Gliomas: Correlation of Histologic Grade,Ki67 and p53 Expression with Patient Survival

Background: Gliomas are grouped into grades 1 to 4 on the basis of morphologic criteria. Grade is the mostsignificant prognostic factor determining survival, but various proliferation markers are being increasinglyemployed by histopathologists as adjuncts to conventional morphologic variables to determine prognosticbehavior of brain tumors. The most widely used and useful of these are MIB1 (Ki67) and p53. Objective: Tocorrelate World Health Organization (WHO) grades of glial neoplasms and expression of MIB1 and P53 by thesetumors with patient survival at the end of one year. Material and Methods: 50 consecutive cases with confirmeddiagnosis of various histologic types of glial neoplasms were included. Grading was done according to the WHOgrading system for CNS neoplasms. Immunohistochemical staining of p53 and MIB1 (Ki67) was performed andscores were calculated. Results: A significant correlation was shown between WHO histologic grade and patientsurvival (p value:0.004) and a marginal correlation was seen between MIB1 score and patient survival (p value:0.233). Conclusion: Histologic grade is the most important prognostic factor with respect to patient survival inglial neoplasms. Immunohistochemical staining with MIB1 and p53 may serve as an additional useful toolindetermining the clinical course in combination with and as an adjunct to tumor grade. However, the fact thatfollow-up was available in only twenty out of the fifty cases is a limitation of the present study.     

Image-guided core breast biopsy: a suitable method for preoperative biological characterization of small (pT1) breast carcinomas

Multiple prognostic indicators, namely histological grade and immunostaining for estrogen (ER) and progesterone receptors (PgR), MIB 1, bc1-2, and p53, were retrospectively determined on preoperative core biopsies from 75 patients with pT 1 breast carcinoma. The association of the preoperatively evaluated factors with those on the corresponding resected tumors (i.e. nodal status, histological grade, presence or absence of vascular invasion and necrosis) was assessed. In univariate analysis, histological grade on resected tumors was significantly associated with histological grade on core biopsy, p53 expression, MIB1 immunostaining. An inverse association was found between postoperative histologic grade and ER, PgR, and bc1-2. Necrosis was significantly associated with grade, p53, MIB1, and inversely with ER, PgR, and bc1-2. Nodal involvement and vascular invasion were significantly associated with MIB1. In multivariate analysis, histological grade and ER were the only independent core biopsy variables associated with postoperative histological grade and necrosis, respectively. This study showed that image-guided core biopsy is a suitable method that can be used to reveal some characteristics of the tumor biology in a preoperative stage.     

Prognostic significance of telomerase activity in soft tissue sarcomas.

Only few reports on the prognostic significance of telomerase activity in human cancer exist. To find a new prognostic marker in soft tissue tumors, we investigated 60 soft tissue sarcomas of different histology and six benign tumors for telomerase activity. Telomerase activity was measured by using the non-radioactive PCR-based TRAP-assay. PCR products were analyzed on an automated fluorescence sequencer. Tumors of grade-II and grade-III histology showed a significantly poorer prognosis. Both disease-free (p<0.03) and the overall survival (p<0.02) were reduced in the highly malignant sarcoma patients. We found telomerase activity in 38.3% of the cases, there being a correlation with a more aggressive behavior of soft tissue sarcomas. Telomerase activity correlated with the grade of malignancy (p=0.04), but not with sex (p=0.64) or age (p=0. 48) of the patients. The total survival was significantly reduced in patients with telomerase-positive sarcomas (p=0.04). Both of the patients having grade I tumors with telomerase activity died of disease, whereas 10 of 11 patients with telomerase-negative grade I tumors are still alive. Only one of the benign tumors showed telomerase activity. We suggest that telomerase activity is a potential prognostic factor in malignant soft tissue tumors. Despite the histological heterogeneity of soft tissue tumors, single entities should be assessed for telomerase activity.     

Prognostic importance of DNA ploidy and p53 in early stages of epithelial ovarian carcinoma.

