Utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria

Gross or microscopic hematuria [≥3 red blood cells (RBC) per high power field (hpf)] may be caused by numerous factors - urinary calculi, hematologic abnormalities, infection, trauma, tuberculosis, and tumor [1]. Some of these factors (e.g., tumor) may be life threatening. Thus prompt, thorough evaluation and treatment are needed. Currently, evaluation for the hematuric patient consists of inspecting the lower urinary tract by cystourethroscopy, inspecting the upper urinary tract with computed tomography scan of the abdomen and pelvis with and without intravenous contrast, ultrasonography or intravenous pyelogram (IVP), and obtaining a urine sample for cytologic evaluation [2, 3].

Urine for cytology can detect cancerous cells shed from any part of the entire urothelium (i.e., collecting system to urethra) in a voided urine specimen. Higher grade tumors or larger tumors (> 3 cm) are more likely to shed cells into the urine and thus the sample is more likely to be positive for cancer. Urinary cytology has a notoriously low sensitivity, but an extremely high specificity, thus making it a useful tool in following patients with high grade cancers [4, 5]. Furthermore, interpretation of urinary cytology may be difficult, especially in the face of such conditions as urinary tract infection. With these notable limitations, the question arises as to how effective is urinary cytology in diagnosing bladder cancer in a patient presenting with microscopic hematuria? Herein, we report the utility of urinary cytology of patients presenting to a urology clinic for evaluation of microscopic hematuria.

A total of 403 cytologic specimens were reviewed. Eighteen samples were unsatisfactory for interpretation due to scant number of cells or severe degradation. Thus 385 specimens were reported. Two hundred and seventy four urinary cytology samples were classified as negative (72%) and 104 (27%) as atypia. The remaining 7 urinary cytologies from 5 patients were categorized as suspicious or malignant, which accounted for 1% of all of the urinary cytology evaluated. Cytology #1 detected 4 cancers and cytology #2 detected an additional cancer case (confirmed 2 cytologies from #1) whereas cytology #3 did not detect any additional cancers.

None of the 23 patients with atypia and negative evaluation were noted to harbor symptoms or signs of bladder cancer on subsequent follow-up. No patient with a normal cystoscopic evaluation and abnormal cytology was noted to have bladder cancer on extensive evaluation. In addition, no patient had a positive cytology and a negative biopsy. Median follow-up was 40 months with no patient with a negative cytology and/or negative bladder biopsy diagnosed with subsequent cancer.

Our study indicates that the prevalence of bladder cancer in patients presenting with microscopic hematuria is low (7%). A key question is what is the proportion of subjects in whom a positive cytology prompted a biopsy that was positive for cancer, in whom a biopsy would not otherwise have been performed? None of our patients had a positive cytology and a negative cytsoscopic/radiologic evaluation. This is consistent with our previous study that demonstrated an extremely low yield of urinary cytology in the evaluation of the patient with microscopic hematuria [12]. To our knowledge, these are the first contemporary report bringing the utility of urinary cytology in patients with microscopic hematuria into question.

As for the application of serial urinary cytologies, previous studies demonstrated a marginally improved by serial examinations [4, 13], which was confirmed in our study. Because of this low prevalence and the low sensitivity, the utility of urinary cytology in the initial evaluation of patients with microscopic hematuria is minimal, especially since all high risk patients proceeded to cystourethroscopy and upper urinary tract radiologic evaluation.

Current AUA guidelines recommend that patients presenting with microscopic hematuria should undergo upper tract evaluation along with cystoscopy. When the CT scan is not feasible, MRI or renal ultrasound with bilateral retrograde pyelograms can be substituted (2). This evaluation is adequate in assessing the kidneys, collecting system, ureters, bladder, and urethra as the cause of the hematuria. Unfortunately, except in select patients our current diagnostic modalities will not allow us to diagnose urothelial carcinomas without visualization of a lesion followed by biopsy, which is the gold standard [14]. With this said, the acquisition of urinary cytology even as an adjunct to the above studies rarely changes the evaluation or management and may lead to an exhaustive, unfruitful, and costly evaluation. In the face of abnormal cytology and normal cystoscopy confirmed by biopsy and normal imaging of the upper tract, the question arises whether to pursue the abnormal cytology as a possible upper tract tumor. Evaluation may include retrograde pyelogram, ureteroscopy, and selective cytology. The yield of these maneuvers is reported to be extremely low and of little benefit, except in highly select patients [15, 16], especially in the face of normal radiologic studies and normal cystoscopic evaluation. However, if an abnormality is noted on radiologic or cystoscopic examination, urinary cytology may prove to be useful as a confirmation of a malignancy prior to formal biopsy.

Recent studies have reported the limitations of urinary cytology in the evaluation of patients with hematuria. Paez and colleagues reported that no tumor could be diagnosed with cytology alone and that a negative cytology could not exclude a malignancy [17]. Because of its limitations, Nabi et al. recommended the judicial use of cytology in the proper clinical context [18]. Similar to the report by Deshpande et al., over 25% of patients with atypical urinary cytology were found to have biopsy proven cancer [19]. Because of this, atypia may require biopsy to rule out malignancy, closer follow-up, or other urinary based assays to improve sensitivity (e.g., fluorescent in situ hybridization, FISH).

Our study has several limitations. First, this is a small, retrospective study from a single institution. Not only could biases have been introduced in patient selection and evaluation, this group may not represent patients with microscopic hematuria seen by urologists outside of a tertiary care setting or those seen by primary care physicians. Secondly, a paucity of outside medical records were available to review in order to determine how the patients initially were found to have microscopic hematuria (i.e., were they diagnosed based on history, urine dipstick, microscopic analysis). Thirdly, other urine based assays (e.g., NMP-22, BTA, etc) also have reduced sensitivity in this cohort. Lastly, there was no standardized follow-up protocol in place to monitor patients with a negative hematuria evaluation in order to determine possible long-term developments.

The interpretation of urinary cytology can be extremely challenging and should be used only as an adjunct to evaluation of upper tract and bladder. Due to the complex nature of evaluating cytologic specimens, it is of utmost importance to have an experienced cytopathologist interpreting these results. Current urine based assays (e.g., NMP-22, BTA) are not at the point of being able to exonerate the bladder of harboring bladder cancer, thus patients suspected of a bladder cancer should be evaluated with upper tract imaging and cystoscopy. The addition of urinary cytology in patients with gross hematuria may be justifiable, however, its addition to the evaluation of the patient with microscopic hematuria has an extremely low yield in detecting cancer and may lead to unnecessary, invasive procedures with known side effects not to mention high costs.

Current practice patterns for the evaluation of microscopic hematuria include assessing the lower and upper urinary tracts. Due to the low prevalence of bladder cancer and the low sensitivity of cytology detecting bladder cancer, the exact role of urinary cytology in the evaluation of the patient with microscopic hematuria may be minimal.