AUA: Upper Tract Urothelial Carcinoma (2023)

See Original Guidelines

• Literature search up to January 2023

Background

• UTUC refers to urothelial tumors that originate from the inner lining of the ureter, calyces, or renal pelvis
• Estimated annual incidence in US: 7000
  • Slightly less than annual incidence of testicular cancer: 8000-10000
• Approximately 25% of cases will present as localized disease, over 50% will have regionally advanced cancers, and nearly 20% will have distant disease at the time of diagnosis.
• Peak incidence is seen in adults aged >70 years
• 3x more common in men than women in western countries
• Risk factors
  • occupational exposure
  • Geographic location
  • Balkan endemic nephropathy associated with aristolochia herbal ingestion
  • Chronic upper tract inflammation
  • Hereditary factors such as Lynch and Lynch-like syndromes

Diagnosis and Evaluation

Recommended investigations in patients with suspected UTUC

Urologyschool.com Summary

• History and Physical Exam
• Laboratory
  • Cytologic washing from the upper tract system being investigated
  • Estimated GFR/Serum Cr
• Imaging
  • CT urogram
• Other
  • Cystoscopy to assess lower urinary tract
  • Upper tract endoscopy and biopsy

History and Physical exam

• History
  • Personal and family history to identify known hereditary risk factors for familial diseases associated with Lynch Syndrome (LS)
    • If positive, referral for genetic counseling should be offered.
    • LS is common among patients with UTUC, accounting for an estimated 7-20% of U.S. cases.
    • LS is a familial, autosomal-dominant multi-organ cancer syndrome
    • LS results from an inherited germline mutation in a group of DNA damage response genes responsible for biologic mechanisms of mismatch repair (MMR), specifically MLH1, MSH2, MSH6, PMS2, or EPCAM.28 Alterations affecting the normal function of these genes results in an accumulation of DNA errors and increases the potential for cancer development
    • patients with LS undergo routine screening due to increased life-long risk for developing associated malignancies, often occurring before 50 years of age
    • Associated cancers (most common first):
      • Colorectal (20-80%) i
      • Urothelial (1-18%)
      • Gastric cancers (1-13%)
      • Endometrial (15-60%) in females
      • Ovarian cancer (1-38%) in females
      • Others: biliary, small bowel, pancreatic, prostate, skin, and brain
    • LS may increase the possibility of contralateral upper tract involvement, which is an important potential clinical consideration when developing a treatment plan.

Laboratory

• Cytologic washing from the upper tract system being investigated
  • Selective ipsilateral upper tract cytology provides supplemental histologic data to tumor biopsies
  • Urine cytology is reported according to seven categories (Paris System): nondiagnostic, negative for HG urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), suspicious for HG urothelial carcinoma (SHGUC), HGUC, low-grade (LG) urothelial neoplasm (LGUN), and other malignancies
  • HG cytology in the setting of LG biopsy findings indicates the likely presence of higher-risk features (e.g., HG tumor) missed on biopsy sampling.
  • Cytologic barbotage washing with saline obtained from selective ipsilateral collection prior to use of any contrast is preferred to a voided urinary specimen due to improved cellular yield, to avoid potential contamination in case of concomitant bladder and/or prostatic urethral disease as well as theoretical dilution of the specimen from a normal contralateral unit, all of which further reduce sensitivity.
  • Selective cytology after tumor biopsy can improve the yield of cells for cytologic analysis.
• Assessment of renal function

Imaging

• Cross-sectional imaging of the upper tract with contrast including delayed images
  • Preferred modality: multiphase computed tomography (CT) scan with excretory phase imaging of the urothelium.
    • Pooled sensitivity of 92%
    • Pooled specificity of 95%
  • If contraindications to contrast-enhanced CT such as chronic kidney disease (CKD) or untreatable allergy to iodinated contrast medium, use magnetic resonance (MR) urography
    • MRI is less sensitive than CT, similar specificity
  • If contraindications to multiphasic CT and MR urography, use retrograde pyelography in conjunction with non-contrast axial imaging (renal ultrasound) to assess the upper urinary tracts.

