The most common presenting symptom or sign of upper tract urothelial tumors is hematuria, which occurs in 56% to 98% of patients, and the second most common symptom or sign is flank pain present in approximately 30% of patients (4,5,6). The subsequent evaluation entails an upper tract imaging study with intravenous urography, computerized tomography, magnetic resonance imaging, or retrograde pyelography. Most patients have a filling defect that suggests an upper tract urothelial tumor. Whether both sides of the urinary system need to be evaluated with retrograde studies, selective cytology, or ureteroscopy, owing to the small chance of a bilateral tumor, depends on the individual practitioner. In general, if good-quality imaging does not show any abnormalities on the contralateral side and an obvious mass appears on one side, additional evaluation of the normal-appearing side is not necessary.

All patients require evaluation of the bladder given the highly similar biology of bladder and upper tract urothelial carcinoma. At this time, retrograde studies, selective cytology, and ureteroscopic evaluation may also be performed. Selective upper tract cytology has been shown to improve the diagnosis of upper tract urothelial carcinoma. The accuracy of detection of high-grade lesions, including carcinoma in situ, is nearly 80%, and this has definite prognostic value (7). Direct ureteroscopic evaluation and biopsy are also important aspects of the evaluation because the additional information is critical for risk stratification. The tumor architecture has been shown in multiple studies to have independent prognostic value; sessile tumors are more often associated with a high pathologic stage than papillary tumors (8). Biopsy results showing high-grade tumors are also associated with high-stage disease at least 65% of the time (9).

The combination of positive voided or selective cytologic findings with a radiographic abnormality consistent with an upper tract urothelial tumor may be considered adequate for diagnosis if nephroureterectomy is intended. However, this practice does not allow for complete clinical risk stratification to determine whether the patient may benefit from multimodal therapy prior to surgery. Given the significant loss of renal function following nephroureterectomy, many patients may not be eligible for postoperative chemotherapy if they are found to have high-stage disease (10). For patients in whom neoadjuvant chemotherapy is not indicated, positive cytologic findings combined with a radiographic abnormality may be sufficient to proceed with nephroureterectomy. If voided cytologic findings are positive, bladder biopsies are necessary to rule out bladder disease, and selective washings can be performed. Patients with positive selective cytologic findings and negative bladder and prostatic urethral biopsies but no identifiable lesion on the ureteroscopic image represent a diagnostic dilemma. Many practitioners consider this set of findings to be diagnostic of carcinoma in situ of the upper tract and treat with nephroureterectomy or topical therapy. Other practitioners recommend that these patients be followed closely rather than undergo nephroureterectomy without a definitive diagnosis.

Once urothelial malignancy is diagnosed, metastatic evaluation consists of abdominal and pelvic computerized tomography and chest imaging with radiography or computerized tomography. A bone scan is performed if the patient has bone pain, elevated alkaline phosphatase or serum calcium levels, or bony abnormalities appearing on other imaging studies. However, owing to lack of bone turnover in cases of bony metastases, a bone scan may be falsely negative. A complete blood count, serum electrolyte analysis with creatinine, and liver function tests should also be performed. If the estimated glomerular filtration rate is reduced (<60 mL per minute per 1.73 m²), a renal scan to determine differential function may aid in decision making.

Patients found to have regional lymphadenopathy will not be cured with surgery alone and will experience systemic recurrence within a short time period. Thus, similar to patients with bladder cancer, these patients should undergo chemotherapy as the primary mode of treatment (11). Those who have an excellent response to chemotherapy may be considered for salvage surgery to include regional lymphadenectomy. All treatment options, including the possibility of lymphadenectomy, should be discussed with the patient. The treatment plan must take into account prognostic variables that may be used to select patients for neoadjuvant systemic therapy, and patients should be counseled properly on the potentially increased likelihood of recurrence if advanced disease is found in the pathologic analysis. Clinical variables that affect the likelihood of recurrence include biopsy tumor grade, tumor architecture, the presence of hydronephrosis, and imaging findings suspicious for advanced disease. Clinical risk stratification is more important in upper tract urothelial malignancies than in bladder cancer, owing to the challenges and significant limitations of performing accurate clinical staging in the upper tract. Two preoperative nomograms that use a combination of the previously described factors can be used for more accurate clinical risk stratification and patient counseling for those with upper tract malignancy (8,12). For example, a patient whose biopsy findings show a high-grade sessile tumor has at least an 80% chance of having advanced disease in the final pathologic evaluation (8).