THE BLADDER TUMOR ANTIGEN (BTA) TEST COMPARED TO VOIDED URINE CYTOLOGY IN THE DETECTION OF BLADDER NEOPLASMS

Purpose

Tests to detect recurrent bladder neoplasms are limited and none is consistently accurate. Recent studies suggest that the bladder tumor antigen (BTA*) test, an agglutination reaction for basement membrane complexes, is superior to voided urine cytology in clinical practice. We compared BTA and voided urine cytology to bladder washings and cystoscopy, emphasizing diagnostic yield among patients with causes of basement membrane complexes other than bladder cancer.

Materials and Methods

Random voided urine specimens from 67 patients with a history of bladder neoplasms were collected before cystoscopy and bladder washing. Urine also was obtained from 34 patients with inflammatory bladder conditions including 5 with a history of prostate cancer. Each urine was tested for BTA according to a commericial kit. Positive results were indicated by yellow on a test pad. Blinded to all other results, each urine and each bladder washing were examined microscopically, and a positive test had malignant/suspicious cells. Bladder biopsies were performed when endoscopic lesions were seen. Specimens were grouped into 4 categories: group 1-biopsy proved bladder neoplasm, group 2-history of bladder cancer but not biopsy proved, group 3-history of prostate cancer and group 4-no history of urological cancer.

Results

Voided urine cytology was positive in 54% of specimens from patients with biopsy proved bladder neoplasms compared to 29% for BTA. Relative yield for voided urine cytology versus BTA was not changed if all group 2 cases having a positive bladder washing and positive cystoscopy were assumed to have bladder cancer, nor was relative yield altered by subsequent short-term followup. Of voided urine specimens 14% from group 1 patients and 41% from group 2 patients had scant cells. Overall diagnostic yield was superior for bladder washing. False-positive BTA occurred in 7 of 34 patients with no history of urological or prostate cancer. There were no false-positive voided urine cytology interpretations in these groups.

Conclusions

BTA is not superior to voided urine cytology in detecting bladder neoplasms and may be limited by false-positive reactions in patients with other causes of basement membrane complexes in urine. Voided urine samples may be limited by high frequency of hypocellularity. Of 34 patients with a hypocellular urine specimen 4 had biopsy proved bladder cancer. Bladder washing yields best results but requires instrumentation. No test, including cystoscopy, is accurate always.     

NONINVASIVE EVALUATION OF BLADDER COMPLIANCE IN CHILDREN USING ULTRASOUND ESTIMATED BLADDER WEIGHT

Purpose

In healthy children as well as those with urinary disturbance we determined ultrasound estimated bladder weight with the aim of revealing its possible usefulness as a measure of bladder compliance.

Materials and Methods

We measured ultrasound estimated bladder weight in 71 healthy children with a mean age of 10.3 years, and determined a standard value. A total of 82 patients with a mean age of 9.6 years with urinary disturbance also underwent ultrasound estimated bladder weight measurement as well as conventional urological examinations, including filling cystometry.

Results

In healthy children ultrasound estimated bladder weight increased with age, showing a significant linear correlation (r = 0.80, p <0.0001). Using the formula for linear correlation, 0.86 x patient age + 6.9 gm., we obtained an age matched estimated weight. In 82 patients the percent deviation of the estimate from age matched values was calculated using the formula, (measured ultrasound estimated bladder weight -age matched ultrasound estimated bladder weight)/age matched ultrasound estimated bladder weight x 100, and then correlated with bladder compliance. In 75 of 77 patients (97%) with compliance of 10 ml./cm. water or more the estimate was within 100% deviation. In contrast, 4 of 5 patients (80%) with a low compliant bladder (less than 10 ml./cm. water) had an ultrasound estimated bladder weight greater than 100% deviation. When the estimate was within 100% deviation, all but 1 patient (75 of 76, 98.7%) had compliance of 10 ml./cm. water or more compared to 33.3% (2 of 6) of those with an estimate greater than 100% deviation. As a result, with the use of a cutoff value of 100% deviation ultrasound estimated bladder weight predicted a low compliant bladder with a diagnostic accuracy as high as 96.3% (79 of 82 cases).

Conclusions

Ultrasound estimated bladder weight may be used to evaluate bladder compliance in children. It seems to be a suitable noninvasive urodynamic test in children with suspected urodynamic abnormalities.     

