Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline (2023) Flashcards
Introduction
Upper Tract Urothelial Cancer (UTUC) is a rare but serious disease which presents distinct clinical and treatment challenges. While it shares similarities with bladder urothelial cancer, differences in their pathogenesis, biology, and clinical attributes have been identified. UTUC, particularly of the renal pelvis, carries a higher 5-year mortality rate (>50%) compared to bladder cancer (<25%). Additionally, the risk of renal functional loss adds to patient morbidity, requiring specialized approaches for disease assessment, clinical staging, and management. A standardized approach, tailored to patient risks, is essential to optimize care, minimize toxicity, improve cancer control, and enhance survival rates. Dissemination of this knowledge, particularly in relation to this rare, clinically complex disease, can inform better patient care and promote referral to experienced, multidisciplinary teams in more complex cases.
Which of the following cancers has a higher 5-year mortality rate?
a) Bladder urothelial cancer
b) Upper Tract Urothelial Cancer of the renal pelvis
c) Both have similar mortality rates
b) Upper Tract Urothelial Cancer of the renal pelvis. UTUC has a >50% mortality rate, which is higher than the <25% rate for bladder cancer.
What additional risk does UTUC pose beyond cancer itself?
a) Risk of renal functional loss
b) Risk of bladder dysfunction
c) Risk of prostate enlargement
a) Risk of renal functional loss. UTUC, especially of the renal pelvis, may result in renal functional loss, adding to patient morbidity.
Why is a standardized, risk-stratified approach considered optimal in managing UTUC?
A standardized, risk-stratified approach to managing UTUC is considered optimal as it helps to customize the treatment and management strategy according to the individual patient’s risk factors. This approach aims to optimize patient care by balancing the need for aggressive treatment with the potential for toxicity, aiming to improve both cancer control and patient survival. Furthermore, it can help reduce under- and over-treatment, thereby minimizing the risk of treatment-associated morbidity.
How might UTUC treatment and management be optimized in more challenging cases?
In more challenging cases, optimization of UTUC treatment and management might be achieved through referral to experienced, multidisciplinary teams. These teams can bring a diverse set of skills and perspectives to patient care, resulting in more comprehensive and specialized management. In complex diseases like UTUC, multidisciplinary teams can offer better informed and coordinated care, improving patient outcomes. The sharing and dissemination of knowledge among these teams also play a crucial role in such optimization.
Background
Upper Tract Urothelial Cancer (UTUC) refers to urothelial tumors originating from the ureter, calyces, or renal pelvis, anatomically distinct from the bladder and urethra. UTUC, though related to lower tract urothelial cancer, is less common, affecting 5-10% of all patients with urothelial carcinoma. The exact incidence rate is difficult to determine but estimates suggest around 7,000 cases per year in the U.S. Knowledge of patient demographics, staging distribution and causative factors is critical for UTUC management. SEER data shows 25% of cases present as localized disease, over 50% as regionally advanced cancers, and nearly 20% as distant disease at diagnosis. Peak incidence is in adults over 70 years, and it’s thrice as common in men than women in western countries. Risk factors include occupational exposure, geographic location, Balkan endemic nephropathy associated with aristolochic acid ingestion, chronic upper tract inflammation, and hereditary factors such as Lynch and Lynch-like syndromes.
What percentage of UTUC cases present as localized disease at the time of diagnosis?
a) 10%
b) 25%
c) 50%
b) 25%. According to SEER data, approximately 25% of UTUC cases present as localized disease at diagnosis.
Which demographic has the highest incidence of UTUC?
a) Women over 70 years
b) Men over 70 years
c) Men under 70 years
b) Men over 70 years. UTUC’s peak incidence is in adults aged over 70 years and is three times more common in men than women in western countries.
What are some risk factors for developing UTUC?
Risk factors for developing UTUC include occupational exposure (potentially to carcinogens), geographic location (it’s notably prevalent in certain regions), Balkan endemic nephropathy (associated with the ingestion of aristolochic acid from certain herbs), chronic inflammation of the upper urinary tract, and hereditary factors such as Lynch and Lynch-like syndromes.
How does the incidence of UTUC compare to that of testicular cancer?
The incidence of UTUC is slightly lower than that of testicular cancer. It’s estimated that there are around 7,000 cases of UTUC per year in the U.S., whereas testicular cancer has an annual incidence of between 8,000 – 10,000 cases.
GUIDELINE STATEMENT 1
For patients with suspected UTUC, a cystoscopy and cross- sectional imaging of the upper tract with contrast including delayed images of the collecting system and ureter should be performed. (Strong Recommendation; Evidence Level: Grade B)
In diagnosing and evaluating suspected Upper Tract Urothelial Cancer (UTUC), a cystoscopy and cross-sectional imaging of the upper tract with contrast, including delayed images of the collecting system and ureter, are recommended due to the risk of concurrent lower tract urothelial cancer. CT urography is advised if no contraindications exist, as it demonstrates high sensitivity (92%) and specificity (95%). When contrast-enhanced CT is not feasible, such as in chronic kidney disease (CKD) or allergy to iodinated contrast medium, clinicians can utilize MR urography, although its sensitivity is lower (63-74%). Retrograde pyelography, in conjunction with non-contrast axial imaging, or renal ultrasound may be used when both multiphasic CT and MR urography are contraindicated, even though ultrasound has not been specifically evaluated for diagnosing UTUC and its routine use is not recommended.
For patients with suspected UTUC, which diagnostic tool is initially recommended?
a) Cystoscopy and cross-sectional imaging of the upper tract with contrast
b) Retrograde pyelography
c) Renal ultrasound
a) Cystoscopy and cross-sectional imaging of the upper tract with contrast. This is recommended due to the risk of concurrent lower tract urothelial cancer.
If a patient has contraindications to contrast-enhanced CT, what alternative imaging method could be used?
a) MR urography
b) Renal ultrasound
c) None of the above
a) MR urography. For patients with contraindications to contrast-enhanced CT, MR urography may be utilized.
