroup of endometrial carcinoma (EC) patients with an apparently paradoxical poor outcome. We therefore analyzed tumor cell proliferation immunohistochemically in a series of 164 endometrial carcinomas (EC) and compared its prognostic impact with that of the standard prognostic factors patient age, FIGO stage, FIGO grading, and histopathologic subtype. In addition to the established proliferation markers Ki-S5 (Ki-67) and KiS4 (topoisomerase IIalpha), we used a novel monoclonal antibody (MAb), anti-repp 86, which binds to a recently described proliferation-specific protein (p86) expressed exclusively in the S, G2, and M phases of the cell cycle. anti-repp 86, Ki-S4, and Ki-S5 immunoreactive labeling indices (LI) correlated significantly with FIGO stage, FIGO grade, and myometrial invasion, but not with histopathologic subtype. By univariate analysis, conventional prognostic factors and proliferation indices were all predictive of disease-related mortality. A multivariate Cox regression analysis selected anti-repp 86 LI (P = .002), FIGO stage (P = .02), and histopathologic type as significant prognosticators of recurrence; anti-repp 86 LI (P = .001) and histopathologic type (P = .0106) also emerged as relevant predictors of mortality. A hierarchical forward regression model with the conventional prognosticators entered first and with anti-repp 86 entered next showed that anti-repp 86 and histopathologic subtype were the superior independent prognostic indicators for an increased risk of recurrence and cancer-related death. We conclude that the evaluation of anti-repp 86 immunostaining is an easily performable and exceptionally reliable method for identifying EC patients with adverse prognosis.     

细胞周期蛋白D1、Ki-67和bcl-2的表达与CD117阳性的胃肠道间质瘤生物学行为的关系

目的 检测细胞周期蛋白D1（cyclin D1）、Ki-67和bcl-2在胃肠道间质瘤（GIST）中的表达,探讨它们在GIST发生、发展中的作用及临床病理意义。方法 59例手术切除GIST标本进行CD117、CD34、平滑肌肌动蛋白（SMA）、结蛋白、S-100、cyclin D1、bcl-2和Ki-67免疫组织化学染色,同时进行病理形态学观察包括形态学类型、肿瘤大小、坏死和核分裂象。所有病例随访2～9年。所有数据进行单因素、多因素和相关分析。结果 随访40例患者一直健在,15例患者死于GIST,4例患者死于其他原因。统计学分析显示肿瘤直径〉5cm、有坏死、核分裂象在每50个高倍视野〉5个、Ki-67增殖指数（LI）〉5％、cyclin D1和bcl-2免疫组织化学染色强阳性都可以作GIST患者手术后的预测指标,且具有统计学意义;核分裂象和Ki-67增殖指数是独立的预测指标;Ki-67 LI≥5％和核分裂象≥5／50 HPF呈正相关（r=0．532,P〈0．01）;cyclin D1与bcl-2强阳性表达呈正相关（r=0.273,P〈0．05）。结论 肿瘤大小、坏死、核分裂象、cyclin D1、Ki-67增殖指数和bcl-2可作为GIST患者临床预测指标;核分裂象和Ki-67增殖指数可作为独立的预测指标;cyclinD1与bcl-2呈明显相关性,Ki-67免疫组织化学染色可以代替核分裂象作为一项很有用的预测指标。     

Prognostic value of Ki-67 in stage I non-small-cell lung cancer: A meta-analysis involving 1931 patients

There is growing interest in exploring the prognostic value of Ki-67 in non-small-cell lung cancer (NSCLC). However, whether Ki-67 can be regarded as a routine biomarker in clinical practice is still under debate. The present meta-analysis investigated the relationship between Ki-67 and the overall survival (OS) or disease-free survival (DFS) of patients suffering from stage I NSCLC. We searched the Web of Science, Cochrane, and PubMed databases to extract eligible articles. In total, 15 studies involving 1931 patients were included. Pooled hazard ratio (HR) analysis revealed that patients with high Ki-67 labeling index (LI) had poorer OS (HR?=?1.95, 95% confidence interval (CI)?=?1.43–2.66, P?<?0.0001) and DFS (HR?=?3.12, 95% CI?=?2.17–4.48, P?<?0.00001) than those with low Ki-67 LI. In subgroup analysis, high Ki-67 LI was significantly associated with poor prognoses in stage I adenocarcinoma. In future studies, a consensus for the optimal cutoff value for high Ki-67 LI needs to be explored and demonstrated in stage I NSCLC patients.     

