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Rashid Sayyid: Hello everyone, and thank you for joining us today. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto. Along with Zach Klaassen, associate professor and former director at Augusta University, we'll be discussing the recently released guidelines with regard to the diagnosis and management of non-metastatic upper tract urothelial carcinoma. These guidelines were recently published, as mentioned, in the Journal of Urology in May 2023, with Dr. Jonathan Coleman as the lead author.

We'll go through these guidelines in a three-part series. In the first part, we'll go over the guidelines that discuss the background of upper tract urothelial cancer and then some information about diagnosis and evaluation. Then, we'll discuss the updated risk stratification of upper tract urothelial carcinoma as well.

In terms of background, upper tract urothelial carcinoma specifically refers to urothelial tumors originating from the inner lining of either the ureter itself, the calyces, or the renal pelvis. It accounts for approximately 5% to 10% of all urothelial carcinomas, clearly the minority of these urothelial carcinomas. As such, it's considered a rare malignancy, with approximately 7,000 Americans diagnosed annually with upper tract urothelial cancer.

There are some differences regarding the disease extent at presentation compared to urothelial carcinoma of the bladder. As opposed to urothelial carcinoma of the bladder, where about 75% present with localized disease, we see a difference here with the upper tract: only 25% present with localized disease, with 50% presenting with regionally advanced disease and 20% presenting with distant metastatic disease. It's quite a different paradigm, and patients present with more advanced disease compared to their lower urinary tract counterparts.

The peak incidence is seen in adults older than 70 years of age, and currently, it's estimated that the male-to-female ratio is about three to one. Known risk factors for upper tract urothelial carcinoma include chronic upper tract inflammation, for example, from stones or infections; smoking; and other environmental exposures. Specific to the Balkan region, you have Balkan endemic nephropathy, which is secondary to aristolochia herbal ingestion, and the often forgotten Lynch syndrome. Up to 28% of patients with known Lynch syndrome may develop upper tract cancer. It's quite common in this cohort of patients.

Just some semantics regarding how the strength of the evidence is defined. The AUA uses Grades A, B, and C to define the strength of evidence categories. Essentially, in a simplified way, Grade A refers to evidence from high-quality RCTs or exceptional observational studies. Grade B refers to RCTs with some weaknesses or moderately strong observational studies with consistent findings. Grade C refers to small observational studies of lower quality.

In terms of AUA nomenclature for strong, moderate, or conditional recommendations, a strong recommendation indicates you should definitely do this or not do this. A moderate recommendation suggests some question about the strength of the evidence. Conditional recommendations are non-directive statements when the evidence indicates no apparent net benefit or harm, or when the balance between benefit and risk burden is unclear. A lot of semantics here, but it's important to understand these in order to interpret the recommendations and guideline statements by the AUA.

Let's start with diagnosis and evaluation. The AUA recommends that for patients with suspected upper tract urothelial carcinoma, cystoscopy and cross-sectional imaging of the upper tract with contrast, including delayed images of the collecting system and ureter, should be performed. This is often a forgotten component when ordering these axial imaging scans, commonly a CT scan with a CT urogram, to fully evaluate the inner lining of the upper tract.

We obviously need cystoscopy to evaluate for the concurrent risk of urothelial carcinoma of the lower tract. When discussing CT urogram performance, a question we commonly get asked is, "What is the sensitivity and specificity? How good is this test?" It appears that the sensitivity is about 92%, so it only misses about 8% of upper tract cancers, and the specificity is 95%. It's quite specific.

Now, what about cases where a patient has chronic kidney disease? If their creatinine is quite high and their estimated GFR is low, or they have an allergy to iodine contrast, an MR urogram is a good alternative. The sensitivity is not quite as good, ranging from 63% to 74%, but it still provides us with information. So, it's a good tool to have in your back pocket if you have a patient with poor renal function or an allergy to iodine contrast.

