mdm2 expression as a prognostic indicator in clear cell renal cell carcinoma: comparison with p53 overexpression and clinicopathological parameters.

The present study was designed to analyze the expression of p53 and mdm2 in clear cell renal cell carcinoma with special emphasis on their association with tumor grade and clinical outcome. In particular, the value of individual protein overexpression as well as combined p53/mdm2 positivity was evaluated because both proteins are functionally connected, and their expression is controlled by an autoregulatory feedback loop. A cohort of 97 clear cell renal cell carcinomas was analyzed. The overexpression of mdm2 and p53 proteins was investigated on paraffin-embedded material by using monoclonal antibodies. Eighteen tumors showed mdm2 positivity, whereas 35 of the tumors overexpressed p53. Whereas p53 and mdm2 positivity correlated significantly (P = 0.00004), no correlation could be found between mdm2 protein overexpression and tumor stage, lymph node involvement, and presence of distant metastases. mdm2 positivity was found significantly more frequently in tumors of higher grade. In univariate analysis, there was a statistically significant correlation between p53 and mdm2 overexpression in the same tumor and poor survival (P = 0.00179). Multivariate analysis revealed that coincident mdm2/p53 overexpression, the presence of distant metastases, and tumor grade were independent predictors for tumor progression. Our results indicate that mdm2/p53 co-overexpression, nuclear grade, and preoperative presence of distant metastasis are independent predictors for poor survival.

Proliferating cell nuclear antigen and MIB-1. An alternative to classic prognostic indicators in renal cell carcinomas?

Tumor progression and clinical outcome for patients with renal cell carcinomas (RCCs) cannot be predicted based solely on tumor staging and grading. In a retrospective study we have therefore attempted to analyze the capacity of proliferation markers to provide additional prognostic information. One hundred seven cases of RCC were investigated by immunohistochemical analysis using two different monoclonal antibodies: PC10, which recognizes a proliferating cell nuclear antigen (PCNA), and MIB-1, which identifies the Ki-67 antigen in formalin-fixed, paraffin-embedded material. PCNA frequency ranged from 0% to 71% (mean, 17%), and MIB-1 expression, from 0% to 43% (mean, 11%). PCNA scores correlated significantly with MIB-1 immunoreactivity. PCNA and MIB-1 immunoreactivity showed a significant correlation with tumor grade. A strong correlation was also observed for T-component of stage and MIB-1 scores, but no correlation was found between PCNA and T-component of stage. In univariate analysis, PCNA immunoreactivity and MIB-1 scores were significant predictors of survival. Multivariate analysis, using a Cox proportional hazard model, showed PCNA index, N-component of stage, and tumor grade to be independent predictors of tumor progression, which is not the case for MIB-1 index.

Primary adenocarcinoma of the ureter. Case report with immunohistochemical characterization.

Genuine adenocarcinomas of the ureter are rare tumors and have to be distinguished from other gland-forming malignancies arising from the transitional epithelium, due to the poor clinical outcome. The histopathological features of a tumor combined with intestinal metaplasia of the adjacent urothelium are described. The tumor has to be distinguished from transitional cell cancer with glandular metaplasia, muco-urothelial cancer, microcystic transitional cell cancer and transitional cell cancer with mucoid cytoplasmatic inclusions. Immunohistochemical analysis of the cancer shows positivity for carcinoembryonic antigen and a staining pattern characteristic for adenocarcinomas. The expression of keratin types 7 and 13, which is typically found in transitional cell carcinomas, is lost.

Accuracy of urinary cytology in the diagnosis of primary and recurrent bladder cancer.

Two thousand two hundred thirteen smears of urinary specimens from 263 patients with bladder disorders were reviewed and the results correlated with the clinical status at the time of urine collection and with the histologic diagnosis during follow-up. In all cases a cytologic diagnosis of malignancy was histologically confirmed at follow-up, reflecting the high predictive value of a positive result in cytology. Cytologic diagnoses were also analyzed for the interval between the cytologic and histologic diagnosis of malignancy. In cases of cytologic diagnosis of malignancy, at times without a clinical suspicion of severe abnormality, an interval of up to 691 days was registered before a malignant process was confirmed histologically. Furthermore, the influence of tumor grade and mode of therapy on the diagnostic accuracy of urinary cytology was evaluated. The accuracy of urinary cytology differed clearly between untreated and treated patients with both high and low grade tumors. Patients who received surgical therapy, radiotherapy and chemotherapy were grouped into three groups. Accuracy of cytologic diagnosis was calculated in relation to variations in therapy and in tumor grade. Minor differences in accuracy were found between specimens from patients after surgical therapy, chemotherapy and radiotherapy. The data from this study suggest that the diagnostic accuracy of urinary cytology is very much related to the histologic grade of bladder tumors, to pretreatment and posttreatment status, and only minimally to the mode of therapy itself (e.g., radiotherapy, chemotherapy or surgical therapy). The high percentage of cytologic diagnoses of atypia in specimens from patients undergoing chemotherapy and radiotherapy reflects the diagnostic problems.