Why is a cystoscopy an essential component of the evaluation for patients with suspected UTUC?
A cystoscopy is an essential part of the evaluation for patients with suspected UTUC due to the risk of concurrent lower tract urothelial cancer. This means that patients suspected of having UTUC could also have cancer in the bladder or urethra, necessitating a comprehensive examination of the lower urinary tract through cystoscopy.
How does the sensitivity and specificity of CT urography compare to MR urography in the evaluation of UTUC?
CT urography has a higher sensitivity and specificity in the evaluation of UTUC compared to MR urography. The pooled sensitivity of CT urography is approximately 92%, with a specificity of 95%. In contrast, MR urography has a lower sensitivity ranging from 63% to 74%, but retains a high specificity of 96% to 97%. The difference in sensitivity means that CT urography is likely more effective in detecting UTUC when it is present.
GUIDELINE STATEMENT 2
Clinicians should evaluate patients with suspected UTUC with diagnostic ureteroscopy and biopsy of any identified lesion and cytologic washing from the upper tract system being inspected. (Strong Recommendation; Evidence Level: Grade C)
For patients with suspected UTUC, a diagnostic ureteroscopy and biopsy of any identified lesion, along with cytologic washing from the upper tract system being inspected, are recommended. The procedure should be standardized and carefully document all key features of UTUC, including tumor size, number, location, focality, and appearance. It is vital to distinguish between diagnostic and therapeutic endoscopic procedures: diagnostic procedures provide crucial clinical information, whereas therapeutic procedures involve more extensive operations aimed at curative treatment. The choice of approach (retrograde ureteroscopy versus antegrade percutaneous nephroscopy and/or ureteroscopy) depends on tumor characteristics and patient factors. Urine cytology can assist in identifying carcinoma in the upper tracts, and urine fluorescence in situ hybridization (FISH) testing also offers high diagnostic accuracy for identifying UTUC. However, the use of FISH is not yet fully established due to its high sensitivity and low specificity compared to voided cytology.
Which of the following should be performed on patients with suspected UTUC for diagnostic purposes?
a) Retrograde ureteroscopy
b) Antegrade percutaneous nephroscopy
c) Either retrograde ureteroscopy or antegrade percutaneous nephroscopy, depending on factors such as tumor location, configuration, size, and patient factors
c) Either retrograde ureteroscopy or antegrade percutaneous nephroscopy, depending on factors such as tumor location, configuration, size, and patient factors
What diagnostic test can be used to assist in identifying carcinoma in the upper tracts?
a) Urine cytology
b) Urine fluorescence in situ hybridization (FISH) testing
c) Both urine cytology and urine fluorescence in situ hybridization (FISH) testing
c) Both urine cytology and urine fluorescence in situ hybridization (FISH) testing
What key features should be documented during a ureteroscopic evaluation in patients with suspected UTUC?
Key features that should be documented during a ureteroscopic evaluation in patients with suspected UTUC include tumor size, number, location, focality, and appearance. These factors are crucial in guiding further diagnostic testing, informing therapeutic interventions, and providing points of comparison for subsequent ureteroscopic surveillance.
What are some of the considerations when choosing between retrograde ureteroscopy and antegrade percutaneous nephroscopy for diagnosing UTUC?
The choice between retrograde ureteroscopy and antegrade percutaneous nephroscopy for diagnosing UTUC is influenced by several factors, including the location, configuration, and size of the tumor, as well as patient-specific factors such as previous surgical history (e.g., prior cystectomy). There is a lack of comprehensive data comparing the effectiveness of these two techniques across all clinical situations, making individualized decision-making based on these factors important.
GUIDELINE STATEMENT 3
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. (Expert Opinion)
The guideline recommends that patients who have concomitant lower tract tumors (in the bladder or urethra) discovered during ureteroscopy should receive appropriate, guideline-directed management for these tumors in the same surgical setting. This could include biopsy, resection, or ablation as clinically indicated. Genomic studies indicate a clonal similarity between upper and lower tract tumors, suggesting potential downstream or upstream tumor implantation. The sequencing of procedures (managing bladder before or after ureteroscopy) is scenario-dependent and lacks consensus. Managing the bladder first may optimize visualization, avoid back-pressure or back-washing into the upper tract, and confirm bladder hemostasis. Addressing the upper tract first could be preferred in cases of bulky tumor involvement where complete resection is not possible or when risk assessment is the priority.
When lower tract tumors are discovered during ureteroscopy for suspected UTUC, what is the recommended approach?
a) Ignore them until the upper tract is fully examined
b) Manage them in the same surgical setting
c) Schedule a separate surgery for lower tract tumors
b) Manage them in the same surgical setting
The sequencing of procedures (managing bladder before or after ureteroscopy) when lower tract tumors are discovered during ureteroscopy is:
a) Always manage bladder first
b) Always manage bladder last
c) Lacks consensus and heavily scenario-dependent
c) Lacks consensus and heavily scenario-dependent
What are the considerations for managing bladder tumors discovered at the same time as UTUC during ureteroscopy?
Several factors are considered when managing bladder tumors discovered concurrently with UTUC during ureteroscopy. The sequence of procedures, whether to address bladder or upper tract first, lacks consensus and heavily depends on the clinical scenario. Arguments for managing the bladder first include optimizing visualization within the bladder, preventing back-pressure or back-washing into the upper tract, and confirming bladder hemostasis. However, addressing the upper tract first might be preferred in cases of bulky bladder tumor involvement where complete resection isn’t feasible or in cases of bulky upper tract disease where risk assessment is the priority. Seeding of tumors from bladder to upper tract or vice versa has been raised as a concern, and some recommend using ureteral access sheaths to mitigate this, but the benefits of this approach need further study.
What insights do genomic studies provide about concomitant upper and lower tract tumors?