Patients with early stages (FIGO stages IA-IIC) of ovarian cancer continue to experience tumor relapses and they succumb due to their disease after seemingly adequate adjuvant therapy. In a series of 113 patients treated with adjuvant radiotherapy 4-6 weeks after primary surgery, the DNA content and p53 status of the tumors were studied and related to other known prognostic factors (age, FIGO stage, histopathologic type, and tumor grade). The DNA analyses were done by flow cytometry and p53 expression was studied by immunohistochemistry on formalin-fixed and paraffin-embedded tissue. DNA analyses of 103 tumors could be made and the p53 status was determined in 106 cases. Univariate analyses showed that both p53-positivity and aneuploidy of the ovarian tumors were strongly associated with tumor grade. There was also a strong association between p53 expression of the tumors and DNA aneuploidy (DNA index >1.10 and S-phase fraction >11.5%). P53-positivity and tumor grade were the only significant factors for the risk of tumor recurrence. DNA and p53 status alone were not adequate predictive factors to identify clinically relevant subgroups of patients who would benefit from adjuvant postoperative therapy. Tumor grade remains the most important prognostic factor with regard to the risk of tumor recurrence and the cancer-specific survival rate in early stage ovarian carcinoma. Overexpression of p53 also increases the risk of tumor recurrence.     

MYC amplification and polysomy 8 in chondrosarcoma: array comparative genomic hybridization, fluorescent in situ hybridization, and association with outcome.

PURPOSE: To identify recurrent regions of genomic gain or loss in chondrosarcoma in a clinically relevant and statistically valid fashion. Materials and METHODS: Array comparative genomic hybridization (CGH) results of 15 frozen tumor samples of high-grade chondrosarcoma for chromosome 8 are presented. A separate subset of 116 cartilaginous tumors with outcome data was used for validation. RESULTS: Array CGH identified gain at 8q24.12-q24.13, the region of the MYC (c-Myc) oncogene, as a frequent change in high-grade chondrosarcoma. In the validation arm of 116 cartilaginous tumors, MYC was frequently amplified in G2 (15%), G3 (20%), and dedifferentiated (21%) chondrosarcomas. No amplification was identified in samples of enchondroma and grade 1 chondrosarcoma. In samples without MYC amplification, polysomy 8 was a frequent finding in grade 1 (18%), grade 2 (31%), grade 3 (80%), and dedifferentiated (29%) chondrosarcomas, but was not found in any samples of enchondroma. MYC protein expression was identified in all samples with amplification, but was also frequent in the remaining samples without amplification or polysomy 8. Kaplan-Meier survival curves for overall survival showed a statistically significant difference for patients with MYC amplification or polysomy 8 (P = .034). Univariate analysis involving Cox proportional hazards models showed that grade (P = .003), polysomy 8 (P = .045), and MYC amplification (P = .053) correlated with shorter overall survival. By multivariate analysis, grade of chondrosarcoma (P = .026) was the only factor to reach statistical significance. CONCLUSION: MYC amplification and polysomy 8 can be used as markers of prognostic importance in chondrosarcoma. Molecular targeting of MYC expression may have therapeutic potential in the future for subsets of chondrosarcoma.     

Prognostic significance of Ki-67 (MIB1), PCNA and p53 in cancer of the oropharynx and oral cavity

