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 haematuria [11]. Flank pain due to clot or tumour tissue obstruction can occur in 20-32% of cases [11]. Preoperative symptoms at diagnosis are associated with a worse prognosis [99]. Systemic symptoms (including anorexia, weight loss, malaise, fatigue, fever, night sweats and cough) in patients with UTUC should prompt evaluation for metastases associated with a worse prognosis [11].

5.2. Imaging

5.2.1. Computed tomography

Computed tomography (CT) urography has the highest diagnostic accuracy of the available imaging techniques [100]. 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) [101].

Rapid acquisition of thin sections allows high-resolution isotropic images of both upper urinary tracts 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 on CT is highly predictive of metastases in UTUC [102,103]. The risk of thoracic metastases is extremely low in low-risk UTUC (see Chapter 6 for UTUC risk classification variables).

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 [104]. The sensitivity of MR urography is 75% after contrast injection for tumours < 2cm [104]. For the diagnosis and staging of UTUC, CT urography is more sensitive and specific compared to MR urography [105].

5.2.3.¹⁸F-Fluorodeoxglucose positron emission tomography/computed tomography

A retrospective multicentre publication on the use of ¹⁸F-Fluorodeoxglucose positron emission tomography/CT (FDG-PET/CT) for the detection of nodal metastasis in 117 surgically treated UTUC patients reported promising sensitivity and specificity of 82% and 84%, respectively. Suspicious LNs on FDG-PET/CT were associated with worse recurrence-free survival (RFS) [106]. These results warrant further validation and comparison with MR and CT. Assessment of (nodal and distant) metastases in patients unfit for iodinated contrast media due to renal impairment and/or allergy can also be performed using FDG-PET/CT.

5.3. Cystoscopy

Urethrocystoscopy is an integral part of the UTUC work-up to rule out concomitant BC [8,22].

5.4. Cytology and urinary markers

Voided cytology may indicate high-grade UTUC when cystoscopy is normal, and in the absence of CIS in the bladder and prostatic urethra [1,107]. However, voided urinary cytology is less sensitive for detecting UTUC compared to selectively obtained cytology from the affected upper tract [108]. Data indicate that barbotage cytology can detect up to 91% of tumours [109]. Barbotage cytology obtained from the renal cavities and ureter is preferred prior to the use of contrast agents for retrograde ureteropyelography as it may compromise cytological specimen quality [107,109]. Retrograde ureteropyelography remains an option to detect UTUC [94,110,111].

Liquid-based biomarkers have the potential to be an adjunct to existing diagnostic modalities in the evaluation of suspected UTUC by improving diagnostic pathways, risk stratification and reducing invasive surveillance strategies. A variety of urinary biomarkers adopting varying technologies have been described for UTUC, such as DNA methylation panels, RNA-based signature panels, fluorescence in situ hybridisation (FISH), protein markers panels (NMP-22, BTA, BTA-stat, uCyt+, surviving, p16/Ki-67), and genetic mutation panels for both bladder-based and upper tract urine. Preliminary data suggest that RNA-based signature panels and DNA methylation panels have favourable diagnostic performance for bladder-based urine [112-114].

For upper tract urine, the reported diagnostic performance for Epicheck^® (DNA methylation) and UroVysion^® (FISH) offer a reasonable balance between sensitivity and specificity. The reported sensitivities of Epicheck^® range from 65% to 83%, while specificity ranges from 79% to 81% [115-117]. The reported sensitivities of UroVysion^® range from 78% to 93% and specificities from 51% to 91% [116,118-120]. Both panels have high sensitivity for high-grade disease [116,120,121].

Preliminary data would suggest circulating tumour DNA (ctDNA) incorporating plasma copy number burden > 6.5 is a promising blood-based biomarker in predicting advanced invasive disease. One study reported a sensitivity of 79% (95% CI: 49-95%) and specificity of 94% (95% CI: 79-100%) for predicting ≥ pT2 and high-grade disease [122].

5.5. Diagnostic ureteroscopy

Diagnostic ureteroscopy (URS) may be used to confirm the diagnosis of UTUC. Complete inspection of the affected upper tract allows for detailed tumour mapping, assessment of tumour size and multifocality, as well as a targeted biopsy of suspicious lesions, before considering kidney-sparing options. Ureteroscopic biopsies can determine tumour grade in over 90% of cases, with a low false-negative rate regardless of sample size [123]. However, undergrading and understaging leading to inaccurate risk stratification occurs with ureteroscopic diagnostic biopsy compared to nephroureterectomy specimens [94,124,125].

Ureteroscopy also enables selective ureteral sampling for cytology [111,126,127]. However, stage assessment based on ureteroscopic biopsy may be inaccurate, as small biopsy specimens frequently lack lamina propria. Integrating the results of ureteroscopic biopsy grading, imaging findings and urinary cytology can improve risk stratification and inform the decision-making process between RNU and kidney-sparing options [127,128]. A meta-analysis comparing patients who underwent URS prior to RNU with those who did not, found that eight out of 12 studies reported an increased risk of intravesical recurrence associated with URS [129]. Performing a biopsy during URS was also identified as a risk factor for intravesical recurrence [129]. A second systematic review of 16 studies demonstrated that URS alone was not significantly associated with intravesical recurrence. However, URS with a concomitant biopsy significantly increased the risk for subsequent intravesical recurrence without an impact on extra urinary tract recurrences and overall survival (OS) [130].

Technical developments in flexible ureteroscopes and the use of novel imaging techniques may improve visualisation and diagnosis of flat lesions [131]. Narrow-band imaging is a promising technique, but results are preliminary [132]. 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 [133,134].

5.6. Molecular testing

Alterations in FGFR 2/3 should be tested for by means of next generation sequencing (see section 7.3.2.b.3) in the metastatic setting, preferably from an invasive part of the tumour or metastatic site [135,136].

5.7. Summary of evidence and recommendations for the diagnosis of upper urinary tract urothelial carcinoma