Genomic studies have shown clonal similarity between upper and lower tract tumors, which indicates a potential downstream or upstream tumor implantation mechanism. This finding underscores the interconnected nature of these tumors and justifies treating them in the same surgical setting when they are discovered concurrently. It’s important to note, however, that while bladder tumor pathology often reflects that of upper tract tumors, it is not reliable enough to avoid separate upper tract endoscopy and biopsy when feasible.
GUIDELINE STATEMENT 4
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. (Expert Opinion)
The guideline recommends minimizing the risk of ureteral injury in patients with existing ureteral strictures or difficult access to the upper tract by using gentle dilation techniques, such as temporary stenting (pre-stenting), and limiting the use of aggressive dilation access techniques like ureteral access sheaths. This is crucial because perforation or disruption of the urothelium in patients with upper tract urothelial carcinoma (UTUC) can risk tumor seeding outside the urinary tract. Pre-stenting can decrease the risk of iatrogenic injury and allow for a safer and more successful procedure. If perforation or injury events occur, they should be immediately documented and the procedure should be stopped as soon as safely possible, with additional steps taken to limit complications.
What is recommended to minimize the risk of ureteral injury in cases of existing ureteral strictures or difficult access to the upper tract?
a) Use of aggressive dilation access techniques like ureteral access sheaths
b) Use of gentle dilation techniques such as temporary stenting (pre-stenting)
c) Use of non-dilation techniques only
b) Use of gentle dilation techniques such as temporary stenting (pre-stenting)
If perforation or injury events occur during the procedure, what should be done?
a) Continue the procedure ignoring the injury
b) Document the injury event immediately and cease the procedure as soon as safely possible
c) Ignore the injury until the end of the procedure
b) Document the injury event immediately and cease the procedure as soon as safely possible
What is the significance of gentle dilation techniques such as pre-stenting in patients with UTUC and difficult ureteral access?
In patients with upper tract urothelial carcinoma (UTUC) who have existing ureteral strictures or difficulty accessing the upper tract, gentle dilation techniques such as temporary stenting or pre-stenting can decrease the risk of iatrogenic injury. This is critical as perforation or disruption of the urothelium in patients with UTUC can risk seeding the tumor outside the urinary tract. Pre-stenting provides an opportunity for a safer and more successful procedure.
What measures should be taken in case of recognized perforation or injury events during the procedure?
If a perforation or injury event is recognized during the procedure, it should be immediately documented, and the procedure should be stopped as soon as it is safe to do so. Additional measures to limit complications should be undertaken, such as stenting, bladder decompression with urethral catheter drainage to limit reflux, and placement of a nephrostomy tube in cases of a completely obstructive ureteral tumor and evidence of contrast extravasation. These measures are important to manage the injury and prevent further complications.
Table 3: Standardized Upper Tract Endoscopy Suggested Reporting Elements
GUIDELINE STATEMENT 5
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. (Conditional Recommendation; Evidence Level: Grade C)
The guideline suggests that in cases where ureteroscopy can’t be performed safely or isn’t possible, attempts at selective upper tract washing or barbotage for cytology can be made, and pyeloureterography could be performed in cases where high-quality imaging such as CT or MR urography cannot be obtained. The findings from these procedures may provide useful and objective information for risk stratification when endoscopic examination of the involved upper tract isn’t feasible. This guidance is considered a conditional recommendation due to limited data from endoscopy, biopsy, and imaging, but is supported by the evidence associated with Statement 2.
When is it recommended to attempt selective upper tract washing or barbotage for cytology?
a) When ureteroscopy can be performed safely and easily
b) When ureteroscopy cannot be safely performed or is not possible
c) When ureteroscopy can be performed, but imaging like CT or MR urography is not possible
b) When ureteroscopy cannot be safely performed or is not possible
When is pyeloureterography recommended?
a) When high-quality imaging such as CT or MR urography is readily available
b) When ureteroscopy is possible
c) When high-quality imaging such as CT or MR urography cannot be obtained
c) When high-quality imaging such as CT or MR urography cannot be obtained
How can selective upper tract washing or barbotage for cytology and pyeloureterography be useful in managing UTUC?
In cases where ureteroscopy can’t be performed safely or isn’t possible, attempts at selective upper tract washing or barbotage for cytology can provide useful, objective information for risk stratification. Furthermore, pyeloureterography can be beneficial in scenarios where high-quality imaging such as CT or MR urography is not obtainable. These methods provide an alternative approach to gather critical information about the patient’s condition when traditional methods are not viable.
GUIDELINE STATEMENT 6
At the time of ureteroscopy for suspected UTUC, clinicians should not perform ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract. (Expert Opinion)
The guideline advises against performing ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract at the time of ureteroscopy for suspected upper tract urothelial carcinoma (UTUC). Indications for upper urinary tract ureteroscopy or percutaneous endoscopy include lateralizing hematuria, suspicious selective cytology, and radiographic presence of a mass or urothelial thickening. These endoscopic procedures carry risks for patient injury and potential for tumor seeding in the presence of urothelial cancer. Unnecessary upper tract endoscopy in the setting of a completely normal contralateral upper urinary tract, without clinical indication or as a “screening” procedure, puts patients at undue risk and is not recommended.
Under what circumstances is it suggested to perform ureteroscopic inspection of the contralateral upper tract?
a) For screening purposes
b) When there are findings such as lateralizing hematuria, suspicious selective cytology, and radiographic presence of a mass or urothelial thickening
c) When the contralateral upper tract appears normal in radiographic and clinical evaluations
b) When there are findings such as lateralizing hematuria, suspicious selective cytology, and radiographic presence of a mass or urothelial thickening
What are the potential risks associated with performing ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract?
a) There are no significant risks associated with this procedure
b) Potential risks include patient injury and the possibility of tumor seeding in the presence of urothelial cancer
c) The only risk is patient discomfort during the procedure
b) Potential risks include patient injury and the possibility of tumor seeding in the presence of urothelial cancer
Why is it recommended not to perform ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract in suspected UTUC?
