Improving diagnostic molecular tests to monitor urothelial carcinoma recurrence.

INTRODUCTION: The high recurrence rates associated with non-muscle invasive bladder cancer require close surveillance with cystoscopy, an invasive and expensive procedure with risk of missing cancer. Finding an accurate urinary biomarker that can detect recurrent disease would represent a significant advancement in management. Areas covered: This review summarizes the commercially-available urinary biomarkers including cytology, UroVysion, BTA, NMP22, uCyt+, and Cxbladder assays. Additionally, we review recent investigational urinary biomarkers that hold promise in bladder cancer surveillance. Expert commentary: The quest for a reliable urinary biomarker for bladder cancer is decades-old and seems intuitive given the direct contact of urine with malignant urothelium. Beyond urine cytology, there are many commercially-available products approved for surveillance. However, none of the assays are routinely used due to lack of sensitivity and/or specificity. As such, emerging technologies, in particular the '-omic' technologies have resulted in a proliferation of promising reports on novel biomarkers in recent literature.

Evaluation of microsatellite instability in urine for the diagnosis of transitional cell carcinoma of the lower urinary tract in dogs.

BACKGROUND: The accumulation of frame-shift mutations in microsatellites (MS), termed microsatellite instability (MSI), is associated with certain tumors. MSI and its detection in urine samples has been used to aid in the detection of human bladder cancer. HYPOTHESIS: Evaluation of MSI in urine is a useful assay test for diagnosis of transitional cell carcinoma (TCC) in dogs and is more specific than the commercially available, veterinary bladder tumor analyte (V-BTA) test. ANIMALS: Seventy-three dogs: healthy controls (n=21), proteinuric (n=12), lower urinary tract disease excluding TCC (n=17), and TCC (n=23). METHODS: Prospective observational study. Urine samples collected from each animal were evaluated for MSI and using the V-BTA. For MSI detection, 22 MS sequences were polymerase chain reaction amplified from urine and blood, subjected to capillary electrophoresis, and the MS genotypes were compared. Aberration in ≥15% of MS was considered indicative of MSI. RESULTS: MSI was detected in 11 of 23 (48%) urine samples from dogs with TCC. MSI was also detected in 12 of 50 (24%) of the control animals, including 29, 16, and 24% of healthy, proteinuric, and lower urinary disease dogs, respectively. In this population, sensitivity and specificity of MSI analysis was 48 and 76%, respectively, compared with 83 and 64%, respectively, for the V-BTA test. CONCLUSIONS: MS analysis as performed in this study is not useful in the diagnosis of TCC.

Role of voided urine cytology in diagnosing primary urethral carcinoma.

OBJECTIVES: To evaluate the role of voided urine cytology in diagnosing primary carcinoma of the urethra in male and female patients. METHODS: We reviewed the medical records of all patients with urethral carcinoma seen at Memorial Sloan-Kettering Cancer Center between 1958 and 1996. The patients who had undergone voided urine cytology before any treatment were the subject of this report. RESULTS: This report included 41 female and 29 male patients. In the cohort of female patients, the most common histologic type was adenocarcinoma (n = 16), followed by squamous cell carcinoma (SCC; n = 9) and transitional cell carcinoma (TCC; n = 6). Urine cytology was positive in 24 patients (59%). The sensitivity was greatest in patients with SCC (77%) and lowest in patients with TCC (50%). In the cohort of male patients, the most common histologic type was SCC (n = 14) followed by TCC (n = 10). Urine cytology was positive in 16 patients (55%). The sensitivity was greatest for patients with TCC (80%) and lowest for patients with SCC (50%). CONCLUSIONS: Voided urine cytology is not a very reliable method of diagnosing primary carcinoma of the urethra in either male or female patients. A cystoscopic evaluation with possible biopsy is warranted if suspicion of carcinoma of the urethra is high.

Urinary cytologic findings in patients with benign and malignant adenomatous polyps of the prostatic urethra.