Then in cases where both a CT and MRI cannot be performed, options include ultrasound, so you get that axial imaging, then a retrograde pyelogram where you can further define the inner lining. By combining those two techniques together, the AUA tells us that this is an acceptable alternative when CT and MR urogram cannot be performed.

With regards to statement number two, the guidelines state that clinicians should evaluate patients with suspected upper tract urothelial carcinoma with a diagnostic ureteroscopy and biopsy of any identified lesions and perform cytologic washing from the upper tract system being inspected. Let's talk about the different techniques with ureteroscopy and biopsy.

With the biopsy, it can be quite a technically challenging procedure and the yield can often be quite poor. Often, we have a tendency to try to use forceps biopsy in order to grab the tissue specimen and have that evaluated by our pathologist. When we look at forceps biopsy, the sensitivity is roughly 83%, and the specificity is quite high. Another tool that we have is brush biopsy, which is specifically helpful for cases where the tumors are flat or it's difficult to directly define a papillary tumor. The data tells us that the sensitivity is quite good: 91%.

It's hard to compare head-to-head given different methodological approaches, but it's quite good and something to keep in our back pocket when we're thinking about different approaches. The specificity is also quite good. The biopsy technique, as I mentioned, is dictated by the tumor and patient characteristics.

Another important component, in addition to trying to get the tissue specimen, is performing selective wash cytology. Then you may ask, "Why can't we just get voided cytology?" Well, selective cytology improves the cellular yield, first of all. It avoids contamination from the bladder and/or prostatic urethra when voided, so it's specific to that upper tract or collecting system. Theoretically, there's dilution from the normal contralateral renal unit. Again, all these reasons are important reasons to perform selective wash cytology.

Now, you can also perform urine FISH testing, which has higher sensitivity but lower specificity compared to voided cytology, and it may be used as an adjunct in indeterminate cases. However, as of yet, there's no strong evidence for it, and in this setting, it is not currently recommended.

When you perform the diagnostic ureteroscopy, it's very important to standardize the documentation. This is something that the AUA wanted to emphasize. So, it's very important, first, for reporting when patients transfer care and also for research purposes. It serves many different purposes and also helps organize the approach for the treating urologist.

First of all, you should document your approach, whether it's antegrade, meaning you got access from the upper collecting system down, or retrograde through the urethra, bladder, and up the upper tract. You need to mention whether bladder lesions are present or known. Then, when you look at the ureteral lesions, you first need to document "yes" or "no," and if the answer is "yes," you need to describe the appearance, the focality, the size, whether it's obstructive or not, and whether you biopsied it. Then, you should also mention cytology.

For the renal pelvis and calyces lesions, it's the same thing. You have to document whether there were any and describe them in detail if there were. You should also describe if you performed any ancillary tests like bladder cytology, upper tract washings, retrograde cystogram, etc., and then note whether the visualization was good, limited, or poor, and then add any other comments. This is a very important component that every urologist should document at the time of their diagnostic ureteroscopy.

With regards to statement number three, the guidelines mention that in patients who have concomitant lower tract tumors, meaning in the bladder or the urethra, discovered at the time of ureteroscopy, these lower tract tumors should be managed in the same setting as ureteroscopy. This is an expert opinion, obviously. There's no level-one evidence to support this, and so there's a lot of evidence that there's clonal similarity between the upper and lower tract tumors. Is this either downstream or upstream tumor implantation?

Then, performing the upper or lower tract procedure first is heavily case-dependent. There are concerns about back pressure into the upper tract from the bladder tumor, and so a ureteral access sheath may be considered in this circumstance. You may want to approach the bladder tumor first, especially if it's bleeding, to get that under control, and then address the upper tract. Or, if you're concerned that the bleeding is going to be quite bad, you place the ureteral access sheath, address the upper tract tumor, and then go back to address the bladder tumor.
You also need to consider, as I mentioned, the ability to fully resect the tumor, ensure hemostasis, and optimize visualization within the bladder. Obviously, if you're going retrograde through the ureter, make sure you keep the ureter visualizable at all times.