Other

• Cystoscopy to assess lower urinary tract
  • Essential component of the evaluation for patients with suspected UTUC due to the risk of concurrent lower tract urothelial cancer in this population

• Upper tract endoscopy +/- biopsy of any identified lesion
  • Diagnostic ureteroscopy
    • Indications for ureteroscopy or percutaneous endoscopy of the upper urinary tract (and when diagnostic and prognostic details are needed)
      1. Lateralizing hematuria
      2. Suspicious selective cytology
      3. Radiographic presence of a mass or urothelial thickening
    • Document key descriptive features of UTUC including:
      1. Location (ureteral segment, renal pelvis, calyceal sites and lower tract)
      2. Size
      3. Number
      4. Focality
      5. Appearance (sessile, papillary, flat/villous)
      6. Quality of visualization
         1. Can impact the accuracy of endoscopic inspection (e.g., bleeding, difficulty in access, tumor location, artifacts from instrumentation) and should be documented in endoscopic reports.
         2. These factors may guide further diagnostic testing and inform therapeutic interventions as well as provide points of comparison for subsequent ureteroscopic surveillance.
         3. See checklist in Table 3
  • Biopsy of any identified lesion
    • Methods of biopsy
      • Ureteroscopic biopsy with forceps
      • Fluoroscopically guided retrograde brush biopsy
      • Mucosal abnormalities may be difficult to biopsy effectively and thus attempted tissue confirmation may be facilitated with the use of brush biopsies or percutaneous image-guided biopsy.
    • The association of HG tumor on ureteroscopic biopsy with high-stage (HS) disease (≥pT2) on final pathology has a PPV of 60% and a pooled NPV of 77%
  • Rare situations where endoscopic upper tract evaluation may not be necessary, when other diagnostic means clearly confirm the diagnosis of UTUC and thus histologic tissue confirmation is not clinically required.
    • High-grade (HG) selective cytology or other source of tissue diagnosis, and clear and convincing radiographic findings of upper tract urothelial-based tumor(s) such as patients with an obvious enhancing, urothelial based soft-tissue filling defect on contrast-enhanced imaging with urography. Such situations may be particularly relevant in patients with a history of HG urothelial cancer.
    • When findings would not influence decision-making, such as patients with severe co-morbidities who are ineligible for intervention or request expectant management.
  • In patients who have concomitant lower tract tumors (bladder/urethra) discovered at the time of ureteroscopy, the lower tract tumors should be managed in the same setting as ureteroscopy.
    • Consensus on prioritization of procedure sequencing (managing bladder before or after same-setting ureteroscopy) is lacking and heavily scenario-dependent. Rationale for managing the bladder first include optimizing visualization within the bladder, avoiding back-pressure or back-washing into the upper tract in the case of post-ureteroscopy stenting, and permitting final confirmation of bladder hemostasis. Addressing the upper tract first may be preferred in cases of bulky bladder tumor involvement where complete resection is not possible or bulky upper tract disease in which risk assessment is the priority. Seeding of tumors from bladder to upper tract or from upper tract to the lower tract have been raised as legitimate concerns which some have addressed by advocating use of ureteral access sheaths in such circumstances, yet the benefits of this approach require further prospective study.
