Urine cytology has always demonstrated accuracy in detecting high grade tumors and carcinoma in situ (CIS) [1, 2]. Mortality from bladder cancer is overwhelmingly due to these lesions. The designation of “Negative for High Grade Urothelial Carcinoma” (NHGUC) as a distinct diagnostic category highlights the utility of cytology in identifying these potentially dangerous lesions within the urinary tract. It also acknowledges the inherent limitations of cytology in detecting low grade noninvasive cancers which represent the majority of bladder cancer diagnoses. It is therefore not surprising that the overall sensitivity for cytology to detect bladder cancer is low [1]. The acceptance of standardized criteria for this category will have the resulting beneficial effect of decreasing the number of specimens allocated to the “wastebasket” diagnostic category of “atypical urothelial cells.”

The primary concern is whether there is a “clinically significant” lesion somewhere in the urinary tract. From the standpoint of the urologist and especially the patient, the first question is whether there is a malignancy, and secondly, whether that cancer is potentially lethal. While cytology may not perform well in answering the first question (due to the poor sensitivity to detect low grade noninvasive tumors), its ability to provide insight into the second question can be very useful depending on the clinical setting.

The role of urine cytology in the initial evaluation for hematuria or irritative voiding symptoms is controversial. In fact, the American Urological Association guidelines on asymptomatic microhematuria do not recommend the use of cytology in the routine evaluation of the asymptomatic microhematuria patient [3]. The Guidelines leave open the option for urine cytology only for those with persistent microhematuria following a negative evaluation or those with risk factors for carcinoma in situ (CIS) (irritative voiding symptoms, current or previous tobacco use, chemical exposures). In the setting of a patient with no previous urothelial malignancy, a negative urine cytology result is certainly reassuring, though should not preclude an otherwise thorough urologic evaluation if the clinical scenario calls for it, which generally should include upper tract imaging and direct cystoscopic visualization.

For the patient undergoing the initial evaluation for a suspected urothelial malignancy, urine cytology may play an important role in risk stratification [4]. The finding of a negative cytology result in the face of an obvious papillary bladder tumor should not come as a surprise given the low sensitivity of cytology for the majority of low grade noninvasive tumors. In this setting, the urologist can be reassured that an underlying high grade invasive lesion or CIS is less likely to be present. A positive cytology without a tumor should raise suspicion of a missed lesion and/or missed CIS, for which adjuncts to regular cystoscopy (such as fluorescence cystoscopy, narrow band imaging, and directed or random biopsies of the bladder) and evaluation of the prostatic urethra and upper tracts should be considered.

Urine cytology plays a critical role in the ongoing surveillance for urothelial recurrences following therapy. While most bladder recurrences will often be detected by routine surveillance cystoscopy, upper urinary tract and prostatic or urethral recurrences can be more difficult to diagnose in a timely manner. Anterior bladder wall and bladder neck lesions can occasionally be missed, while carcinoma in situ may not always be readily distinguishable cystoscopically from other benign inflammatory conditions. Thoughtful utilization of contrast-enhanced imaging along with urine cytology represents the primary initial diagnostic modalities when direct endoscopic visualization can be difficult or impractical.

A variety of surveillance strategies have been advocated following transurethral resection with and without intravesical therapies. The most common approach has included cystoscopic assessment every 3 months in the first 2 years, followed by every 6 months for the subsequent 2–3 years, and then annually thereafter (American Urological Association Guidelines) [4]. The European Association of Urology recommends a risk-adapted approach for surveillance depending on the primary tumor stage and grade and presence of CIS [5]. Urine cytology may be obtained at each follow-up surveillance cystoscopy via voided specimen or bladder barbotage (washing) as the situation dictates.

Urine cytology is also an essential component in the surveillance of patients who undergo urinary diversion, as these patients remain at risk for recurrences in the remnant urothelium (upper tracts and urethra) following radical cystectomy [6–9]. Voided specimens for those with orthotopic neobladders, catheterized specimens from incontinent and continent cutaneous diversions, as well as urethral washings provide important diagnostic information some times before lesions become radiographically or symptomatically evident. Risk factors for urethral and upper tract recurrences following radical cystectomy have previously been described [7–10]. A “negative for high grade urothelial carcinoma” diagnosis is reassuring and the patient may continue routine surveillance at intervals commensurate with the risk of recurrence. It must be noted, however, that cytology in the setting of a urinary diversion requires special attention and skill by the cytopathologist to interpret, and hence imaging and symptom review remain essential parts of the surveillance paradigm.

The management of “atypical urothelial cells (AUC)” has always presented a diagnostic dilemma for the urologist. Traditionally, this category has included a wide spectrum of benign and malignant conditions. The use of the current reporting system should decrease the rate of AUC diagnoses, as known benign conditions such as reactive/inflammatory conditions and cellular changes associated with polyomavirus and urolithiasis will now be categorized as NHGUC. At this point, it is not entirely clear how this will impact the risk of malignancy associated with an AUC diagnosis. On the one hand, as the number of benign conditions will be shifted to the NHGUC category, some cases of AUC will likely now fall into the category of suspicious for HGUC (SHGUC). In either case, the frequency of AUC should decrease.

From the standpoint of the urologist, the workup for AUC should be individualized based on the risk assessment of the patient. Those with hematuria or persistent irritative voiding symptoms still require a thorough evaluation with upper tract imaging and cystoscopy. A patient with known risk factors for urothelial carcinoma and an atypical cytology should prompt consideration of performing further testing to rule out malignancy. For patients with a prior history of urothelial malignancy, the extent of the workup is dependent on the clinical suspicion for recurrent disease. Evaluation of the upper urinary tract and urethra may be considered if not recently performed. The utility of random bladder biopsies of “normal” appearing urothelium is likely of minimal benefit.

The role of additional molecular testing, such as UroVysion FISH and other urinary biomarkers, remains to be determined [1, 2, 11] (see Chap. 9). Several centers have instituted reflex UroVysion FISH testing for AUC diagnoses, whereby a positive FISH assay is managed similarly to a suspicious diagnosis and a negative FISH test is followed expectantly [12–14]. Further investigation is needed to determine the clinical effectiveness of this protocol in light of The Paris System (see Chap. 9).

From a practical standpoint, the clinical management of “suspicious for HGUC” (SHGUC) is similar to a “positive for HGUC” (HGUC) diagnosis. These patients require active investigation in order to identify the source of the suspicious or positive cells. When a “suspicious” or “positive” for HGUC cytology result is obtained in the setting of a low grade noninvasive bladder cancer (LGUC), consideration should strongly be given to further evaluation for other high grade lesions or CIS utilizing adjuncts to regular cystoscopy (fluorescence cystoscopy, narrow band imaging, directed/random bladder biopsies) and evaluation of the prostatic urethra and upper tracts.