Now, in statement number four, the guidelines mention that in cases of existing ureteral strictures or difficult access to the upper tract, clinicians should minimize the risk of ureteral injury by using gentle dilation techniques such as temporary stenting. This is what is called pre-stenting and limits the use of aggressive dilation access techniques such as ureteral access sheaths.

A common question that we ask is, "Well, how long should I leave the stent in place?" The AUA gives us some guidance about this, and the recommended duration of pre-stenting is one to two weeks. The message here is don't force the situation and dilate aggressively, causing a ureteral injury that may lead to stricturing, especially since many of these patients will need serial follow-up. For that reason, it's better to be safe, pre-stent, bring the patients back, and do it at a later time using a safer technique.

At this point, I'm going to turn it over to Zach, who will go over the remaining statements from this guideline.

Zach Klaassen: Thanks so much, Rashid. Statement five takes us into when ureteroscopy cannot be safely performed. An attempt to do upper tract washing or barbotage or cytology may be performed when good-quality imaging such as CT or MR urography cannot be obtained. Barbotage is essentially irrigation and active aspiration, whereas washing is irrigation with passive collection. Both of these recommendations are conditional recommendations with an evidence level of grade C.

Moving on to statement six, at the time of ureteroscopy for suspected disease, clinicians should not perform ureteroscopy on a radiographically and clinically normal contralateral upper tract. This is an expert opinion and is secondary to the risk of iatrogenic injury and tumor seeding of the contralateral collecting system. In these situations, we rely on our imaging. If the other side is essentially negative, we leave that side alone and just focus on the suspected disease side.

For statement seven, patients with a suspected diagnosis of upper tract urothelial carcinoma should obtain a personal and family history to identify known hereditary risk factors, especially those associated with Lynch syndrome. Lynch syndrome is a constellation of malignancies. As you can see listed here, they include colorectal, ovarian, endometrial, gastric, biliary, small bowel, pancreatic, prostate, skin, and brain cancer. In these situations, when we have a pattern that appears to be associated with Lynch syndrome, genetic counseling should be offered, based on expert opinion from the AUA guidelines.

Looking a little further at Lynch syndrome, as this is important for our UroToday listeners to understand, it is also called hereditary non-polyposis colorectal cancer. It's an autosomal dominant mutation due to germline mutations in mismatch repair genes such as MLH2, MSH2, MSH6, PMS2, and EPCAM. It's actually relatively common, affecting one in 280 Americans. Between 5% to 20% of these patients in the US with upper tract cancer will have Lynch syndrome.

It's recommended to undergo early routine screening for the following malignancies. You can see colorectal with high penetrance between 20% and 80%, urothelial between 1% and 18%, gastric between 1% and 13%, endometrial between 15% and 16%, and ovarian between 1% and 38%. In cases where we see patients, particularly younger ones or those with a family history, we should obtain a thorough family history because one in 280 will have the potential for Lynch syndrome.

Continuing with the Lynch syndrome theme, statement eight suggests universal histological testing of upper tract urothelial carcinoma with additional studies such as immunohistochemical or microsatellite instability should be performed to identify patients who do have a high probability of Lynch-related cancers and for whom genetic counseling should be recommended for the possibility of germline testing. This is based on clinical screening criteria, which we will look at in the next slide. These include the Amsterdam II criteria and the Bethesda guidelines. These are somewhat unreliable and difficult to implement, so it's important to focus on a strong family history and taking a comprehensive history from these patients.

As you can see here, the Amsterdam II criteria relate to patients who have three relatives with Lynch syndrome-associated cancers, and the revised Bethesda guidelines are quite thorough but can be cumbersome, as you can see listed here. Most of this focuses on colorectal cancer, which has the highest penetrance for Lynch syndrome.