  • In cases of existing ureteral strictures or difficult access to the upper tract, clinicians should minimize risk of ureteral injury by using gentle dilation techniques such as temporary stenting (pre-stenting) and limit use of aggressive dilation access techniques such as ureteral access sheaths.
    • Perforation or disruption of the urothelium in patients with UTUC can risk tumor seeding outside the urinary tract.
    • Precautionary measures in cases of difficult ureteral access such as avoiding dilation or placing a stent without performing ureteroscopy and then returning one-two weeks later to repeat the procedure (pre-stenting) can decrease the risk of iatrogenic injury and provide opportunity for a safer and more successful procedure.
    • Recognized perforation or injury events should be documented with immediate cessation of the procedure as soon as safely possible with additional steps to limit sequelae (e.g., stenting, bladder decompression with urethral catheter drainage to limit reflux, nephrostomy tube placement in cases of a completely obstructive ureteral tumor and evidence of contrast extravasation).
  • In cases where ureteroscopy cannot be safely performed or is not possible, an attempt at selective upper tract washing or barbotage for cytology may be made and pyeloureterography performed in cases where good quality imaging such as CT or MR urography cannot be obtained.
    • when endoscopic examination of the involved upper tract is not possible, findings from selective cytology and retrograde pyelography may provide useful, objective and sufficient information for risk stratification .
      • Example scenarios may include washings taken at the time of percutaneous nephrostomy tube placement or during attempted retrograde ureteroscopy that is abandoned for safety concerns.
      • Cytologic sampling from the upper urinary tract, either by barbotage (irrigation and aspiration) or by irrigation with passive collection (washings) can be used to improve cellular yield for cytologic evaluation and best performed prior to pyelography to avoid artifactual cellular changes from contrast solutions
  • At the time of ureteroscopy for suspected UTUC, clinicians should not perform ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract.
    • Endoscopic procedures have risks for patient injury and the potential for tumor seeding in the presence of urothelial cancer. Performing upper tract endoscopy in the setting of a completely normal contralateral upper urinary tract without clinical indication or as a “screening” procedure is unnecessary, placing patients at undue risk and should not be performed
• Universal histologic testing of UTUC with additional studies, such as immunohistochemical (IHC) or microsatellite instability (MSI)
  • Routine tissue testing provides a more sensitive, first-line means to identify LS-associated features in tumor samples, thus providing clinically significant information for patient counseling and management as well as screening for family members.
    • Immunohistochemical testing for example, which is widely available, can preliminarily identify the altered proteins associated with LS, and thus help to identify patients who may have the syndrome, who then require confirmation with further genetic (germline) testing.
    • Identifying the presence of LS-associated and MSI-high cancers also has clinical implications related to therapeutic treatment options, including identified sensitivity of urothelial cancers with mutations in DNA damage repair genes to systemic agents such as immune checkpoint inhibitors and cis�platinum-based chemothera