Performing a ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract is not recommended because it unnecessarily exposes the patient to risks associated with the procedure. These risks include potential injury to the patient and the possibility of tumor seeding in the presence of urothelial cancer. The guideline suggests that this procedure should only be performed when there are specific indications such as lateralizing hematuria, suspicious selective cytology, and radiographic presence of a mass or urothelial thickening.
Under what circumstances should ureteroscopy or percutaneous endoscopy of the upper urinary tract be performed?
Ureteroscopy or percutaneous endoscopy of the upper urinary tract should be performed when there are specific clinical indications. These indications include lateralizing hematuria, suspicious selective cytology, and the radiographic presence of a mass or urothelial thickening. The decision to perform these procedures should be guided by the need to diagnose and treat suspected upper tract urothelial carcinoma, balanced against the potential risks associated with the procedures.
GUIDELINE STATEMENT 7
For patients with suspected/ diagnosed UTUC, clinicians should obtain a personal and family history to identify known hereditary risk factors for familial diseases associated with Lynch Syndrome (LS) (colorectal, ovarian, endometrial, gastric, biliary, small bowel, pancreatic, prostate, skin and brain cancer) for which referral for genetic counseling should be offered. (Expert Opinion)
Clinicians should obtain a personal and family history from patients with suspected or diagnosed upper tract urothelial carcinoma (UTUC) to identify known hereditary risk factors for familial diseases associated with Lynch Syndrome (LS), including colorectal, ovarian, endometrial, gastric, biliary, small bowel, pancreatic, prostate, skin, and brain cancer. If such risks are identified, referral for genetic counseling should be offered. LS is common among UTUC patients, accounting for 7-20% of U.S. cases. It’s an autosomal-dominant multi-organ cancer syndrome affecting approximately 1 in 280 individuals in the U.S. LS is associated with several cancers, with patients recommended to undergo routine screening due to increased life-long risk for developing associated malignancies. For UTUC patients with familial risk factors, clinical suspicion, or interest in further testing for hereditary syndromes, clinicians can perform initial screening tests and should offer referral for genetic counseling and, if indicated, genetic testing.
What is the estimated percentage of UTUC cases in the U.S. associated with Lynch Syndrome?
a) 1-3%
b) 7-20%
c) 25-30%
b) 7-20%
Lynch Syndrome is associated with which of the following cancers?
a) Colorectal, ovarian, and endometrial
b) Gastric, biliary, and small bowel
c) Pancreatic, prostate, skin, and brain
d) All of the above
d) All of the above
How should clinicians approach patients with suspected or diagnosed UTUC in the context of potential Lynch Syndrome?
Clinicians should obtain a detailed personal and family history from patients with suspected or diagnosed UTUC to identify known hereditary risk factors for familial diseases associated with Lynch Syndrome. If such risk factors are identified, clinicians should offer referral for genetic counseling and, if indicated, genetic testing. Routine evaluation should include specific questions about Lynch Syndrome associated cancers to help identify at-risk patients and their family members. In UTUC specifically, Lynch Syndrome may increase the possibility of contralateral upper tract involvement, which should be considered when developing a treatment plan.
Why is it important to recognize Lynch Syndrome as a potential risk factor in patients with UTUC?
It’s important to recognize Lynch Syndrome as a potential risk factor in patients with UTUC as it’s common among such patients, accounting for an estimated 7-20% of U.S. cases. Moreover, Lynch Syndrome is an autosomal-dominant multi-organ cancer syndrome that increases the lifetime risk for developing associated malignancies. Therefore, recognition of this syndrome can help guide clinical decision-making, including routine screening, development of treatment plans, and referral for genetic counseling and testing. It’s particularly important to consider when LS might increase the risk of contralateral upper tract involvement in UTUC. Also, future therapeutic options are likely to target LS-associated cancers, further emphasizing the importance of aligning clinical guidelines with genetic risk factors for the preventative and therapeutic management of UTUC in patients with LS.
Table 4: Clinical Screening Criteria for LS (also referred to as hereditary non-polyposis colorectal cancer [HNPCC])
GUIDELINE STATEMENT 8
Universal histologic testing of UTUC with additional studies, such as immunohistochemical (IHC) or microsatellite instability (MSI), should be performed to identify patients with high probability of Lynch-related cancers whom clinicians should refer for genetic counseling and germline testing. (Strong Recommendation; Evidence Level: Grade B)
Universal histologic testing of upper tract urothelial carcinoma (UTUC) should be performed, using additional studies like immunohistochemical (IHC) or microsatellite instability (MSI) testing. This helps identify patients with high probability of Lynch-related cancers, who should then be referred for genetic counseling and germline testing. Lynch Syndrome (LS) results from inherited germline mutations in DNA damage response genes responsible for mismatch repair (MMR), specifically MLH1, MSH2, MSH6, PMS2, or EPCAM. Histologic studies like IHC can indicate loss of these specific MMR proteins or evaluate for MSI status as a standard means to assess for the possibility of LS association. Recommendations in other LS-related cancers strongly endorse universal MMR and MSI testing. The panel recommends genetic testing to all patients with UTUC due to the higher identified prevalence of LS association in UTUC relative to colorectal cancer.
Why should universal histologic testing of UTUC be performed?
a) To identify patients with high probability of Lynch-related cancers
b) To evaluate for the presence of mismatch repair proteins
c) To assess microsatellite instability
d) All of the above
d) All of the above
Which genetic mutations are commonly associated with Lynch Syndrome?
a) BRCA1 and BRCA2
b) TP53 and PTEN
c) MLH1, MSH2, MSH6, PMS2, or EPCAM
d) FLT3 and IDH1
Which genetic mutations are commonly associated with Lynch Syndrome?
a) BRCA1 and BRCA2
b) TP53 and PTEN
c) MLH1, MSH2, MSH6, PMS2, or EPCAM
d) FLT3 and IDH1
What is the importance of universal histologic testing of UTUC and what additional studies should be performed?
