Tumor Markers For Urothelial Carcinoma
Detection of epithelial neoplasia of the urinary tract remains challenging due to the anatomical contour of the bladder. Papillary growths may be readily visible but other flat lesions and carcinoma in situ, a diffuse high grade intraepithelial neoplasia, can be difficult to detect. The same is true of the spectrum of abnormalities that include atypia and dysplasia which are associated with or have malignant potential. Methods of detection include visual inspection, fluorescent detection, molecular imaging, and the use of tumor-associated markers. Fluorescent detection has improved sensitivity for detection of tumors but with a decreased specificity so its best use is in conjuction with standard visual inspection. Newer diagnostic light technologies such as optical coherent tomography (OCT) provide endoscopic means to improve evaluation of epithelial surfaces and the potential for tumor invasion.
Bladder tumor markers which may assist in detection are a valuable adjunct to diagnosis. The ideal tumor marker would have both high sensitivity and high specificity and be inexpensive, performed in the office, and easy to interpret. Unfortunately the array of tests currently available lack one or more of these characteristics and this holy grail of a test has not yet been discovered. Recent discoveries suggest that microarray technology may provide a powerful tool for tumor detection.
Urinary cytology remains the standard by which other diagnostic tests are compared. Cytology has an average sensitivity of 49% and specificity of 96% in one review of multiple studies. The use of nuclear mitotic apparatus protein (NMP-22) has an average sensitivity of 71% but a specificity of 75% in a similar review and is often used in combination with cytology for selected higher risk patients. Multicenter clinical trials with fluorescent in situ hybridization (FISH) have shown an overall sensitivity of 69%, specificity of 78%, and negative predictive value (NPV) of 95%. Fluorescent immunochemistry assaying 3 antibodies to mucin glycoprotein and carcinoembryonic antigen (CEA) has provided 85% sensitivity in patients previously treated with Bacille-Calmette-Guerin (BCG) immunotherapy, an improvement over the other tests in this patient group. This fluorescent immunochemistry has a 95% NPV and is a strong predictor of upper urinary tract neoplasia.
Molecular biological marker candidates are abundant and under evaluation for clinical use. Fibrin-fibrinogen degradation products (FDP) have a sensitivity and specificity of 68% and 86%, respectively, but suffer from false positive results when hematuria is present, a common symptom with urothelial malignancy. Telomerase, which blocks apoptosis, has high sensitivity but poor specificity and has variable stability. Hyaluronic acid/hyaluronidase has promise with improved sensitivity for lower grade lesions. Cytokeratins 18, 19, and 20 are highly expressed in transitional cell carcinoma (TCC) but also with infections. The anti-apoptotic protein survivin has been detected in 64% of cystectomy specimen tumors and 94% of metastatic lymph nodes but not in normal tissue in one study. A host of other glycoproteins and nuclear matrix proteins are under evaluation as well. Perhaps the most promise has been found through evaluation of DNA microarrays where a recent study of 14, 551 different genes identified 40 genes that were upregulated in superficial TCC and 34 different genes upregulated with invasive TCC. The fact that the upregulated genes for superficial TCC were related to epithelial cell dedifferentiation, apoptosis, transcription, cell adhesion, and keratinization while those for invasive disease related to different cell functions of extracellular matrix degradation, angiogenesis, and immune response strongly suggests that we may be able to have an array of markers to differentiate superficial from invasive disease. This is an extremely interesting and important implication for future use of bladder tumor markers.
Presented by: Michael J. Manyak, MD, FACS, at the Masters in Urology Meeting - July 31, 2008 - August 2, 2008, Elbow Beach Resort, Bermuda
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