INTRA-OPERATIVE ULTRASOUND FOR THE DETECTION OF HEPATIC METASTASES FROM COLORECTAL CANCER

The aim of this study was to compare the accuracy of intra-operative ultrasound (IOUS) with other imaging modalities and with surgical palpation in detecting liver metastases from colorectal cancer (CRC). Intra-operative ultrasound was performed in 100 patients undergoing surgery for CRC. All patients had pre-operative liver function tests, transcutaneous ultrasound and computerized tomography (CT) scan of the liver. The liver was palpated intra-operatively by a surgeon who was unaware of the pre-operative findings. The liver was then assessed by IOUS. Intra-operative ultrasound detected more patients with metastases than either CT scan, transcutaneous ultrasound or surgical palpation. It also detected a greater number of smaller metastases in these patients and allowed better anatomical definition compared with pre-operative investigations.     

PREDICTIVE VALUE OF p53 AND pRb IMMUNOSTAINING IN LOCALLY ADVANCED BLADDER CANCER TREATED WITH CYSTECTOMY

Purpose

We elucidate the association between altered immunostaining for retinoblastoma gene protein (pRb) and p53 nuclear proteins, and cancer specific death in patients treated with cystectomy for locally advanced bladder cancer.

Materials and Methods

The hospital records of 173 patients treated with cystectomy for advanced urothelial bladder cancer between 1967 and 1992 were retrospectively reviewed. Representative biopsies obtained before treatment were sectioned and stained using the standard immunohistochemical technique with antibody DO-7 (p53) and antibody PMG3-245 (pRb). A tumor was considered to have an altered p53 expression if 20% or more of tumor cells exhibited nuclear staining. Similarly, if no tumor cell had nuclear immunostaining the tumor was considered to have an altered pRb expression.

Results

An altered expression was observed for p53 in 98 tumors (57%) and for pRb in 60 (35%). In a proportional hazards analysis no association was found between an altered expression of pRb or p53 and cancer specific death. This finding was also true in another analysis when the results of immunostaining for pRb and p53 were combined.

Conclusions

An altered expression for pRb and/or p53 was not correlated to cancer specific death. Thus, these parameters could not be used as predictors of treatment outcome after cystectomy for locally advanced bladder cancer.     

COMPARATIVE EVALUATION OF THE DIAGNOSTIC PERFORMANCE OF THE BTA STAT TEST, NMP22 AND URINARY BLADDER CANCER ANTIGEN FOR PRIMARY AND RECURRENT BLADDER TUMORS

PURPOSE: We compared overall sensitivity and specificity of the urinary bladder cancer antigen enzyme-linked immunosorbent assay (UBC, IDL Biotech, Sollentuna, Sweden), BTA stat test (Bion Diagnostic Sciences, Inc., Redmond, Washington) and NMP22 test kit (Matritech, Newton, Massachusetts), and the differential sensitivity regarding the histological pattern of tumors. MATERIALS AND METHODS: A total of 213 patients with clinical and/or imaging signs of bladder cancer provided a single voided urine sample for the bladder cancer antigen, BTA stat test and NMP22 before cystoscopy. Of these patients 95 were monitored for superficial bladder cancer, while the remaining 118 had no history of bladder cancer. All detected bladder tumors or suspicious lesions were resected transurethrally. A group of 21 age and sex matched healthy volunteers were also evaluated with the same tests. RESULTS: Bladder cancer was confirmed histologically in 118 patients, of whom primary and recurrent tumors were in 68 and 50, respectively. The optimal cutoffs calculated with receiver operating characteristics curves were 8 units per ml. for NMP22 and 12 microg./l. for bladder cancer antigen. Overall sensitivity and specificity were 72.9% and 64.6% for the BTA stat test, 63.5% and 75.0% for NMP22, and 80.5% and 80.2%, respectively, for bladder cancer antigen. Bladder cancer antigen proved significantly more sensitive than NMP22 for detecting bladder cancer (p = 0.001) but not more than the BTA stat test, while the specificity of it was significantly higher than that of the BTA stat test (p = 0.009). Bladder cancer antigen had a sensitivity of 80.7% for stage Ta tumors, which was significantly higher than NMP22 (52.6%, p = 0.001) and the BTA stat test (57.9%, p = 0.01). In grade I tumors the sensitivity of bladder cancer antigen (70%) did not differ significantly than that of the BTA stat test (50%) and NMP22 (50%, p = 0.14). Bladder cancer antigen had the least false-positive results in patients with a history of bladder cancer and negative cystoscopy, and those with urological disease other than bladder cancer. CONCLUSIONS: Our data indicate that bladder cancer antigen may be a more potent diagnostic marker for bladder cancer than NMP22 and the BTA stat test based on the higher sensitivity for detecting low stage and low grade tumors, and the higher specificity. The contribution of these tests for detection of bladder cancer should still be considered adjunctive to cystoscopy.     