Up to now results concerning the prognostic value of tumor proliferation markers in squamous cell head and neck carcinoma have been equivocal. Beside biological reasons, different treatment modalities are hypothetically responsible for contradictory findings. The aim of this study was to investigate the relationship between proliferative capacity, represented by the immunohistochemical labeling index of proliferation markers Ki-67, PCNA and p53 status, and treatment failure in a matched-pair study design of recurrent and non-recurrent carcinoma initially treated with primary surgery combined with curative post-operative radiation. From a group of 239 patients with T1–T3 carcinoma of the oropharynx or oral cavity, 28 patients with recurrent disease were selected and matched with 28 patients with non-recurrent disease regarding stage and location of tumor as well as age and therapy. All patients received primary surgery combined with post-operative radiation. Immunohistochemistry determined the p53 status and the PCNA and MIB1 (Ki-67) labeling index. The Ki-67 labeling index was significantly (p=0.032) higher in tumors from patients suffering from treatment failure (mean=59.1%) than in non-failures (mean=50.5%). Carcinoma with a Ki-67 (MIB1) labeling index above the median (53.7%) of the general study population showed a mean time to relapse of 45 months (n=25), whereas mean time-to-relapse was 61.7 months for those cases (n=31) below the median of the general study population (p=0.029). The PCNA labeling index did not correlate significantly with tumor recurrence (mean=50.2% for treatment failures, 45% for non-failures, p=0.31), nor with time-to-relapse (p=0.26). Forty-six percent of tumors showed p53 over-expression. However, there was no significant correlation between p53 over-expression and tumor recurrence or time-to-relapse. We present the largest series of oropharyngeal and oral cavity carcinoma investigated by immunohistochemistry in a controlled study. We conclude that a high Ki-67 labeling index is an indicator for treatment failure in these patients. Like other investigations for different head and neck subsites, we found no relationship between p53 or PCNA status and tumor prognosis. Our data, obtained from a group of patients treated with a combination of surgery and post-operative irradiation, show that for squamous cell carcinoma of the oropharynx and oral cavity the detection of Ki-67 is an unfavorable prognostic factor.     

Expression of p21/waf1 in oral squamous cell carcinomas--correlation with p53 and mdm2 and cellular proliferation index

The cyclin-dependent kinase inhibitor p21/waf1 is regulated by p53-dependent and p53-independent pathways. In addition, mdm2 is an oncogene which forms an auto-regulatory loop with the normal p53 protein and its role has been implicated in oncogenesis. To determine whether a correlation exists between the expression of these gene products, tumor differentiation, tumor staging and radiation therapy, we investigated the expression of p21, p53 and mdm2, and cellular proliferation by Ki-67 (MIB1) labeling index using immunohistochemistry in 88 human oral squamous cell carcinoma (SCC) samples from 56 patients. Tumor expression of all nuclear proteins was scored according to the percentage of positive cancer nuclei, both with the cancer tissue as a whole as well as in different epithelial compartments of differentiation. Positive p21, p53, mdm2 and MIB1 staining was present in 82.4, 67.8, 25.9 and 98.8% of the SCC samples. The staining in different epithelial compartments of differentiation varied: those of p21 and mdm2 present predominantly in suprabasal and upper regions of the tumors: those of p53 and MIB1 in basal and suprabasal regions. Higher levels of p21 expression were seen in actively proliferating tumors (P = 0.025). p21 expression positively correlated with mdm2 expression but not with p53 expression. Moreover, the level of p21 expression was higher in older patients (P = 0.024) and female patients (P = 0.008). There was no significant association among p53, mdm2 and MIB1. Expression of p53 was higher in tumors with poorer cellular differentiation and in younger patients (P = 0.038 and 0.028). There was no association between tumor stage by TNM classification and the expression of any of these gene products or proliferation index. Radiation therapy did not alter the expression of any of these. To conclude, p21 protein was overexpressed in oral SCCs, and this overexpression was related to cell proliferation index and mdm2 expression but independent of p53 protein alteration. Overexpression of p21 alone appeared to be insufficient to suppress tumor progression.     

Rb-loss is associated with high malignancy in chondrosarcoma

Loss of function of the human retinoblastoma gene (Rb) is a frequent genetic abnormality in human malignancies and causes a disturbance in the cell cycle and loss of normal proliferation and differentiation. We studied the loss of heterozygosity (LOH) of the Rb gene in 31 formalin-fixed, paraffin-embedded cartilaginous tumors using polymerase chain reaction. The tumors were subdivided into 8 cases of dedifferentiated (DD) chondrosarcoma, 17 cases of conventional chondrosarcoma (nine grade 1, seven grade 2 and one grade 3), 4 enchondromas and 2 chondroblastomas. Both components of DD chondrosarcoma, the low-grade and anaplastic components, were separated by a microdissection approach. The genetic data were correlated with the expression of the Rb protein examined by Rb immunohistochemistry. We found Rb-LOH in one grade 3 chondrosarcoma, and in the anaplastic component in 7 of 8 cases of DD chondrosarcoma (89% of all high-grade chondrosarcomas). All tumors with Rb-LOH were immunohistochemically Rb-negative. The only case of DD chondrosarcoma negative for Rb-LOH in both components of the tumor also showed weak expression of the Rb protein in the anaplastic component. All benign cartilaginous tumors, low-grade chondrosarcomas and low-grade tumor components of DD chondrosarcomas were negative regarding Rb-LOH but positive in Rb immunohistostaining. We concluded that Rb-LOH predominantly occurs in high-grade chondrosarcomas. However, it is not a marker for identifying low-grade tumors with a tendency towards progression or local recurrence.     