CONTEXT: Urethral adenomatous polyps with prostatic epithelium (also known as benign prostatic epithelial polyps [BPEPs]) are a documented cause of hematuria, dysuria, and hematospermia, conditions that may prompt cytologic evaluation of urine. DESIGN: The urine cytologic test findings in 5 cases of biopsy-proven BPEPs and in 1 case of prostatic ductal adenocarcinoma (PDA) that presented as a urethral polyp were retrospectively evaluated. Immunocytochemical stain for prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and high-molecular-weight cytokeratin (34betaE12) were used in evaluation of the lesions. RESULTS: In 4 of 5 cases of BPEPs, clusters of bland columnar cells with uniform, oval nuclei were seen. Positive immunostaining for PSA and PAP confirmed the prostatic origin of the clusters in 2 cases. One urine sample contained abundant goblet cells and extracellular mucin, consistent with intestinal metaplasia coexisting in the bladder biopsy specimen. The urine sample in the fifth case of BPEPs contained no columnar cells. The last case had multiple urine cytologic evaluations that demonstrated PSA-positive, malignant-appearing clusters of columnar cells. A biopsy specimen of the polyps was described as a high-grade prostatic intraepithelial neoplasm in adenomatous polyp. However, in this patient, PDA was diagnosed on transurethral resection of the prostate specimen 4 years after the initial urine cytologic test. CONCLUSION: Benign prostatic epithelial polyps should be considered in the differential diagnosis of clusters of columnar cells in urine cytologic testing. Cells with malignant nuclear features should instigate a careful search for a (prostatic) neoplasm, which may present as urethral polyps (e.g., PDA). Stains for PSA or PAP are useful adjuncts in differential diagnosis of this condition.

Cytologic features of clear cell carcinoma of the urethra and urinary bladder.

Clear cell carcinoma (CCL) arising in the lower urinary tract is unusual and we report the cytohistologic findings of three cases retrieved from our files. All patients presented with bleeding, and the tumors were localized in either the urethra or bladder base. Filter and cytocentrifuge preparations of the urine were studied and all cases displayed numerous scattered aggregates or single tumor cells in an inflammatory background. The enlarged cells had abundant clear, wispy cytoplasm with discrete vacuolation. Hobnail and signet ring cells were apparent. The nuclei had granular to vesicular chromatin with prominent often multiple nucleoli. The tumors were histologically distinctive and typically had a tubulocystic configuration with varying proportions of papillary and diffuse patterns. One patient has died of metastatic cancer and two are presently free of tumor. The cytohistologic features of this cancer are characteristic and from our review we conclude that this lesion can be diagnosed by cytologic means.

Human papillomavirus detection in urine samples from male patients by the polymerase chain reaction.

Human papillomavirus (HPV) detection was performed using the polymerase chain reaction technique on urine samples from 17 male patients with condylomata acuminata in the meatus urethrae. Urine samples from 14 male laboratory volunteers were analyzed as controls. The DNA was extracted and purified from urine sediments, centrifuged at 1,800 and 100,000 x g, and subjected to 40 cycles of amplification with HPV 6 and HPV 11 type-specific anticontamination primers and the heat-stable Taq DNA polymerase. HPV was detected in the urine of 15 (88%) patients. In all positive patients the urine sediments of both the 1,800 and 100,000 x g centrifugation steps contained HPV DNA. Eight patients were found to be positive for HPV 6 DNA, six were positive for HPV 11 DNA, and one was positive for both HPV 6 and HPV 11 DNA. None of the males in the control group was positive for either HPV 6 or HPV 11 DNA. The results demonstrate that HPV can be transported by the urine, probably in exfoliated HPV-infected cells. A similar mechanism may occur during ejaculation, allowing sexual transmission of HPV viruses harbored in the cells of the male genital tract.

Grade 2 urethroprostatic papillary urothelial carcinoma with positive urinary cytology.

A rare case of papillary urothelial grade 2 carcinoma of the prostate and urethra in a patient with a previous papillary neoplasm of the bladder is reported. The tumor caused hematuria and prostatic enlargement suspicious for cancer. Urinary cytology was diagnostic.