Universal histologic testing of UTUC is crucial as it helps to identify patients with a high probability of Lynch-related cancers. It’s the first-line means to detect Lynch Syndrome-associated features in tumor samples, thus providing clinically significant information for patient counseling, management, and screening for family members. Additional studies that should be performed include immunohistochemical (IHC) testing and microsatellite instability (MSI) testing. IHC testing can preliminarily identify the altered proteins associated with Lynch Syndrome, while MSI testing can assess the genome stability. These tests serve as a standard means to assess for the possibility of LS association, and suspicious findings with these tests require further confirmatory testing.
Why is genetic testing recommended for all patients with UTUC?
Genetic testing is recommended for all patients with UTUC due to the higher identified prevalence of Lynch Syndrome association in UTUC relative to colorectal cancer. Lynch Syndrome results from inherited germline mutations in mismatch repair (MMR) genes, specifically MLH1, MSH2, MSH6, PMS2, or EPCAM. Alterations in these genes can lead to the accumulation of DNA errors and increase the potential for cancer development. Therefore, genetic testing can help to identify patients who have a high probability of Lynch-related cancers, leading to more effective patient counseling, management strategies, and familial screening. Furthermore, recommendations and guidelines in other LS-related cancers strongly endorse universal MMR and MSI testing.
GUIDELINE STATEMENT 9
At the time of identified UTUC, clinicians should perform a standardized assessment documenting clinically meaningful endoscopic (focality, location, appearance, size) and radiographic (invasion, obstruction, and lymphadenopathy) features to facilitate clinical staging and risk assessment. (Strong Recommendation; Evidence Level: Grade B)
At the time of identifying upper tract urothelial carcinoma (UTUC), a standardized assessment documenting endoscopic (focality, location, appearance, size) and radiographic (invasion, obstruction, lymphadenopathy) features should be performed to facilitate clinical staging and risk assessment. Such tumor features identified by endoscopic and radiologic assessment are strongly associated with disease risk, hence vital for proper risk stratification, treatment decision-making, and treatment response assessment. Key features to document include sites of involvement, number of tumors or presence of multifocality, and tumor appearance. Quality of visualization and possible impacts on accuracy should be documented. Radiographic characterization of tumor features is also important for clinical staging, including details of tumor characteristics suggesting invasive features, obstruction of the urinary tract, locoregional progression, and presence of metastatic disease.
Why should a standardized assessment be performed at the time of identified UTUC?
a) To facilitate clinical staging and risk assessment
b) To ensure proper risk stratification
c) To guide treatment decision-making
d) All of the above
d) All of the above
What key features should be documented during the endoscopic examination of UTUC?
a) Sites of involvement
b) Number of tumors or presence of multifocality
c) Tumor appearance
d) All of the above
d) All of the above
Why is it important to document the endoscopic and radiographic features of a UTUC?
The endoscopic and radiographic features of a UTUC are strongly associated with disease risk, which is crucial for proper risk stratification, guiding treatment decisions, and assessing the response to treatment. By standardizing the assessment and documentation of these features, clinicians can better communicate and evaluate the objective clinical findings, enhancing patient management and treatment outcomes.
What is the importance of radiographic characterization of tumor features in UTUC?
Radiographic characterization of tumor features is crucial for clinical staging of UTUC. It provides details about tumor characteristics suggesting invasive features, obstruction of the urinary tract, locoregional progression, and the presence of metastatic disease. This information assists in determining the extent of the disease, helping to inform the appropriate treatment strategy and assess the potential treatment response. Moreover, these radiographic features can aid in the monitoring of disease progression and response to therapy over time.
GUIDELINE STATEMENT 10
Following standardized assessment, clinicians should risk-stratify patients as “low-” or “high” risk for invasive disease (pT2 or greater) based on obtained endoscopic, cytologic, pathologic, and radiographic findings. Further stratification into favorable and unfavorable risk groups should then be based on standard identified features (Table 5). (Strong Recommendation; Evidence Level: Grade B)
After standardized assessment, clinicians should categorize patients into “low-“ or “high” risk for invasive disease (pT2 or greater) based on endoscopic, cytologic, pathologic, and radiographic findings. Further stratification into favorable and unfavorable risk groups should be based on standard identified features. The factors assisting sub-stratification include biopsy, cytology, fluorescence in situ hybridization (FISH), and CT imaging. Biopsy has a positive predictive value (PPV) of 60% and negative predictive value (NPV) of 77% for high-stage (HS) disease. FISH may have value as an adjunct test where tissue sampling is challenging and cytology is indeterminate. The sensitivity and specificity of specific CT findings for identifying high-grade (HG) disease varies; heterogenous texture (versus homogeneous) has a sensitivity of 70% and specificity of 100%. Moreover, retrograde pyelograms, MRI, and features such as tumor appearance, growth characteristics, and lower tract involvement also contribute to risk stratification. However, the panel advises that studies like endoluminal US and MRI should only be used as supplements to current standards of care.
Which factors can aid in sub-stratification within the high-risk and low-risk categories for UTUC?
a) Biopsy
b) Cytology
c) FISH
d) CT Imaging
e) All of the above
e) All of the above
Which CT finding has the best combination of sensitivity and specificity for identifying high-grade UTUC?
a) Hydroureteronephrosis
b) Heterogeneous texture
c) Local invasion
d) Pathologically enlarged lymph nodes
b) Heterogeneous texture
How does cytology contribute to the risk stratification of UTUC?
Selective ipsilateral upper tract cytology provides supplemental histologic data to tumor biopsies. If high-grade cytology is found in the setting of low-grade biopsy findings, it indicates the likely presence of higher-risk features, such as a high-grade tumor, that were missed on biopsy sampling. Obtaining selective cytology after tumor biopsy can improve the yield of cells for cytologic analysis, providing more accurate and detailed information about the tumor.
How can imaging modalities like CT and MRI be used in the risk stratification of UTUC?