Comparison of proliferative activities and metastases between two subtypes classified at the deeply infiltrating sites of colorectal moderately differentiated adenocarcinomas

Twenty-eight moderately differentiated adenocarcinomas invading beyond the muscularis propria of the colorectum were subclassified as 13 moderate- and 15 poor-subtype tumors based on the histology at the deeply infiltrating sites. Moderately differentiated cancer cells were correlated with liver metastasis and p53 immunoreactivity. Poorly differentiated cancer cells were correlated with lymph node metastases but not to p53 immunoreactivity. The proliferative cell nuclear antigen (PCNA) labeling index (LI), Ki-67 LI and agyrophilic nuclear organizer regions (AgNOR) values determined for the poorly differentiated cancer cells in the poor-subtype tumors were significantly lower than those of moderately differentiated cancer cells in the moderate-subtype tumors. In cells from tumors classified as poor-subtype, poor differentiation was associated with decreased PCNA LI levels, but with unchanged Ki-67 LI and AgNOR values. These results indicate that colorectal adenocarcinoma cells that are histologically subclassified as moderately differentiated have different proliferative and metastatic activities from cancer cells that are poorly differentiated. Moderately differentiated cancer cells are associated with hematogenous metastasis to liver and high proliferative activity, and loss of tubular formation of cancer cells may be fundamentally related to lymph node metastasis and infiltrative growth.     

Reliability of Ki-67 Determination in FNA Samples for Grading Pancreatic Neuroendocrine Tumors

Neuroendocrine pancreatic tumors (PanNETs) are graded on the basis of their proliferative activity. Cytological samples are commonly the only samples available, but the determination of Ki-67 in cytology and its reliability as a measure of tumor mitotic activity is not well settled. We have retrospectively reviewed all the cases of FNA under EUS control of PanNETs in a 10-year period (2006–2016) in the Hospital Clínico San Carlos (Madrid). We identified 10 PanNET cases with histological correlation. Median age was 49.4 years and the patients were mainly women. PanNETs were located more frequently in the tail of the pancreas, with a median size of 33.8 mm. None of our cases was a grade 3 tumor. The seven grade 1 tumors confirmed in histology had consistent Ki-67 in cytology. In three cases (30 %), there were discrepancies between the Ki-67 index measured in cytology and histology, and the differences ranged from 2 to 15 %; all these cases were grade 2 tumors in histology and were graded as grade 1 tumors in FNA material. Our results are consistent with previous studies which showed understaging when tumor grade was assessed in cytological samples, mainly in G2 tumors. Previous literature has shown that Ki-67 assessment in EUS-FNA samples is a useful tool to rule out G3 tumors, but can be problematic for distinguishing G1 and G2 tumors.     

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.     