p53 expression in dedifferentiated chondrosarcoma

Background. p53 acts as a tumor suppressor gene because of to its negative control of the cell cycle and its central role in programmed cell death. It frequently is mutated, as observed in a variety of human neoplasms. The mutations inhibit tumor-suppressor activities of p53, which may gain a new function of tumor promotion. In this study, p53 was investigated in various components of dedifferentiated chondrosarcoma and correlated with their proliferative activities. Methods. Immunohistochemical assays for p53, Ki-67, and proliferating cell nuclear antigen (PCNA) were used in a series of eight dedifferentiated chondrosarcomas of bone. The cartilaginous component was low grade (Grade I-II) in five cases. It was predominantly low grade with foci of a high grade (Grade III) chondrosarcoma in the remaining three cases. The noncartilaginous (de-differentiated) high grade component consisted of malignant fibrous histiocytoma in five cases and osteosarcoma in three. Results. Regardless of the histological type, diffuse strong nuclear staining for p53 occurred in the high grade noncartilaginous component of all eight of the tumors. The low grade cartilaginous component of six cases was negative for p53, with focal weak staining in the two remaining cases. The high grade cartilaginous component showed strong positive staining for this protein in all three cases. Ki-67 and PCNA expression were similar to that of p53. Conclusions. The percentage of p53 positive staining roughly was parallel to the proliferating fraction of cells in various components of dedifferentiated chondrosarcoma. Moreover, p53 overexpression was consistently present in the high grade noncartilaginous (dedifferentiated) component of the tumor and was accompanied by increased proliferative activity. Cancer 1995; 76:223-7.     

The combined evaluation of p53 accumulation and of Ki-67 (MIB1) labelling index provides independent information on overall survival of ovarian carcinoma patients

Background: The prognostic implications of p53 accumulation, bcl-2immunoreactivity and tumour proliferative fraction in ovarian carcinomas arestill debated.Patients and methods: One hundred twelve ovarian carcinomas wereimmunostained for p53 protein, for bcl-2 and for the cell cycle-associatedKi-67 antigen. The immunostaining results were correlated with conventionalclinico-pathological variables, response to induction chemotherapy, andpatient survival.Results: p53 accumulation and bcl-2 immunoreactivity in more than10% of neoplastic cells were detected in 61 (54.5%) and 42(37.5%) cases, respectively. A positive correlation between p53accumulation and high (more than 30% neoplastic cells) MIB1 labellingindex (r = 0.235; P = 0.015) was ascertained, whereas no significantassociation was found between bcl-2 immunoreactivity and p53 accumulation orMIB1 labelling index. Both p53 accumulation and MIB1 immunoreactivitycorrelated significantly with a reduced overall survival, but the associationwas lost in multivariate analysis. However, patients with tumourssimultaneously showing p53 accumulation and MIB1 labelling index higher than30% had significantly reduced overall survivals, in both univariate andmultivariate analyses.Conclusion: The simultaneous evaluation of p53 accumulation and MIB1labelling index has independent prognostic implications in common epithelialmalignancies of the ovary, irrespective of the disease stage.     