Specific CT findings, such as the presence of heterogeneous texture, can be indicative of high-grade disease in UTUC. It’s important to note that the sensitivity and specificity of CT findings for identifying high-stage UTUC vary widely. MRI can provide some soft tissue details in patients who cannot receive contrast, offering some advantages by identifying features of fat invasion with diffusion-weighted imaging associated with very advanced, T3 disease. However, MRI can falsely overestimate tumor stage due to surrounding tissue effects that may mimic tumor invasion. At present, the guidelines recommend such studies only as supplements to current standards of care.
Table 5: Presurgical Clinical Risk Categories
GUIDELINE STATEMENT 11
Patients with UTUC should be assessed prior to surgery for the risk of post-NU CKD or dialysis. (Expert Opinion)
The 11th guideline emphasizes the assessment of patients with Upper Tract Urothelial Carcinoma (UTUC) for risk of Chronic Kidney Disease (CKD) or dialysis following nephroureterectomy (NU). This process is crucial for operative decision-making and systemic therapy administration. An estimated glomerular filtration rate (eGFR) should be obtained before surgery. If hydronephrosis or renal atrophy is present, these may affect accurate preoperative renal function estimation. Hence, renal decompression may be needed. Considerations for postoperative renal function, especially for patients needing perioperative systemic treatment, must be taken into account. Regular monitoring and management of CKD risks, such as Diabetes Mellitus (DM) and hypertension, are also crucial.
What tests are recommended to assess renal function before surgery in UTUC patients?
a) Serum creatinine
b) Differential renal scan
c) CT volumetric studies
d) All of the above
d) All of the above. All these tests are recommended to assess the renal function before surgery.
What factors could potentially cause a false under-estimate or overestimate of renal function in UTUC patients prior to surgery?
a) Hydronephrosis
b) Renal atrophy
c) Both a and b
d) None of the above
c) Both a and b. Hydronephrosis may falsely under-estimate, and renal atrophy may overestimate the preoperative renal function.
Why is it crucial to assess patients with UTUC for the risk of post-NU CKD or dialysis prior to surgery?
Assessing UTUC patients for the risk of post-NU CKD or dialysis is crucial because the operative approach and administration of systemic therapy are decided based on the patient’s baseline renal function and their estimated post-operative glomerular filtration rate (eGFR). Further, since the postoperative renal function can diminish due to the loss of a renal unit in NU, this can exacerbate CKD and affect a patient’s eligibility to receive adjuvant chemotherapy. Thus, an accurate preoperative assessment helps in planning the treatment strategy and managing the risks effectively.
Explain the importance of optimizing glycemic and blood pressure control in the management of postoperative renal function in UTUC patients.
Optimizing glycemic and blood pressure control is essential in managing postoperative renal function in UTUC patients because it helps reduce the degree of renal dysfunction in the perioperative period. Particularly in patients with diabetes mellitus, maintaining good glycemic control can prevent the risk of acute kidney injury. Similarly, effective blood pressure control can mitigate the risk of hypertensive nephropathy. These measures, along with smoking cessation and minimizing the risk of acute kidney injury, can significantly contribute to preserving renal function and managing CKD in the postoperative period.
GUIDELINE STATEMENT 12
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. (Clinical Principle)
The 12th guideline underlines the importance of informing patients about the short- and long-term risks associated with diagnostic and therapeutic options for Upper Tract Urothelial Carcinoma (UTUC). These risks include the need for endoscopic follow-up, possible complications like significant strictures, surgical treatment toxicities, and side effects from neoadjuvant and adjuvant therapies. Urothelial recurrences are common in UTUC management, necessitating long-term surveillance and possible additional treatments. Ablative therapies, while providing local control and durable long-term kidney-sparing outcomes, come with added endoscopic surveillance requirements and associated risks such as stricture and infection. Treatment options such as chemoablative treatment with reverse thermo-hydrogel preparation of mitomycin carry specific risks and require appropriate patient counseling.
Why is long-term surveillance necessary in the management of UTUC?
a) To monitor the effectiveness of the therapy
b) Due to the common occurrence of urothelial recurrences
c) To check for possible complications from therapies
d) All of the above
d) All of the above. Long-term surveillance is necessary to monitor the effectiveness of the therapy, due to the common occurrence of urothelial recurrences, and to check for possible complications from therapies.
What are the risks associated with ablative therapies in UTUC treatment?
a) Need for additional endoscopic surveillance
b) Risk of significant stricture formation
c) Risk of infection
d) All of the above
d) All of the above. Ablative therapies for UTUC can lead to a need for additional endoscopic surveillance, risk of significant stricture formation, and the risk of infection.
What is the importance of informing patients about the short- and long-term risks associated with diagnostic and therapeutic options for UTUC?
Informing patients about the short- and long-term risks associated with diagnostic and therapeutic options for UTUC is a crucial part of care as it enables the patient to understand the potential consequences and complications of the treatment. It allows the patients to make informed decisions about their treatment options, prepare for possible long-term surveillance and additional treatments, and manage their expectations. Additionally, this information helps patients to adhere to the treatment plan and encourages them to promptly report any side effects or complications, which contributes to better overall management of UTUC.
What are the specific risks associated with the use of chemoablative treatment with reverse thermo-hydrogel preparation of mitomycin for pyelocaliceal instillation for low-grade tumors?
The specific risks associated with the use of chemoablative treatment with reverse thermo-hydrogel preparation of mitomycin for pyelocaliceal instillation for low-grade tumors include a high risk of ureteral obstruction (over 44%), potential bone marrow suppression, and embryo-fetal toxicity. These risks necessitate specific patient counseling and careful monitoring of the patient’s condition during the treatment.
KIDNEY SPARING MANAGEMENT
GUIDELINE STATEMENT 13
Tumor ablation should be the initial management option for patients with LR favorable UTUC. (Strong Recommendation; Evidence Level: Grade B)
The 13th guideline states that tumor ablation should be the initial management option for patients with low-risk (LR) favorable Upper Tract Urothelial Carcinoma (UTUC) due to low rates of metastatic progression. Endoscopic management is recommended as the first-line treatment when feasible. Observational studies have shown comparable cancer-specific survival (CSS) and improved renal functional outcomes with endoscopic ablation compared to nephroureterectomy (NU). However, there is strong case-selection bias, and outcomes should be interpreted within this context. There have been instances where complete endoscopic ablation may not be feasible, and chemoablation can serve as an alternative. The benefits of chemoablation, however, need to be balanced against the risk of potential ureteral stricture. Whenever possible, complete endoscopic ablation is preferred over chemoablation.