Ki-67 is a reliable pathological grading marker for neuroendocrine tumors

In neuroendocrine tumors (NETs), proliferation markers, especially Ki-67, have become increasingly important. This study was designed to examine the reproducibility of Ki-67 for use in the current classification of NETs. A retrospectively assembled integrated database with prospectively collected data of patients undergoing multidisciplinary management for NETs from 2000 to 2009 was analyzed. Original pathology was reviewed to reassess Ki-67 values. Ki-67 was then categorized to grades G1 (≤2 %), G2 (3–20 %), or G3 (>20 %) according to the European Neuroendocrine Tumor Society (ENETS) guidelines and the 2010 World Health Organization (WHO) classification. Original Ki-67 values were compared to reviewed values. All statistical analyses were carried out using SAS 9.1.3. A total of 184 patients were included of which 48 % were male. The most common primary NET site was the small bowel, in 27 %. On pathology review, there was 94 % agreement for G1, with 4 % of cases upgraded at review to G2 and 2 % of cases upgraded to G3. For G2, there was 94 % agreement, with 6 % of cases downgraded to G1 and 0 % upgraded. For G3, there was 90 % agreement, with 10 % of cases downgraded to G2 and none to G1 (kappa?=?0.89). Ki-67 is a proliferative marker for NETs that is highly reproducible when used to grade tumors according to ENETS and WHO categories. The high inter-institutional reliability in the determination of tumor grade as assessed by Ki-67 makes it a reliable tool in the assessment of patients with NETs.     

Decreased nm23 expression, but not Ki-67 labeling index, is significantly correlated with lymph node metastasis of breast invasive ductal carcinoma.

The nm23 gene was originally identified by differential hybridization of metastatic murine melanoma cell lines. Some experimental studies demonstrated a significantly reduced metastatic potential of melanoma cell lines transfected with the nm23 gene. In this study, we clarified the relationship between lymph node status and nm23 immunoreactivity, as well as Ki-67 labeling index (LI), of human breast cancer. Of the 44 breast invasive ductal carcinomas, nm23-diffusely positive expression [nm23(+)] was detected in 17 (38.6%), and focally positive/negative expression [nm23(+/-/-)] in 27 (61.4%) cases. Lymph node metastasis was found at a significantly higher incidence in the nm23(+/-/-) cases (18/27, 66.7%) than in the nm23(+) cases (4/17, 23.5%) (p>0.001). In the lymph node metastasis-positive cases, mean LI of Ki-67 cells was 20.9% at the center of the tumors and 24.0% at the advanced margins. In the lymph node metastasis-negative cases, mean LI of Ki-67 cells was 12.4% at the center of the tumors and 27.2% at the advanced margins. Decrease of nm23 expression, but not Ki-67 LI, was significantly correlated with lymph node metastasis of breast invasive ductal carcinoma.     

Malignant mesothelioma of the peritoneum: case reports and immunohistochemical findings including Ki-67 expression

A malignant mesothelioma (MM) is an aggressive neoplasm, although some patients have shown long-term survival, and factors related to survival remain uncertain. We present three cases of MM of the peritoneum including autopsy results, in which factors related to long-term survival were investigated. Case 1 was a 69-year-old man who died 6 years after the initial diagnosis. In case 2, a 67-year-old woman came to us with abdominal distention and, despite chemotherapy, died 9 months after the initial diagnosis. The patient in case 3 was a 68-year-old man who also had abdominal distention and died 9 months after the initial diagnosis. We studied the clinicopathological appearance and performed immunohistochemical staining including Ki-67 labeling index (Ki-67 LI) in primary and metastatic sites of these cases. The histological findings of case 1 indicated epithelioid type; case 2 and 3 were of biphasic type. Immunohistochemical results were consistent with MM. The Ki-67 LI value for both primary and metastatic sites of case 1 was significantly lower than those in cases 2 and 3. We consider Ki-67 LI to be a useful prognostic indicator for MM of the peritoneum.     

Ki-67 cytological index can distinguish well-differentiated from poorly differentiated pancreatic neuroendocrine tumors: a comparative cytohistological study of 53 cases