Optional

• Urine fluorescence in situ hybridization (FISH)
  • May be considered adjunctively to adjudicate atypical or suspicious cytology results.
• Retrograde pyelograms
  • Provide a roadmap for evaluation and possibly planning kidney-preserving strategies
  • Should be considered at initial evaluation with images retained in the patient record

Risk Stratification

• Categorized as high- vs. low-risk, based on biopsy grade
  • High risk
    • Defined by the association of high grade cancer (HG biopsy or cytology) with disease progression risk and pathologic stage T2 or greater disease
  • Low risk
    • Associated with low rates of metastatic progression
  • Sub-stratified into favorable vs. unfavorable, based on
    • Cytology
    • Radiographic appearance
      • Multifocality
      • Size
      • Invasive features
        • Heterogenous texture on enhanced and even unenhanced CT imaging has been associated with invasive disease
      • Obstruction of the urinary tract
      • Locoregional progression such as suspicious lymphadenopathy
      • Presence of metastatic disease
    • Endoscopic appearance
      • Multifocality
      • Size
        • Tumors < 1.5 cm in size may be optimal for endoscopic ablation given a lower risk of invasive disease.
          • Tumors ≥ 1.5 cm in size are associated with a > 80% risk of invasive disease
          • Larger tumors (≥ 1.5 cm) may be considered for ablation based on the provider’s experience and assessment of the need for kidney sparing surgery.
        • Measurement in the pre-surgical setting is not standardized and has not been shown to be independent of other more easily determined clinically identified features such as multifocality, invasion and obstruction.
      • Appearance (sessile, papillary, flat/villous)
    • Lower tract involvement
      • Pan-urothelial disease as indicated by history of prior cystectomy, concomitant or metachronous lower tract urothelial cancer or contralateral UTUC diagnosis
• Patients with UTUC should be assessed prior to surgery for the risk of post-NU CKD or dialysis.
  • Initial decisions regarding operative approach and administration of systemic therapy are based on patients’ baseline renal function and their estimated post-operative estimated glomerular filtration rate (eGFR). Patients undergoing NU have diminished postoperative renal function due to loss of a renal unit.
  • Patients with UTUC should, therefore, undergo an assessment of renal function and, for individuals who are scheduled to undergo NU and especially those who may require perioperative systemic treatment, an estimation of post-operative renal function should be made. Recommended tests include serum creatinine to calculate an eGFR and, at the clinician’s discretion for more refined evaluation, split function testing such as with differential renal scan or CT volumetric studies. Perioperative nephrology consultation can be considered as well, particularly in patients with pre-existing kidney disease. Attention should be paid in the settings of renal atrophy and hydronephrosis, which may alter clinical estimates of resulting post-operative renal function. Hydronephrosis caused by tumor obstruction may falsely under-estimate preoperative renal function and alter decision-making around the use of neoadjuvant chemotherapy (NAC). Thus, in settings of hydronephrosis, renal decompression either by indwelling ureteric stent or a percutaneous nephrostomy tube placed in an uninvolved renal calyx along with oral fluid hydration for 7-14 days before re-checking eGFR will help to establish a more accurate estimation of baseline renal function. Ureteric stenting is the preferred method of drainage given the known risk of tract seeding with percutaneous nephrostomy tubes in the setting of UTUC as well as quality of life considerations59 Atrophy of the contralateral (unaffected) renal unit may lead to over�estimates of postoperative renal function in the setting of NU since the kidney with lower differential function will remain in situ60, 61 Results of renal function investigations can help with patient counseling, strategizing treatment sequence, and determination of downstream risks of CKD and potential dialysis. In patients with sufficiently poor CKD in which NU could precipitate ESRD, a post operative plan for dialysis in conjunction with nephrology colleagues should be in place preoperatively including plans for dialysis access. Referral to nephrology for detailed evaluation and recommendations for perioperative management is warranted in such cases
  • In patients with pre-existing CKD or a solitary kidney, attempts to preserve renal function can be made, if oncologically feasible and appropriate, with segmental or endoscopic organ-sparing approaches which preferentially are associated with improved postoperative renal function.62-64
  • predictive factors for post-operative development of CKD or progression of pre-existing CKD include older age, diabetes mellitus, hypertension, as well as male sex, obesity, tobacco use, larger tumor size, and post-operative acute kidney injury.70-76 Patients who present with eGFR less than 45 mL/ min/1.73m2 or confirmed proteinuria are at particularly HR from a functional standpoint and should be considered for nephrology consultation. Patients who are expected to have an eGFR less than 30 mL/ min/1.73m2 after intervention will also be at HR long-term, and a nephrologist should be involved in their care. Identifying modifiable risk factors including diabetes mellitus (DM), hypertension (HTN) and smoking is essential. Optimizing glycemic and blood pressure control, smoking cessation and minimizing risk of acute kidney injury (with avoidance of hypotension and nephrotoxic agents such as intravenous contrast or non-steroidal anti-inflammatory drugs) should reduce the degree of renal dysfunction in the perioperative period.
  • With significant nephron mass loss, hyperfiltration can occur resulting in glomerular damage, exacerbation of proteinuria and progressive sclerosis with further decline in GFR. Therefore, repeat assessment of blood pressure, eGFR, and proteinuria should be performed soon after nephrectomy then again in three to six months to assess for development or progression of CKD. With any compromise in eGFR or presence of CKD complications, additional regular monitoring of kidney function should be performed and further management of CKD would be recommended with referral to nephrology. Careful management of DM and HTN and avoidance of substantial weight gain may slow or prevent CKD progression and should be prioritized on a long-term basis

