Upper Urinary Tract Urothelial Cell Carcinoma

5. DIAGNOSIS

5.1. Symptoms

The diagnosis of UTUC may be incidental or symptom related. The most common symptom is visible or nonvisible haematuria (70–80%) [81,82]. However, the pooled incidence rate in a systematic review of 44 studies assessing haematuria for the presence of UTUC, was only 0.75% (95% CI: 0.4–1.2%) for visible haematuria and 0.17% (95% CI: 0.081–0.299%) for nonvisible haematuria [18]. Flank pain, due to clot or tumour tissue obstruction or less often due to local growth, occurs in approximately 20–32% of cases [17]. Systemic symptoms (including anorexia, weight loss, malaise, fatigue, fever, night sweats, or cough) associated with UTUC should prompt evaluation for metastases associated with a worse prognosis [17].

5.2. Imaging

5.2.1. Computed tomography urography

Computed tomography (CT) urography has the highest diagnostic accuracy of the available imaging techniques [83]. A meta-analysis of 13 studies comprising 1,233 patients revealed a pooled sensitivity of CT urography for UTUC of 92% (CI: 0.85–0.96) and a pooled specificity of 95% (CI: 0.88–0.98) [84].

Rapid acquisition of thin sections allows high-resolution isotropic images that can be viewed in multiple planes to assist with diagnosis without loss of resolution. Epithelial “flat lesions” without mass effect or urothelial thickening are generally not visible with CT.

The presence of enlarged LNs is highly predictive of metastases in UTUC [85,86].

5.2.2. Magnetic resonance urography

Magnetic resonance (MR) urography is indicated in patients who cannot undergo CT urography, usually when radiation or iodinated contrast media are contraindicated [87]. The sensitivity of MR urography is 75% after contrast injection for tumours < 2 cm [87]. Computed tomography urography is more sensitive and specific for the diagnosis and staging of UTUC compared to MR urography [88].

5.2.3. ¹⁸F-Fluorodeoxglucose positron emission tomography/computed tomography

A retrospective multicentre publication on the use of ¹⁸F-Fluorodeoxglucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of nodal metastasis in 117 surgically-treated UTUC patients reported a promising sensitivity and specificity of 82% and 84%, respectively. Suspicious LNs on FDG-PET/CT were associated with worse recurrence-free survival [89]. These results warrant further validation and comparison with MR urography and CT. FDG-PET/CT can also be used to assess (nodal) metastasis in patients unfit for iodinated contrast media due to renal imairment or allergy.

5.3. Cystoscopy

Urethrocystoscopy is an integral part of UTUC diagnosis to rule out concomitant BC [10,13].

5.4. Cytology

Abnormal cytology may indicate high-grade UTUC when bladder cystoscopy is normal, and in the absence of CIS in the bladder and prostatic urethra [1,90,91]. Cytology is less sensitive for UTUC than bladder tumours and should be performed selectively for the affected upper tract [92]. In a recent study, barbotage cytology detected up to 91% of cancers [93]. Barbotage cytology taken from the renal cavities and ureteral lumina is preferred before application of a contrast agent for retrograde ureteropyelography as it may cause deterioration of cytological specimens [94]. Retrograde ureteropyelography remains an option to detect UTUCs [75,95,96]. The sensitivity of fluorescence in situ hybridisation (FISH) for molecular abnormalities characteristic of UTUCs is approximately 72–84% [97,98]. A prospective study in 82 patients with a suspicion of UTUC using upper tract urine collected just before URS, reported sensitivities for Xpert Bladder, FISH and cytology of 100%, 93% and 52%, respectively. Negative predictive values were 100%, 96% and 81%, respectively [99]. These promising results suggest that URS might be avoided in selected patients with a positive urine biomarker test. However, further confirmation in comparative trials will be needed.

5.5. Diagnostic ureteroscopy

Flexible ureteroscopy (URS) is used to confirm the diagnosis of UTUC by visualising the ureter, renal pelvis and collecting system and perform a biopsy of suspicious lesions. It is also essential for meticulous tumour mapping before considering kidney-sparing options for UTUC. Presence, appearance, multifocality and size of the tumour can be determined using URS. In addition, ureteroscopic biopsies can determine tumour grade in more than 90% of cases with a low false-negative rate, regardless of sample size [100]. However, undergrading occurs with ureteroscopic diagnostic biopsy compared to nephroureterectomy specimens [101], making intensive follow-up necessary if kidney-sparing treatment is chosen [75,102].

Ureteroscopy also facilitates selective ureteral sampling for cytology in situ [96,103,104]. Stage assessment using ureteroscopic biopsy can be inaccurate. Combining ureteroscopic biopsy grade, imaging findings such as hydronephrosis, and urinary cytology may help in the decision-making process between radical nephroureterectomy (RNU) and kidney-sparing therapy [104,105]. In a meta-analysis comparing URS vs. no URS prior to RNU, 8/12 studies found an increased risk for intravesical recurrence if URS was performed before RNU [106]. Performing a biopsy at URS was also identified as a risk factor for intravesical recurrence [106]. A second systematic review of 16 studies showed that URS alone was not significantly related to intravesical recurrence; whereas URS with a biopsy significantly increased the risk for subsequent intravesical recurrence albeit with no concurrent impact on (long-term) survival outcomes [107]. This underlines the need for a study evaluating an immediate intravestical instillation in patients who underwent URS plus biopsy, or laser treatment, for UTUC.

Technical developments in flexible ureteroscopes and the use of novel imaging techniques may improve visualisation and diagnosis of flat lesions [108]. Narrow-band imaging is a promising technique, but results are preliminary [109]. Optical coherence tomography and confocal laser endomicroscopy (Cellvizio^®) have been used in vivo to evaluate tumour grade and/or for staging purposes, with a promising correlation with definitive histology in high-grade UTUC [110,111]. Recommendations for the diagnosis of UTUC are listed in Section 5.7.

5.6. Distant metastases

Prior to any treatment with curative intent, it is essential to rule out distant metastases. Computed tomography is the diagnostic technique of choice for lung- and abdominal staging for metastases [84]. A SEER analysis showed that approximately 9% of patients present with distant metastases [112].

5.7. Summary of evidence and recommendations for the diagnosis of UTUC