The Ki-67 labeling index has been found to bear prognostic significance in gastrointestinal neuroendocrine tumors (NETs), and it was recently incorporated in NET histological grading. Nevertheless, a reliable preoperative determination of NET grading could be useful in clinical practice. The aim of this study is to compare the results of Ki-67 labeling index, as measured on cytological samples and on surgical specimens of patients with pancreatic NETs (P-NETs). We also investigated whether concordance might be improved, using a 5 % (instead of 2 %) cutoff value for defining G2 tumors. We retrospectively identified 48 consecutive patients with 53 P-NETs, from our five institutions, and we measured Ki-67 labeling index on their cytological samples and surgical specimens. The traditional 2 % and the alternative 5 % cutoff values were used to classify G2 tumors. The concordance rate between cytological and histological grading was 46/53 (86.8 %; weighted κ statistic 0.77; 95 % confidence interval (95 % CI) 0.60–0.94). No cases of cytological G1-G2 NETs were upgraded to G3 neuroendocrine carcinoma (NEC) at histological grading. Cytology was found to be highly specific in the diagnosis of both G2 (94.1 %; 95 % CI 80.3–99.3) and G3 tumors (100.0 %; 95 % CI 92.8–100), but the sensitivity was poor for G2 NETs (66.7 %; 95 % CI 38.4–88.2) and high for the prediction of G3 NECs (100 %; 95 % CI 39.8–100.0). When the 5 % cutoff value was adopted, concordance rate was 49/53 (92.4 %; weighted κ 0.82; 95 % CI 0.64–1.00). In conclusion, Ki-67 cytological expression can distinguish well-differentiated (both G1 and G2) from poorly differentiated P-NETs, and it may be useful for their preoperative classification.     

p53 Immunostaining distinguishes malignant from benign lesions of the gall-bladder

The expression of p53 protein was studied in formalin-fixed paraffin-embedded specimens of 41 well-differentiated adenocarcinomas of the gall-bladder, six cases of acute cholecystiiis and 23 cases of chronic cholecystitis, using a monoclonal p53 (PAb 1801) antibody and streptavidin-biotin. p53 staining was divided into diffuse, focal or sporadic patterns. The relationship between the p53 Labeling Index (p53 LI) and cellular proliferation was also investigated using monoclonal Ki-67 (MIB1) antibody. Twenty-four of the 41 carcinomas (58.5%) had a diffuse staining pattern with a high p53 Ll (47–93%) and 9.8% (4141) had a focal staining pattern with an intermediate p53 LI (22–34%), with no relation to pT stage, tumor size, histologic type or grade of cytologic atypia. The p53 LI was higher than the Ki-67 LI in these tumors except for one. On the other hand, p53 staining was completely sporadic in the non-neoplastic specimens with a low p53 LI (0.2–2.8%). The p53-positive cells in these specimens were located only within areas of Ki-67-positive cells. In conclusion, p53-protein overexpression occurs as an early event in approximately 70% of well-differentiated adenocarcinomas of the gall-bladder, and this alteration is maintained during progression from intramucosal to invasive carcinoma. p53 immunostaining can distinguish malignant from benign lesions of the gall-bladder.     

Quantitative immunohistochemical evaluation of MIB-1 labeling index in adult soft-tissue sarcomas by computer-assisted image analysis

We have found that the MIB-1 grade, based on tumor differentiation/histological type, necrosis and Ki-67 (MIB-1) score, is a valid and reproducible prognostic system for adult soft-tissue sarcomas. However, there are limited data available on Ki-67 labeling indices (LI) from adult soft-tissue sarcomas for testing the validity of quantitative image analysis. In this study, the records of 146 adult patients with soft-tissue sarcomas of the extremities and trunk were retrieved, and MIB-1 immunostaining was carried out for the grading. The counted MIB-1 LI values and the scores estimated from microscopic observation were defined as the gold standard. The correlation between MIB-1 LI as assessed by computer-assisted image analysis and by microscopic observation was determined. The image analysis -based MIB-1 LI was highly correlated with the microscopic observation-based MIB-1 LI (r = 0.87, 95% confidence interval (CI) = 0.82-0.92). In addition, agreement between the MIB-1 scores was very high (kappa statistic = 0.83, 95% CI = 0.75-0.91), as was the percentage agreement (89%, 95% CI = 82.8-93.6%) between the results from image analysis and microscopic observation. We conclude that quantitative immunohistochemical evaluation of MIB-1 LI by image analysis enables pathologists to improve interobserver agreement in the assessment of MIB-1 score, and can help to objectively assign the correct histological grade to cases of adult soft-tissue sarcoma, resulting in optimal clinical management.     