The diagnostic value of pericardial cytology. An analysis of 95 cases.

Cytologic specimens of 105 pericardial fluids collected from 95 cases during a seven-year period were reviewed. Clinical reports and descriptions of the histologic antemortem and postmortem specimens were correlated with the cytologic diagnoses, and the interobserver variation was estimated. Of the collected material, 48.4% was from patients suspected of having nonmalignant disorders, 40.0% was from patients with previously diagnosed carcinomas and 11.6% was from cases in which the etiology was unknown at the time of pericardiocentesis. Cytologic examination of the pericardial fluids revealed tumor cells in a sample from one patient suspected of having a heart disorder and in a sample from another patient with an obscure disease. Of the pericardial fluids from the cancer patients, 66.7% contained malignant cells; the most frequent primary site in these cases was the lung. Correlated with the histologic diagnosis, the specificity of cytology was 100%. The results prove that, in experienced hands, pericardial cytology is a valuable diagnostic tool.

[Cytology of the urinary tract. A modern investigation method?]. / Zytologie des Harntrakts. Eine zeitgemässe Untersuchungsmethode?

Urinary cytology is used in the detection of nephrologic and uro-oncologic diseases. The advantages and limitations of cytology for the detection and follow-up of bladder cancer have been well known since Papanicolaou. The low sensitivity of urinary cytology, especially in the detection of more frequent urothelial tumors with low malignancy potential, led to the development of a number of new tumor markers. Nevertheless, the ideal tumor marker for bladder cancer has not yet been found. Cystoscopy combined with cytology is still the most widely accepted method for bladder cancer screening. The acceptance of this method can be improved by the use of case-specific preparation methods of a variety of materials. In addition to the follow-up of bladder cancer, urinary cytology is also used in the follow-up of renal transplant patients and therefore remains a worthwhile method leading to clinically relevant diagnoses.

European guidelines for quality assurance in cervical cancer screening: recommendations for cytology laboratories.

The quality of a cervical cytology laboratory depends on adequate handling and staining of the samples, screening and interpretation of the slides and reporting of the results. These guidelines give an overview of procedures recommended in Europe to manage the balance between best patient care possible, laboratory quality assurance and cost effectiveness and will be published as a chapter 4 in the European Guidelines for Quality Assurance in Cervical Cancer Screening. The laboratory guidelines include protocols for personnel and organisation, material requirements, handling and analysing cervical samples, recording of results, quality management and communication. The section on quality management is comprehensive and includes protocols for all aspects of internal and external quality assurance. The guidelines are extensively referenced and as far as possible the recommendations are evidence-based.

Expression of the cell cycle proteins p21, p27, and pRb in clear cell renal cell carcinoma and their prognostic significance.

OBJECTIVES: To determine whether p21, p27, and pRb can predict disease progression in clear cell renal cell carcinoma. METHODS: The expression of three negative regulators of the cell cycle, the retinoblastoma gene product (pRb), the WAF1/Cip1 gene product (p21), and the Kip1 gene product (p27), was investigated by immunohistochemistry on paraffin sections from 104 formalin-fixed clear cell carcinoma specimens and related to p53 overexpression, the clinicopathologic parameters, and survival. RESULTS: pRb expression was not associated with tumor stage, but the correlation with p27 and p21 positivity was statistically significant (r = 0.26, P = 0.008 and r = 0.3, P = 0.002, respectively). Tumors representing p53 overexpression showed a higher pRb labeling index compared with p53-negative tumors (P = 0.0004). p21 protein expression correlated significantly with p27 positivity (r = 0.2, P = 0.04) and was associated with p53 overexpression (P = 0.0005), but did not correlate with tumor stage or grade. No association could be found between p27 positivity and tumor grade, tumor stage, or p53 overexpression. In univariate survival analysis, an increased pRb positivity (P = 0.002) and a low p27 expression (P = 0.0001) predicted a poor outcome, especially if combined with p53 overexpression (P = 0.004 and P = 0.0002, respectively). p21 did not give any prognostic information. Moreover, in multivariate analysis, pRb and p27 were revealed to be statistically significant. CONCLUSIONS: The results of our study indicate that in clear cell renal cell carcinoma, the cell cycle proteins p27 and pRb are powerful and independent prognostic factors and that p21 has no predictive value.

Biologic behavior of and p53 overexpression in multifocal renal cell carcinoma of clear cell type: an immunohistochemical study correlating grading, staging, and proliferation markers.