Prognostic Evaluation of Proliferative Activity and DNA Content in the Phyllodes Tumor of the Breast: Immunohistochemical and Flow Cytometric Study of 118 Cases

The goal of this study was the prognostic evaluation of histology, mitotic rate, S-phase fraction (SPF) and expression of proliferative antigen Ki67 and p53 protein in phyllodes tumor of the breast. The study was performed in the group of 118 patients with phyllodes tumor treated by surgery from 1952 to 1998. Mitotic rate was assessed on the representative histological specimens. Expressions of Ki67 and p53 were evaluated by immunohistochemistry on a section from the corresponding paraffin blocks which were also used for flow cytometric DNA evaluation. Histologically, 52 tumors were benign (LGM), 24 borderline malignancies (BM) while among 42 malignant tumors, 20 were monomorphous (HGM) and the remaining 22 revealed heterologic elements (HGH). Tumor recurrencies occurred in 17 patients, predominantly during the first three years after surgery, and 13 patients died of the tumor (1 BM, 12 both malignant variants). Multivariate analysis demonstrated mitotic rate, SPF and p53 expression as independent prognostic parameters for the disease-free survival. Histological tumor type and expression of Ki67 influenced independently the overall survival. In conclusion, the histological type of tumor phyllodes forms the basis for the prognosis of clinical outcome, but the indicators of the proliferative activity, especially Ki67 index, are valuable prognostic factors among patients with malignant variant of phyllodes tumor of the breast. Expression of the p53 protein in tumor cells could be also useful when the percentage of cells and intensity of expression are considered.     

Proliferation rate, hormone receptor status and p53 expression in skeletal metastasis of breast carcinoma

Immunohistochemistry was used to analyze ER, PgR, MIB, and p53 of primary breast carcinomas and their skeletal metastases in 43 patients operated on for 47 pathological fractures. Femoral lesions predominated (24), followed by metastases to the spine (13). The median survival time from diagnosis of the primary breast carcinoma was 5.5 (0.5-20) years and from pathological fracture 5 (0-76) months. No clinical characteristics of the primary tumor were prognostic for survival after pathological fracture. Thirty of 47 tissue specimens from skeletal metastases were ER positive and 17 negative. Fourteen of 47 tissue specimens from skeletal metastasis were positive for PgR. Forty-five of the 47 metastases could be evaluated for p53 positivity and 43 tumors showed nuclear staining of varying intensity. In a majority of the cases there was a good correlation between ER, PgR and p53 in the primary tumors and their corresponding metastases. p53 negative primary tumors were associated with longer survival from diagnosis, but also found after pathological fracture. No correlation was observed between ER index or MIB-1 in the skeletal metastases and postoperative survival. PgR positivity in skeletal metastases was associated with longer survival after pathological fracture. This study shows that biological markers such as PgR and p53 provide prognostic information after pathological fracture. The findings should be regarded with caution as there are many confounding factors such as prior chemo- and radiotherapy. Nevertheless, the approach, to gather prognostic data at the time of pathological fracture, warrants further study as expected survival time is paramount in the choice of surgical treatment.     

Ki-67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification

Approximately 80% of bladder tumors are urothelial superficial papillary carcinomas (USPC). Despite a generally good prognosis, these tumors have a strong propensity to recur and about 1/3 of them compared to disease progression. Histological assessment of these superficial tumors is not sufficiently discriminator in predicting prognosis; therefore, we decided to evaluate the prognostic significance of p53 and Ki-67 immunoexpression in low-grade (GI-II) USPC in order to predict the potential outcome of these tumors. P53 and Ki-67 immunoexpression were studied in function of recurrence-free and progression-free survival in 159 primary superficial bladder tumors. A prognostic risk model based on grade, stage and multifocality was also evaluated. P53 accumulation was significantly related to tumor progression (p=0.006). High Ki-67 index (>/=18%) and multifocality were significantly related to recurrence (both p=0.0001) and progression-free survival (both p=0.0001) and were independent prognostic factors in the multivariate analysis. The prognostic risk model based on grade, stage and multifocality was not an efficient discriminator of outcome. Adding the Ki-67 index into the risk model, single pTa/T1-GI Ki-67 positive tumors, usually classified as low risk, were reclassified as of intermediate risk. After this reclassification, the risk group model identified a subgroup of pTa/T1-G1 with a high risk of recurrence and progression. Ki-67 index is a reliable prognostic marker in urothelial superficial bladder carcinoma and, when included into a risk profile classification of the low-grade USPC, the accuracy of the prognostic discrimination is enhanced.     