Prognostic significance of Bcl-2 in clinically localized prostate cancer.

The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. To study the prognostic significance of Bcl-2 and p53 overexpression in prostate cancer, 137 consecutive radical prostatectomy specimens were examined by immunohistochemistry. Both Bcl-2 and p53 were associated with malignant phenotype. Bcl-2 expression was more frequent in pT3 tumors (31% positive) than in pT2 tumors (5% positive, P = 0.001). p53 overexpression (found in 8%) was associated with high Gleason score (P = 0.03) and increased tumor growth fraction (Ki67 labeling index (LI); P = 0.017). Survival analysis showed that Bcl-2 expression (P = 0.03), high Ki67 LI (P = 0.018), high grade (P = 0.0037), advanced local stage (P = 0.0005), and positive lymph nodes (P = 0.026) were predictors of progression. The combined analysis of Ki67 LI and Bcl-2 allowed the distinction of three groups with different clinical outcome. Prognosis was best in Bcl-2-negative tumors with low Ki67 LI, worst in Bcl-2-positive tumors with high Ki67 LI, and intermediate in the remaining tumors (P = 0.03). These data suggest that altered expression of both Bcl-2 and p53 play a role in prostate cancer progression. Combined analysis of factors regulating both apoptosis and cell proliferation may be relevant in prostate cancer.     

胃肠道间质瘤中p16、p27、Ki-67表达

目的探讨胃肠道间质瘤中p16、p27和Ki67表达与临床预后的关系。方法根据核分裂象的多少、肿瘤体积的大小及有无浸润等将胃肠道间质瘤划分为良性、交界性和恶性,并运用免疫组化SP方法检测p16、p27和Ki67在胃肠道间质瘤中的表达,并统计分析其良性、交界性、恶性和复发死亡病例中的表达差异。结果p16、p27和Ki67的阳性表达率分别为48%、26%和24%。p16在良、恶性中的表达无明显差异,但在良性和交界性中的表达与复发和转移相关;p27低标记指数和Ki67高标记指数与复发和转移相关。结论p16、p27和Ki67在胃肠道间质瘤中的表达对判断预后有价值。     

Diversity in expression and prognostic significance of G1/S cyclins in human primary lung carcinomas

Expression of cyclin A, cyclin E and cdk2 was examined immunohistochemically in 144 cases of primary non-small cell lung carcinoma to evaluate their prognostic value. Cyclin A was co-expressed with cdk2 in the proliferating cells, ie those showing positive Ki-67 staining. The labelling index (LI) of cyclin A revealed a positive correlation with the S-phase fraction and an inverse correlation with histological differentiation. Furthermore, high cyclin A LIs indicated a poor prognosis in all histological types. Cyclin E exhibited a characteristic staining pattern: in squamous cell carcinoma (SCC), differentiated cells without Ki-67 staining revealed cyclin E positivity with expression of cdk2. Conversely, in adenocarcinoma (AC), proliferating cells revealed cyclin E positivity. Cases of large cell carcinoma showed heterogeneous cyclin E staining patterns, unlike those of SCC or AC. Statistical analyses also revealed a marked contrast between SCC and AC. In AC, the LI of cyclin E was inversely correlated with histological differentiation and a high LI predicted a worse prognosis. In contrast, in SCC, the LI of cyclin E correlated positively with histological differentiation and better prognosis. However, the expression levels of cyclin E mRNA evaluated by quantitative RT-PCR were higher in poorly differentiated SCC and AC, suggesting that protein turnover plays a large role in determining cyclin E protein levels. Although the expression of cyclins was demonstrated to be diversely regulated depending on the histological type, the combined immunohistochemical analyses performed in this study on these proteins could be useful tools for evaluating patient prognosis in lung carcinomas.     