DEVELOPMENT OF NONINVASIVE AND QUANTITATIVE METHODOLOGIES FOR THE ASSESSMENT OF CHRONIC ULCERS AND SCARS IN HUMANS

Chronic ulcers are a significant and common cause of morbidity and mortality worldwide. They disrupt the epidermis and dermis, resulting in a loss of barrier function. Keloids and hypertrophic scars (benign cutaneous tumors) represent an abnormal healing response. These fibroproliferative disorders are characterized by an overabundance of collagen and accumulation of extracellular matrix due to an imbalance between synthesis and degradation, culminating in excessive scarring. The objectives of this study were to evaluate and compare noninvasive biophysical methods for the measurement of outstanding quantitative parameters of scars and chronic ulcers, and to establish correlations between the parameters measured and the results of conventional subjective clinical evaluations. The development of new technologies, based on ultrasonography and laser Doppler, makes possible new dermatological evaluation methods. Fifteen patients (6 females and 9 males) with 15 chronic ulcers (4 diabetic ulcers, 10 venous ulcers and 1 pressure ulcer) and 30 patients (19 females and 11 males) with 30 scars (25 hypertrophic and 5 keloids) were included in this study. Clinical evaluation was performed by a dermatologist, an aesthetic surgeon and an endocrinologist. Biophysical measurements were used to assess local blood flow by laser Doppler flowmetry (Moor DRT4), thickness and echogenicity by high frequency ultrasonography (20 MHz, Dermascan C) and ulcer linear dimensions by image analysis. Our results show that blood flow within the ulcers and scars was higher than within normal skin. Also, skin thickness of chronic ulcers was decreased when compared to normal skin; the thickness of hypertrophic scars, but not of keloids, was increased in comparison to normal skin, and presented the possibility of measuring wound and scar surfaces with precision. In summary, this pilot study established the feasibility of measuring various biophysical parameters and adapted their potential utility to research on wounds.     

CD1A DENDRITIC CELLS PREDOMINATE IN TRANSITIONAL CELL CARCINOMA OF BLADDER AND KIDNEY BUT ARE MINIMALLY ACTIVATED

PURPOSE: In this study, we employed similar techniques to detail dendritic cell subsets within bladder transitional cell carcinoma and kidney transitional cell carcinoma. MATERIALS AND METHODS: To identify both the CD1a+ and CD1a- antigen-expressing dendritic cell populations we employed a double labeling technique to identify non-lineage-expressing leukocytes similar to that employed to isolate blood dendritic cells. RESULTS: Dendritic cells were found in significant numbers within both bladder and kidney derived transitional cell carcinoma. Almost all the dendritic cells among the tumor cells belonged to the CD1a+ subset of epithelial dendritic cells. Similar numbers of dendritic cells were observed in the lamina propria adjacent to the tumor. These dendritic cells belonged predominantly to the CD1a- subset. These differences appear to reflect the different dendritic cell phenotypes reported for the epidermis and dermis. CONCLUSIONS: The number of dendritic cells increased as the grade of the tumor increased, reflecting an overall higher leukocyte density in higher grade tumors. However, a possible trend for less dendritic cell activation in higher grade cancers was noted, raising the intriguing possibility that this might be a relevant prognostic factor, to be confirmed in a larger study.     

A NEW SCORING SYSTEM BASED ON THE HISTOLOGICAL BEHAVIOR AND PROLIFERATIVE ACTIVITY OF TUMOR CELLS FOR GRADING THE MALIGNANT POTENTIAL OF BLADDER CANCERS

Urothelial cancer can be considered to consist of a spectrum of diseases with diverse natural histories and the conventional morphological classifications provided by classical histology remain the basis for any decision-making process. The proliferative rate of the tumor cells may be significant since the rate of DNA synthesis is directly related to the rate of tumor growth or tumor involvement. We have previously reported that flow cytometric deoxyribonucleic acid (DNA)/bromodeoxyuridine (BrdU) bivariate analysis can provide important information about the malignant potential of bladder cancer. In the present study, we have formulated a new system based on the histological grade and tumor proliferative activity determined by the BrdU labeling index. An attempt has been made, moreover, to investigate whether this grading system can be used to determine the malignant potential of bladder cancers. A total of 86 patients with bladder tumors, histologically proven to be transitional cell carcinomas, were analyzed. Immediately after removal of tumor specimens, in vitro BrdU labeling was performed. Multivariate survival analysis was conducted using Cox's regression model, followed by estimation of the risk ratio for survival. Based on the risk ratio of the histological grade and the BrdU labeling index, a score ranging from 1 to 52 was assigned to each tumor. Forty-four patients with a score of 1 had a 100% survival rate at 3 years, compared with 42.9% for patients having a score greater than 1. Conversely, 26 patients with the highest score, 52 exhibited a survival rate of only 17.3% at 3 years. These results suggest that the new grading system can be used as an indicator for making decisions about treatment in cases of transitional cell carcinoma of the bladder.