The prognostic value of p53 and c-erbB-2 expression, proliferative activity and angiogenesis in node-negative breast carcinoma

AIMS AND BACKGROUND: p53, c-erbB-2 and Ki-67 protein expression and microvessel density (MVD) determined by CD34 antibody were evaluated by immunohistochemistry and their correlation with clinicopathological parameters including estrogen (ER) and progesterone (PR) receptor status and survival were investigated in patients with axillary lymph node-negative infiltrating ductal breast carcinoma. METHODS: The study population consisted of 47 patients with axillary lymph node-negative infiltrating ductal breast carcinoma. RESULTS: p53 and c-erbB-2 expression was detected in 36.2% and 31.9% of patients, respectively. Median Ki-67 expression was 10%. There were no statistically significant differences in the distribution of p53, Ki-67 and c-erbB-2 protein expression in relation to the age of the patients or to the size, histological grade or ER and PR status of the tumors. p53 protein expression correlated positively with c-erbB-2 and Ki-67 protein expression (P < 0.05). The mean MVD was 63.65 +/- 29.1 and it correlated positively with histological grade and Ki-67 expression (P < 0.05). Survival analysis revealed that age, tumor size, p53 and c-erbB-2 expression and PR status had no significant prognostic impact, whereas histological grade, proliferative activity and angiogenic activity were significant prognostic factors. Although ER-positive patients had a statistically significant overall survival advantage, the difference in disease-free survival was not significant. CONCLUSION: In axillary lymph node-negative breast carcinoma the histological grade and the proliferative and angiogenic activity of the tumor could be useful prognostic indicators.     

Angiogenesis, p53, and c-erbB-2 immunoreactivity and clinicopathological features in male breast cancer

BACKGROUND AND OBJECTIVES: p53, c-erbB-2, and tumor microvascular density have been shown to be potential prognostic tools in female breast cancer. Our objective was to assess the significance of these biomarkers as prognostic factors in infiltrating male breast cancer. METHODS: A retrospective study of expression of p53, c-erbB-2, and tumor microvascular density was done on a group of 26 male breast cancer patients. Biotin-streptavidin immunohistochemical study with specific anti-p53, anti-c-erbB-2, and anti-CD34 antibodies was carried out on paraffin sections of breast carcinoma. The data of expression of the biomarkers were merged with clinicopathological data such as tumor grade, T class, TNM stage, estrogen receptor status, tumor recurrence, and patient survival. RESULTS: p53 and c-erbB-2 were expressed in 46% and 39% of carcinomas, respectively. No correlation was found between positive immunoreactivity of p53, and tumor grade, size, T class, TNM stage, and survival. Nor was any relation found between tumor size, T class, TNM stage, survival, and c-erbB-2 overexpression. c-erbB-2 overexpression was significantly higher in high grade carcinomas. Estrogen receptor (ER) were positive in 21 out of 26 of tumors (81%). No trends were observed between estrogen receptor status and clinicopathological parameters or survival (data not shown). There was a positive correlation between mean microvascular density (MVD), advanced T class, and survival: higher MVD counts were found in patients with advanced tumors and in those who had tumor relapses or died of metastatic disease. CONCLUSIONS: This study suggests that tumor microvascular density may serve as a potential prognostic tool in male breast carcinoma.     

Low p27 expression is an independent predictor of survival for patients with either hilar or peripheral intrahepatic cholangiocarcinoma.

PURPOSE AND EXPERIMENTAL DESIGN: The prognosis for intrahepatic cholangiocarcinoma (ICC) depends mainly on the feasibility of complete surgical resection. In the absence of demonstrated biological predictors of survival, we evaluated the prognostic value of the cyclin-dependent kinase inhibitor p27 by immunohistochemistry in a series of routine specimens from 47 ICC patients, 22 with the hilar and 25 with the peripheral subtype. Proliferation rate was also evaluated in the same cases by the MIB1 index. Tumors were scored as high, low, and negative p27 expressers (> or =50%, <50%, and no positive nuclei, respectively). RESULTS: High, low, and negative p27 expression was recorded in 18 (38%), 17 (36%), and 12 (26%) cases, respectively. No significant correlation was found between p27 expression and gender, age, tumor grade, tumor location, vascular or perineural invasion, or proliferative index. Tumors with low or absent p27 expression were associated with poor survival compared with the high-expresser group. Kaplan-Meier curves comparing different p27 expression levels with survival showed highly significant separation (P < 0.0001, log-rank test). With univariate Cox proportional hazard regression, only p27 score among all of the parameters was found to influence survival (P = 0.0003). CONCLUSION: We conclude that in ICC, low or absent p27 expression can predict poor survival, regardless of tumor location, pathological features, and tumor proliferation. Immunohistochemical detection of p27 on routine sections may provide the first biological prognostic marker for ICC, thus influencing the therapeutic strategies for these patients.     

Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients.

BACKGROUND: Recent evidence indicates that a subset of axillary node-negative (ANN) breast cancer patients can benefit from adjuvant therapy. Reliable prognostic markers are needed, however, to help clinicians identify these patients and arrive at more rational treatment decisions. PURPOSE: Mutations of the p53 tumor suppressor gene often result in overexpression of the p53 protein. In this study, we evaluated the prognostic significance of p53 protein overexpression in patients with ANN breast cancer. We also studied the association between the tumor cell proliferation rate and overexpression of the p53 and c-erbB-2 proteins, both of which have been implicated in cell cycle control. The c-erbB-2 protein is the product of the ERBB2 gene. METHODS: Two hundred eighty-nine ANN cases were randomly selected from a population-based cohort of patients who had not received any kind of adjuvant chemotherapy or endocrine therapy. Overexpression of the p53 and c-erbB-2 proteins was studied immunohistochemically in archival paraffin-embedded tumor samples, using the CM-1 polyclonal and the TAb 250 monoclonal antibodies, respectively. The tumor cell proliferation rate was measured as the S-phase fraction by DNA flow cytometry. Statistical analyses were performed using BMDP software. RESULTS: High-level p53 protein overexpression, found in 41 of the 289 tumors, was most common in tumors with high histologic grade, negative estrogen receptor status, c-erbB-2 protein overexpression, DNA index greater than 1.3, or high S-phase fraction. The lowest S-phase levels were found in tumors with neither p53 nor c-erbB-2 protein overexpression; the highest levels were seen in tumors showing overexpression of both proteins (P less than .0001). Both p53 and c-erbB-2 overexpression, as well as tumor size, had independent prognostic value in multivariate analysis. Eight-year survival of patients with p53 protein overexpression was 56% compared with 81% in patients with no overexpression (relative risk, 3.7; P less than .0001). If the S-phase fraction was included in a Cox regression analysis, however, only the tumor size and the S-phase fraction emerged as independent predictors of survival. CONCLUSIONS: Overexpression of the p53 and c-erbB-2 proteins indicates a high malignant potential in ANN breast cancer, but it is not a significant prognostic factor independent of the cell proliferation rate. The correlation between overexpression of these proteins and an increased S-phase fraction suggests that they may confer a proliferative advantage to cancer cells in vivo.     

Early recurrences in histologically benign/grade I meningiomas are associated with large tumors and coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone

Tumor recurrence is the major clinical complication in meningiomas, and its prediction in histologically benign/grade I tumors remains a challenge. In this study, we analyzed the prognostic value of specific chromosomal abnormalities and the genetic heterogeneity of the tumor, together with other clinicobiological disease features, for predicting early relapses in histologically benign/grade I meningiomas. A total of 149 consecutive histologically benign/grade I meningiomas in patients who underwent complete tumor resection were prospectively analyzed. Using interphase fluorescence in situ hybridization, we studied the prognostic impact of the abnormalities detected for 11 different chromosomes, together with other relevant clinicobiological and histopathological characteristics of the disease, on recurrence-free survival (RFS) at 2.5, 5, and 10 years. From the prognostic point of view, losses of chromosomes 9, 10, 14, and 18 and del(1p36) were associated with a shorter RFS at 2.5, 5, and 10 years. Similarly, histologically benign/grade I meningiomas showing coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone displayed a higher frequency of early relapses. In fact, coexistence of -14 and del(1p36) in the ancestral tumor cell clone, together with tumor size, represented the best combination of independent prognostic factors for the identification of those patients with a high risk of an early relapse. Our results indicate that patients with large histologically benign/grade I meningiomas carrying monosomy 14 and del(1p36) in their ancestral tumor cell clone have a high probability of relapsing early after diagnostic surgery. These findings suggest the need for closer follow-up in this small group of patients.     