Cytoproliferative activity in colorectal poorly differentiated clusters: Biological significance in tumor setting

BackgroundPoorly differentiated clusters (PDCs) have gained a significant prognostic role in colorectal carcinomas (CRCs) being associated to high risk of lymph node metastasis, shorter survival time and poor prognosis. The knowledge in PDC biology is not completely clear.Materials and methodsWe assessed Ki-67 LI in 45 CRCs showing ≥10 PDCs. We distinguished PDCs at the periphery of the tumor masses (pPDCs) from those within the tumor masses (cPDCs). We chose 3 cut-offs of Ki-67 labeling index (Ki-67 LI): <10%, 10–50%, and >50% of the labeled cells.ResultsKi-67 LI in pPDCs was<10% in 37 cases (82%), 10–50% in 6 cases (13%) and >50%in 2 cases (5%); Ki-67 LI in cPDCs was<10% in 4 cases (23.5%), 10–50% in 4 (23.5%) and >50% in 9 (54%). Ki-67 LI in tumor budding foci (TBs) was <10% in 8 cases (32%), 10–50% in 8 (32%) and >50% in 9 (36%). The difference of Ki-67 LI reaches the statistical significance (p < 0.005). Ki-67 LI <10% in the pPDCs was associated with nodal metastases (pN+) (p < 0.0001), pTNM stage III and IV(p < 0.0001) and TB (p < 0.001). Ki-67 LI > 50% in cPDC was significantly associated withpT3-pT4 and advanced pTNM stages (p < 0.0001), N+ (p = 0.0001) and LVI (p < 0.05).ConclusionDifferent Ki-67 LI detected between cPDCs and pPDCs suggesting a biological difference in PDCs. An actively proliferating central tumor areas can be distinguished from the peripheral portion of the tumors in which the cells interact with the stroma acquiring invasive and metastatic potential.     

High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus.

Telomerase activity, a mechanism granting cellular immortality, has been detected in most cancer entities, but its association with clinical, histopathologic, and prognostic parameters is not fully understood. We investigated whether quantitative telomerase levels are correlated to established prognostic factors, telomere lengths, cell cycle kinetics, and the clinical course in endometrioid adenocarcinoma of the uterus (EC). A modified telomeric repeat amplification protocol (TRAP) was used to quantify the relative telomerase activity in a series of 53 primary tumors. Mean telomere length was determined by Southern blot analysis. Cell cycle kinetics were studied immunohistochemically on paraffin sections using monoclonal antibodies to 2 distinct proliferation-specific proteins: Ki-67, which is expressed throughout the cell cycle, and a novel cell cycle-associated protein, repp86, the expression of which is restricted to the cell cycle phases S, G2, and M. The ratio of the 2 immunolabeling indices defines the rate of transition through the restriction point. Telomerase activity was detected in 50 of 53 ECs (94%). Its levels correlated significantly with FIGO stage (P =.01) and FIGO grade (P =.003) but not with myometrial invasion. They were weakly associated with the overall proliferative activity (Ki-67, r =.48) but significantly with the repp86 index (r =.64) and even more strongly with the repp86:Ki-67 ratio (r =.77). There was no correlation with mean telomere length. In the group of tumors with high telomerase activity, 5 patients had relapses and 2 died of the disease within a median follow-up period of 29 months. Recurrence showed no relation to FIGO grade and stage. No events were observed in the group with low telomerase activity. In a multivariate model including tumor stage, histopathologic grade, depth of myometrial invasion, and Ki-67 indices, telomerase activity emerged as the only independent predictor of disease progression (P =.0002). It is concluded that beyond a link to proliferation, high telomerase activity reflects a deregulation of the cell cycle associated with an increased rate of cells entering S phase and a higher degree of malignancy. Therefore, quantitative analysis of telomerase activity may be useful for identifying EC patients at high risk for recurrence.