Why is tumor ablation the initial management option for patients with low-risk UTUC?
a) It has lower rates of metastatic progression
b) It preserves kidney function
c) It has a lower risk of ureteral stricture
d) Both a and b
d) Both a and b. Tumor ablation is the initial management option because it is associated with lower rates of metastatic progression and helps preserve kidney function.
When is chemoablation considered in the management of UTUC?
a) When complete endoscopic ablation is not feasible
b) When tumor is at high risk
c) In all patients with UTUC
d) When tumor is low grade
a) When complete endoscopic ablation is not feasible. Chemoablation is considered when specific tumor (location and focality) and patient factors (age, comorbidities, baseline renal function, procedural risk) make complete endoscopic ablation unfeasible.
How does the effectiveness of endoscopic management compare with nephroureterectomy (NU) in treating patients with low-risk UTUC?
Observational studies have found endoscopic management to have similar cancer-specific survival (CSS) outcomes as nephroureterectomy (NU) in patients with low-risk UTUC. Additionally, endoscopic management has been shown to lead to improved renal functional outcomes compared to NU. However, these findings must be interpreted in the context of strong case-selection bias inherent in retrospective studies. Therefore, while the endoscopic approach can be advantageous, especially in terms of preserving renal function, the decision between endoscopic management and NU must be made on a case-by-case basis.
What are some potential drawbacks of using chemoablation in the management of UTUC, and when should it be considered?
The primary drawback of using chemoablation is the potential risk of ureteral stricture. However, it can be considered in situations where complete endoscopic ablation is not feasible due to specific tumor characteristics (such as location and focality) or patient factors (like age, comorbidities, baseline renal function, and procedural risk). Despite these drawbacks, chemoablation can be a beneficial treatment alternative in certain clinical scenarios. But it’s important to note that chemoablation should not be used as a substitute for complete endoscopic ablation when the latter is feasible.
GUIDELINE STATEMENT 14
Tumor ablation may be the initial management option offered to patients with LR unfavorable UTUC and select patients with HR favorable disease who have low-volume tumors or cannot undergo RNU. (Conditional Recommendation; Evidence Level: Grade C)
The 14th guideline proposes that tumor ablation may be the initial management option offered to patients with low-risk (LR) unfavorable UTUC and select patients with high-risk (HR) favorable disease with low-volume tumors or those who cannot undergo radical nephroureterectomy (RNU). There’s no high-quality evidence comparing endoscopic management versus RNU for these patients. Nonetheless, comparable cancer-specific survival and improved renal functional outcomes have been reported for endoscopic management compared to RNU. Certain considerations need to be factored, such as tumor size. Tumors less than 1.5 cm may be optimal for endoscopic ablation due to a lower risk of invasive disease. However, larger tumors (≥ 1.5 cm) could also be considered for ablation based on provider’s experience and assessment for kidney sparing surgery. For LR unfavorable disease showing progression in tumor size, focality, or grade, further endoscopic-assisted attempts are discouraged, and definitive resection via segmental ureterectomy (SU) or NU is recommended.
Tumor ablation may be considered the initial management option for which types of UTUC patients?
a) Patients with LR unfavorable UTUC
b) Select patients with HR favorable disease with low-volume tumors
c) Patients who cannot undergo RNU
d) All of the above
d) All of the above. Tumor ablation can be considered for patients with LR unfavorable UTUC, select patients with HR favorable disease with low-volume tumors, and patients who cannot undergo RNU.
When might larger tumors (≥ 1.5 cm) be considered for ablation?
a) When the tumor is at a low-risk stage
b) When the provider’s experience supports it and there is a need for kidney sparing surgery
c) When the tumor is high-grade
d) In all cases
b) When the provider’s experience supports it and there is a need for kidney sparing surgery. Larger tumors may be considered for ablation based on provider’s experience and assessment of the need for kidney sparing surgery.
What are the considerations when deciding the initial management for LR unfavorable or HR favorable UTUC?
Several factors need to be considered when deciding the initial management for LR unfavorable or HR favorable UTUC. These include the size of the tumor, the volume of the tumor, and the patient’s ability to undergo radical nephroureterectomy (RNU). Tumors less than 1.5 cm in size may be more optimal for endoscopic ablation due to a lower risk of invasive disease. However, larger tumors (greater or equal to 1.5 cm) may also be considered for ablation based on the provider’s experience and the need for kidney-sparing surgery. For patients with LR unfavorable disease showing progression in size, focality, or grade, further endoscopic attempts are discouraged, and definitive resection via segmental ureterectomy (SU) or NU is recommended.
What should be done if there is progression in tumor size, focality, or grade in patients with LR unfavorable disease?
For patients with low-risk unfavorable disease who demonstrate progression in tumor size, focality, or grade, further endoscopic-assisted attempts are discouraged. Instead, consideration should be given to definitive resection via segmental ureterectomy (SU) or radical nephroureterectomy (NU). This decision must be made based on the individual patient’s circumstances, the extent of disease progression, and the potential benefits and risks of the different surgical approaches.
GUIDELINE STATEMENT 15
Tumor ablation may be accomplished via a retrograde or antegrade percutaneous approach and repeat endoscopic evaluation should be performed within three months. (Expert Opinion)
Guideline 15 emphasizes that tumor ablation in UTUC can be accomplished via either a retrograde or antegrade percutaneous approach, and it’s crucial to repeat endoscopic evaluation within three months. Retrograde approaches, including ureteroscopy with pyeloscopy, are common, while percutaneous techniques are typically reserved for larger tumors, those difficult to access in a retrograde fashion, or in patients who have undergone prior radical cystectomy or urinary diversion. The energy source for ablation can vary, including thulium laser, holmium laser, Neodymium (Nd:YAG), electrocautery devices, or chemoablation. Using a ureteral access sheath during ureteroscopic ablation can provide advantages, such as allowing repeated scope passage and managing irrigation solutions. Because UTUC has a high chance of recurrence and residual disease after the first ablation, repeat endoscopic evaluation should take place within three months, with a 30-day window on either side of this period. Clinicians may opt for shorter intervals for more challenging cases.