The prognostic value of p53 and c-erb B-2 immunostaining is overrated for patients with lymph node negative breast carcinoma: a multivariate analysis of prognostic factors in 613 patients with a follow-up of 14-30 years

BACKGROUND: Approximately 30% of breast carcinoma patients with negative lymph nodes die of their disease. Biologic markers such p53 protein and c-erb B-2 have been related to tumor progression, but their prognostic value remains controversial. METHODS: Two large series of a total of 613 lymph node negative breast carcinoma patients from a single institution were analyzed with respect to tumor size, histologic grade, and immunohistochemical staining for p53, c-erb B-2, estrogen receptor (ER), and progesterone receptor (PgR). Interobserver variation in histologic grading was evaluated by Kappa statistics. The two series had different treatment modalities: 228 patients (SACGS group) were treated surgically with mastectomy and given 1 perioperative chemotherapy course, and 385 patients (HOST group) were treated with mastectomy and ovarian radiation and further randomized to receive postoperative treatment with radiotherapy or no adjuvant treatment. The follow-up ranged from 14-30 years. RESULTS: Immunoreactivities for p53, c-erb B-2, ER, and PgR did not differ significantly in the two series. p53 immunostaining was present in 187 of 613 tumors (29%), and c-erb B-2 immunoreactivity was present in 58 of the tumors (10%). Three hundred forty-eight tumors (57%) were positive for ER. Kappa statistics value of interobserver variation in the histologic grading of ductal carcinomas was 0.69, which is considered to be a substantial degree of agreement. No significant differences in survival were found when comparing p53, c-erb B-2, ER, and PgR positive and negative cases. However, both recurrence free survival rates and overall survival rates after 10 years were significantly better in the T1N0M0 group compared with the T2N0M0 group (81% vs. 67% [P < 0.0001] and 85% vs. 70% [P < 0.0001]). Ten-year recurrence free survival rates for patients with histologic Grade 1 versus Grades 2-3 (according to Elston and Ellis' modification of the Bloom and Richardson method) tumors were 90% and 70%, respectively (P < 0. 0001), and overall survival rates for the same groups were 94% and 81%, respectively (P=0.0002). After 30 years of follow-up, the overall survival rate for patients with tumors of histologic Grade 1 versus Grades 2-3 were 87% and 68%, respectively, and were 78% and 66%, respectively, for patients with tumors 20-50 mm. Approximately 35% of the patients with tumors of histologic Grades 2-3 and measuring > 20 mm were dead after 10 years of follow-up, contrary to 6% of the patients with tumors of histologic Grade 1 measuring 相似文献   

Prognostic value of cytosolic p53 protein in breast cancer.

The prognostic value of cytosolic p53 protein was evaluated in 458 operable breast carcinomas by immunoblotting using the monoclonal antibody PAb 1801. Two hundred and five carcinomas (45%) showed positive p53 accumulation and 55% were p53 negative. When comparing p53 positivity and other clinicopathological parameters, significant differences were found with younger age (p = 0.017), premenopausal status (p = 0.003), increasing tumor size (p = 0.026), negative estrogen receptor (p = 0.003) and negative progesterone receptor (p = 0.047), but not with histologic grade, axillary lymph node status, stage or erbB-2 expression. With a median follow-up of 34 months (range 3-70), relapse has occurred in 73 patients. Disease-free survival curves showed that patients with p53-positive tumors had a significantly shorter disease-free survival than patients with p53-negative carcinomas (log-rank test, p = 0.027). A multivariate analysis of disease-free survival showed that p53, tumor size, histologic grade and progesterone receptor had significant independent prognostic value. The immunoblotting technique was controlled with p53 immunohistochemistry in 94 paired samples. We obtained a statistically significant correlation (p = 0.0004) between the two methods. Our results show that the immunoblotting technique offers an alternative approach in evaluating the p53 status of breast biopsy material using cytosolic extracts, and confirm that p53 accumulation is a significant independent indicator of a poor prognosis in operable breast carcinoma.