SIU 2018: Diagnosis and Staging: The Pitfalls and the Challenges of Upper Urinary Tract Transitional Cell Carcinoma

Seoul, South-Korea ( Jean de la Rosette, MD provided the second talk in this course focusing on the diagnosis and staging of upper tract urothelial carcinoma (UTUC), with an emphasis on pitfalls and challenges.  The key points being highlighted below.

- 5-10% of renal tumors/masses are UTUC
- 2-5% of urothelial tumors occur in the upper tract (kidney and ureter)
- Peak incidence occurs between age 75-79
- Mean age at presentation: 65 (rare before age 40)
- Male: Female ratio 2:1
- Caucasian: Black ratio 2:1
- While the incidence of UTUC is rising, DSS is improving – but may be due to stage migration and earlier detection
- Symptoms:
  - Hematuria (almost routinely)
  - Flank pain
- The disease is often multifocal
- Presents with advanced disease
  - 60% are invasive at diagnosis, 25% with regional Mets

Risk factors:
- Bladder cancer
  - 2-4% incidence of UTUC in a patient with prior bladder urothelial carcinoma
  - Increased with CIS, multifocality, etc.
- Contralateral UTUC
  - 2-6% incidence
- Tobacco use
- Occupational exposure
- Cyclophosphamide
- Balkan nephropathy, NSAID abuse, Chinese herbal exposure (Aristolochia)
- Lynch syndrome (colon cancer, endometrial and UTUC)

Current management of UTUC has split down two pathways, depending on diagnostics tests – either management of low-risk (usually low-grade) UTUC or high-risk (usually high-grade UTUC). The management of low-risk UTUC is nephron-sparing surgery (endoscopic or minimally invasive) and the management of high-risk is nephroureterectomy.
- Yet, correctly identifying patients with low and high-risk disease is the challenge!

The current EAU guidelines published just last year have expanded the definition of low-risk UTUC to the following:
- Unifocal disease
- Tumor size < 2 cm (previously 1 cm)
- Low-grade urine cytology
- Low-grade URS biopsy pathology
- Non-invasive features on CTU (imaging)

For the rest of the talk, he focused on diagnostics and guideline recommendations.

- Imaging (Strong level of evidence)
  - CTU is the gold standard – has replaced IVU. Sensitivity and specificity exceed 95%.
     - Lowest sensitivity for small tumors (but still around 89% for lesions < 5 mm, but only 40% for those < 3 mm)
  - MRU if CTU not feasible due to renal function, etc.
  - Staging for TNM requires CTU or MRU, though PET/CT may work
- Cystoscopy and urine cytology (strong level of evidence)
  - Positive urine cytology is suggestive of UTUC in absence of bladder cancer/tumors or CIS
  - Urine cytology detection yield is ~50-70% - but highly dependent on pathology at your institution and their experience!
     - Depends on collection technique and sample handling too
     - Has low sensitivity but high specificity
     - Voided urine cytology – 23-92% accuracy
     - Selective ureter cytology is much better – 77-100% accuracy
- Diagnostic URS
  - The best approach to diagnose UTUC
  - However can be technically challenging! Difficult to get a significant tissue sample
  - He recommends basketing tumor (push away from you rather than pulling towards the scope) to get the best tissue sample
  - Best efficacy when you use smaller instruments, digital scopes, and multifunctional graspers
     - Increased deflection is key to access and survey the most of the upper tract
  - Major pitfalls of URS and biopsy:
     - Insufficient sample
     - Sampling error
     - Difficulties in sampling muscle and deeper tissue
     - False positive after instrumentation
     - Misinterpretation

He did briefly talk about other diagnostic tools, including:

1) FISH – fluorescence in-situ hybridization
- Most experienced members in the audience did NOT use this regularly, but added it only in difficult cases where routine evaluation (cysto, cytology) was inconclusive
- Useful for suspicious imaging but negative cytology

2) Immuno-Cyt - no one in the audience really used this

3) PDD – enhancing endoscopic imaging with instillation of photodynamic agents
- Increases visual diagnostic yield ~37%
- It is more sensitive and specific than white light imaging

- This may lead to better, more complete therapeutic effect – and subsequent lower recurrence rates, similar to bladder cancer results
- However, most of the audience members primarily use this for bladder cancer and not the upper tract

4) Narrowband imaging (NBI) at the time of URS
- Dr. de la Rosette insists that be used during every URS
- Additional tumor diagnosis ~14%, detection of extended limits of tumor ~9%
- The greatest benefit in newly diagnostic UTUC, ~38%

5) OCT – optical coherence tomography
- Expensive technology, but has lots of potential
- Introduction of a narrow probe via the URS into the lumen of the ureter
- Based on light scattering, it provides very detailed staging information (re: depth) in a live situation
- AUC is 0.92! to predict low vs. high-grade disease
- It has 83% concordance with histopathology, 100% sensitivity, and 92% specificity
- Limitations: large, exophytic tumors, CIS and inflammation

6) CLE – Confocal Laser Endomicroscopy
- Another new, expensive technology with lots of potential
- Ultrahigh resolution microscopy in real-time, in vivo

- Provides detail regarding microscopic architecture and therefore can be very useful for grade evaluation

All these new imaging techniques need validation, however, and should be used primarily in a clinical trial or academic settings at this time.

From a diagnostic standpoint, there is lots of established data looking at the discrepancy between biopsy grade/stage and final biopsy grade/stage.
- The biopsies ability to predict grade is poor, especially for higher grade
- 37-96% upgrading on final nephroureterectomy pathology in most studies
- 29-36% upstaging on final nephroureterectomy pathology in most studies
- This makes accurate management of patients difficult, as Dr. Khochikar notes in his next talk on conservative management

Presented by: Jean de la Rosette, MD, Professor, and Chairman of the Department of Urology, at AMC University Hospital in Amsterdam, the Netherlands

Further Related Content: 
Is it an Aggressive Disease? - Upper Urinary Tract Transitional Cell Carcinoma
Conservative Management in Upper Urinary Tract Transitional Cell Carcinoma