BACKGROUND: In the treatment of small renal cell carcinoma (RCC), there is controversy between radical and nephron-sparing surgical treatment because of the risk of tumor multifocality. The biologic behavior of multifocal RCC compared with that of unifocal RCC is not well investigated, and the relevance of p53 and the proliferation markers MIB-1 and proliferating cell nuclear antigen (PCNA) to multifocal RCC is not yet established. METHODS: In this study, p53 protein overexpression was investigated immunohistochemically in 27 multifocal and 65 unifocal clear cell RCCs using a monoclonal antibody (DO-1). The nuclear expression of p53 was compared with the expression of PCNA and MIB-1 (Ki-67 antigen) and other prognostic factors, including grade and stage. RESULTS: Thirty-three RCCs (35.9%) had p53 positive nuclear staining. MIB-1 positivity was significantly higher in p53 positive tumors than in p53 negative tumors. PCNA positivity was not different in p53 positive tumors compared with p53 negative tumors. Proliferation marker expression was not associated with tumor focality. p53 overexpression was more often found in unifocal tumors than in multifocal tumors. Intracellular accumulation of the p53 protein was related to tumor grade but not to the T classification of tumor stage. In addition, lymph node involvement was significantly associated with p53 overexpression in tumors of the kidney. Focality did not influence progression free survival. CONCLUSIONS: This study demonstrated that there is no difference in the proliferative activity or biologic behavior of multifocal and unifocal tumors.

Quick-staining urinary cytology and bladder wash image analysis with an integrated risk classification: a worthwhile improvement in the follow-up of bladder cancer?

BACKGROUND: With an end toward an increase in patient quality of life, morphologic methods were tested for their combinatory value in expanding the effectiveness of follow-up appointments and finding a more specific supervision of patients with bladder cancer. METHODS: Voided urine and bladder washing specimens were gathered in 223 follow-up sessions of 124 patients with a history of bladder cancer. Hemacolor (Merck, Darmstadt, Germany)-stained cytospin preparations of voided urine specimens were ready for diagnosis within 15 minutes, and results were available shortly before cystoscopy. Feulgen-Schiff-stained cytospin preparations of bladder washings entered the image analysis system. A special software was used to classify the DNA histogram by a risk factor for bladder cancer. RESULTS: Follow-up of patients revealed 83 tumor recurrences. Depending on the grade of the underlying tumor, the sensitivity of quick-staining cytology was 86.4%, 46.2%, or 13.6% for grade 3 to grade 1 TCC, respectively. Cytology and image analysis data demonstrated complementary potency. The combination of methods increased sensitivity to 90.9%, 66.7%, and 31.8%, respectively. Although 24 of 140 image analyses denoted high risk for bladder cancer without simultaneously visible tumor, correct evidence of high risk could be found for 92.2%. CONCLUSIONS: The combinatory use of quick-staining urinary cytology and bladder wash image analysis was demonstrated to be most valuable in diagnosing recurrent bladder cancer and selecting patients needing more intensive follow-up. At a minimum of patients discomfort, the tested combination also seems helpful to surpass diagnostic limits in cystoscopy and cytology caused by therapeutic effects on the bladder epithelium. Cancer (Cancer Cytopathol)

Can urine bound diagnostic tests replace cystoscopy in the management of bladder cancer?

PURPOSE: We compare the diagnostic value of NMP22 and BTA stat testing, and QUANTICYT computer assisted dual parameter image analysis to cytology and cystoscopy in patients who had symptoms suggestive of transitional cell cancer or were being followed after treatment for that disease. MATERIALS AND METHODS: We prospectively evaluated voided urine and/or barbotage specimens from 291 patients a mean of 65.2 years old. All voided urine samples were evaluated by quick staining and standard cytology, the BTA stat 1-step qualitative assay (which detects a bladder tumor associated antigen) and the NMP22 test (which detects a nuclear mitotic apparatus protein). In addition, barbotage specimens were evaluated by QUANTICYT computer assisted dual parameter image analysis. All patients underwent subsequent cystoscopy and biopsy evaluation of any suspicious lesion. Sensitivity, specificity, and the predictive value of positive and negative results were determined in correlation with endoscopic and histological findings. RESULTS: In 91 patients with histologically proved transitional cell carcinoma overall sensitivity was 48, 57, 58, 59 and 59% for the NMP22 test, the BTA stat test, rapid staining cytology of barbotage samples, rapid staining cytology of voided urine specimens and image analysis, respectively. For histological grades 1 to 3 underlying transitional cell carcinoma sensitivity was 17, 61 and 90% for urinary cytology, 48, 58 and 63% for the BTA stat test, and 52, 45 and 50% for the NMP22 test, respectively. Specificity was 100% for cytology, 93% for image analysis, 70% for the NMP22 test and 68% for the BTA stat test. CONCLUSIONS: Immunological markers are superior to cytological evaluation and image analysis for detecting low grade transitional cell carcinoma but they have low specificity and sensitivity in grade 3 transitional cell carcinoma. Urine bound diagnostic tools cannot replace cystoscopy.