When is a percutaneous approach to tumor ablation generally reserved?
a) For smaller tumors
b) For tumors that are easy to access in a retrograde fashion
c) For patients who have undergone prior radical cystectomy or urinary diversion
d) For tumors with low recurrence risk
c) For patients who have undergone prior radical cystectomy or urinary diversion. Percutaneous techniques are typically reserved for larger tumors, those difficult to access in a retrograde fashion, or in patients who have undergone prior radical cystectomy or urinary diversion.
What is one advantage of using a ureteral access sheath during ureteroscopic ablation?
a) Increases the risk of intravesical recurrence
b) Allows for repeated scope passage up and down the ureter
c) Allows for excess pelvicalyceal hydrostatic pressure from irrigation solutions
d) Reduces the need for repeat endoscopic evaluation
b) Allows for repeated scope passage up and down the ureter. The use of a ureteral access sheath allows for repeated scope passage up and down the ureter and provides a means of fluid egress from the upper tract to avoid excess pelvicalyceal hydrostatic pressure from irrigation solutions.
What are the considerations for the choice of approach and energy source for tumor ablation in UTUC?
The choice of approach for tumor ablation in UTUC depends on the size and accessibility of the tumor and the patient’s past surgical history. Retrograde approaches, including ureteroscopy with pyeloscopy, are commonly used, while percutaneous techniques are usually reserved for larger tumors, those difficult to access in a retrograde fashion, or in patients who have undergone prior radical cystectomy or urinary diversion. The choice of energy source for ablation can vary based on the availability of instrumentation and tumor characteristics. These can include the thulium laser, holmium laser, Neodymium (Nd:YAG), and electrocautery devices. Additionally, chemoablation can be employed either through retrograde ureteral catheter instillation or percutaneous access with fluoroscopic imaging guidance.
Why is it recommended to perform a repeat endoscopic evaluation within three months of initial treatment?
The recommendation to perform a repeat endoscopic evaluation within three months of the initial treatment is due to the propensity of UTUC to recur and for residual disease to remain after the first ablation. Optimal timing of follow-up endoscopic evaluation has not been definitively established, but several factors such as tumor size, visualization, access, treatment efficacy, etc., could influence this decision. A 30-day window on either side of the three-month period is justified to allow for timely identification of recurrences. Especially for more challenging cases or when incomplete treatment is a possibility, clinicians may opt for a more conservative approach with shorter interval endoscopic diagnostic and therapeutic procedures.
GUIDELINE STATEMENT 16
Following ablation of UTUC tumors and after confirming there is no perforation of the bladder or upper tract, clinicians may instill adjuvant pelvicalyceal chemotherapy (Conditional Recommendation; Evidence Level: Grade C) or intravesical chemotherapy (Expert Opinion) to decrease the risk of urothelial cancer recurrence.
Guideline 16 advocates for the instillation of adjuvant pelvicalyceal chemotherapy or intravesical chemotherapy following the ablation of UTUC tumors, provided there is no bladder or upper tract perforation. This recommendation is aimed at decreasing the risk of urothelial cancer recurrence. The principle of immediate instillation of chemotherapy after endoscopic tumor ablation for UTUC comes from extrapolation of data related to urothelial carcinoma of the lower tract. Despite limited compelling evidence, some studies show a trend towards improved urothelial recurrence-free survival with the use of chemotherapy post-ablation. Technical aspects are still not fully established, but the guideline considers three approaches to be acceptable: 1) antegrade perfusion by nephrostomy tube, 2) retrograde perfusion via ureteral catheter, and 3) bladder instillation by transurethral catheter with reflux via a double J ureteral stent. While bacillus Calmette-Guerin (BCG) is the primary topical therapy for UTUC, other agents have been described including mitomycin c, gemcitabine, docetaxel, epirubicin, adriamycin, thiotepa, and BCG with interferon.
After UTUC tumor ablation, why might clinicians instill adjuvant pelvicalyceal or intravesical chemotherapy?
a) To facilitate wound healing
b) To decrease the risk of urothelial cancer recurrence
c) To reduce the risk of post-operative infection
d) To manage post-operative pain
b) To decrease the risk of urothelial cancer recurrence. The purpose of instilling adjuvant pelvicalyceal or intravesical chemotherapy after UTUC tumor ablation is to reduce the risk of urothelial cancer recurrence.
What are the three approaches to chemotherapy instillation considered acceptable by the Panel following UTUC tumor ablation?
a) Antegrade perfusion by nephrostomy tube, retrograde perfusion via ureteral catheter, and bladder instillation by transurethral catheter with reflux via a double J ureteral stent
b) Oral chemotherapy, retrograde perfusion via ureteral catheter, and bladder instillation by transurethral catheter with reflux via a double J ureteral stent
c) Antegrade perfusion by nephrostomy tube, oral chemotherapy, and bladder instillation by transurethral catheter with reflux via a double J ureteral stent
d) Antegrade perfusion by nephrostomy tube, retrograde perfusion via ureteral catheter, and intravenous chemotherapy
a) Antegrade perfusion by nephrostomy tube, retrograde perfusion via ureteral catheter, and bladder instillation by transurethral catheter with reflux via a double J ureteral stent. These are the three approaches considered acceptable for the administration of chemotherapy following UTUC tumor ablation.
FIGURE 1: REANALYSIS OF RECURRENCE-FREE SURVIVAL FROM CHAN 2020 SYSTEMATIC REVIEW
TABLE 6: SURVEILLANCE AFTER COMPLETE TREATMENT