Management

Patient counseling

• Clinicians should provide patients with a description of the short- and long-term risks associated with recommended diagnostic and therapeutic options. This includes the need for endoscopic follow-up, clinically significant strictures, toxicities associated with surgical treatment and side effects from neoadjuvant and adjuvant therapies.
• Urothelial recurrences are common in the management of UTUC, regardless of approach, and mandate long-term surveillance for which patients must be prepared – including the potential need for additional treatments. Ablative options can provide local control including durable long-term kidney sparing outcomes but incur additional endoscopic surveillance requirements and associated risks such as stricture and infection.78 Specifically, the use of chemoablative treatment with the reverse thermo-hydrogel preparation of mitomycin for pyelocaliceal instillation for LG tumors carries an FDA label warning for ureteral obstruction (>44%), bone marrow suppression, and embryo-fetal toxicity.79 Systemic chemotherapy and immunotherapy treatments also have toxicities requiring specific counseling best provided as part of multi-disciplinary care

Kidney Sparing Management

• Tumor ablation
  • Indications
    • Preferred initial management for LR favorable UTUC, when technically feasible
      • Observational studies suggest similar cancer-specific survival, similar complication rates, and improved renal function outcomes with endoscopic ablation, compared to nephroureterectomy
      • If LR UTUC and complete endoscopic ablation not feasible, chemoablation (in-situ tissue destruction) with mitomycin containing reverse thermal gel can be a treatment alternative
        • Risk of ureteric stenosis Instillation of mitomycin containing reverse thermal gel
    • Optional initial management for LR unfavorable UTUC and select patients with HR favorable disease who have low-volume tumors or cannot undergo RNU
  • Approach
    • May be accomplished via a retrograde or antegrade percutaneous approach and
  • Adjuvant chemotherapy
    • Following ablation of UTUC tumors and after confirming there is no perforation of the bladder or upper tract, clinicians may instill adjuvant pelvicalyceal chemotherapy
  • Repeat endoscopic evaluation should be performed within three months

Surgical management

• When performing NU or distal ureterectomy, the entire distal ureter including the intramural ureteral tunnel and ureteral orifice should be excised, and the urinary tract should be closed in a watertight fashion.
• . In patients undergoing RNU or SU (including distal ureterectomy) for UTUC, a single dose of perioperative intravesical chemotherapy should be administered in eligible patients to reduce the risk of bladder recurrence.
• Lymph node dissection
  • If HR UTUC, LND recommended
    • No RCTs to evaluate the effect of LND on oncologic outcomes in patients undergoing NU or SU
    • There is sufficient non-randomized evidence to suggest an oncologic benefit to LND at the time of NU for patients with “HR” stratification by guidelines
    • Recommended minimal templates in non-metastatic disease
      • Tumors in the pyelocaliceal system: lymph nodes of the ipsilateral great vessel extending from the renal hilum to at least the inferior mesenteric artery.
      • Tumors in the proximal 2/3 of the ureter: lymph nodes of the ipsilateral great vessel extending from the renal hilum to the aortic bifurcation.
      • Tumors in the distal 1/3 of the ureter: ipsilateral pelvic LND to include at minimum the obturator and external iliac nodal packets.
      • Internal and common iliac nodal packets may be removed in the appropriate clinical setting.
      • Limited data suggest cranial migration of lymph node metastases to the ipsilateral great vessels such that higher dissection may be considered in the appropriate clinical setting and per clinician judgement
  • If LR UTUC, LND optional
• Neoadjuvant/Adjuvant Chemotherapy and Immunotherapy

Watchful waiting

• Clinicians may offer watchful waiting or surveillance alone to select patients with UTUC with significant comorbidities, competing risks of mortality, or at significant risk of End-Stage Renal Disease (ESRD) with any intervention resulting in dialysis.

Surveillance and Survivorship

Post-Treatment Surveillance

Surveillance after kidney sparing

Surveillance after radical NU

References

1. Coleman, Jonathan A., et al. "Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline." The Journal of Urology 209.6 (2023): 1071-1081.