Continuing statement eight, tissue testing provides a more sensitive technique for the identification of MMR gene mutations and the evaluation of MSI status. This paradigm has already been established for colorectal cancer, and all newly diagnosed colorectal cancer cases undergo reflex IHC studies for MMR and MSI testing due to the high rate of Lynch syndrome in this cohort. However, the incidence of Lynch syndrome may be even higher in upper tract urothelial carcinoma patients, at roughly 5%.

The NCCN guidelines currently recommend universal MMR testing for all potential Lynch syndrome-related malignancies, and Lynch syndrome has been detected in 16% of patients with MSI-high signatures, including 38% of urothelial cancer cases. Finally, MMR and MSI testing may have important implications for future choices of systemic therapies, such as immune checkpoint inhibitors versus cisplatin-based chemotherapy.

To conclude, let's talk about risk stratification as covered in the guidelines. Statement nine suggests that at the time of identification of upper tract urothelial carcinoma, clinicians should perform a standardized assessment documenting clinically meaningful endoscopic and radiographic features to facilitate clinical staging and risk assessment.
This is important when we're doing these procedures to really pay attention to several key components. One of those is the site of involvement, whether this is in the ureter, the renal pelvis, or the calyceal site, number of tumors, and the presence of multifocality, the tumor appearance, whether it's sessile, papillary, or flat, and the size of the mass. This can be used as a reference with regards to the scope of the tip, the basket, or the laser fiber.

Statement 10, following standardized assessment, clinicians should risk-stratify patients as low or high for risk of invasive disease based on these factors we just discussed. Further stratification into favorable and unfavorable risk groups should be based on these standard identified features. This is grade B level evidence.

I think this is arguably the most important slide from this deck because it really does risk-stratify these patients. We can see on the left, based on the features, whether this be biopsy grade, cytology, radiography, the appearance of the tumor, lower tract involvement, this then stratifies patients into low and high risk. This is based on low grade and high grade.

We have favorable low risk, we have unfavorable low risk, we have favorable high risk, and we have unfavorable high risk. This really all sets up the bottom part of this table, and this is what treatment and what therapy we should be offering these patients. For low-risk favorable disease, ablative therapies are preferred and systemic therapy is not recommended. For low-risk unfavorable, ablative treatments may be offered in select patients and systemic therapy is still not recommended.

When we switch to high-risk favorable, ablative therapies are rare, and this is really for patients who are too unhealthy to undergo more aggressive therapy. We should be considering systemic therapy in the form of neoadjuvant or adjuvant therapy for these patients, and for sure, for high-risk and unfavorable, this may be patients who have very aggressive disease or significant comorbidities. Palliation is essentially just for ablative techniques and we should be offering these patients neoadjuvant or adjuvant therapy. This table really does allow us to risk-stratify patients, and ultimately decide what therapies are reasonable.

For statement 11, patients with upper tract disease should be assessed prior to surgery for risk of post-nephroureterectomy chronic kidney disease or dialysis. We know that after radical nephroureterectomy, the median decline in renal function is up to 32%, and this has important implications for timing of potential systemic cisplatin-based chemotherapy, whether in the neoadjuvant or adjuvant setting.

There are several ways we can assess kidney function, obviously with creatinine and with an eGFR. Other potential options include split function testing and nephrology consultation, and in these patients who present with obstructive hydro, a stent or percutaneous nephrostomy tube may be important and necessary to improve kidney function. We also need to assess patients for the possibility of end-stage renal disease following nephrectomy, which may require pre-op hemodialysis access. Certainly, these patients are quite comorbid, so modifying risk factors such as diabetes, hypertension, and smoking minimizes the risk of AKI as well as post-treatment CKD.

To conclude this section, upper tract urothelial carcinoma makes up 5% to 10% of urothelial carcinomas and is associated with smoking and environmental factors. When we see patients, they should undergo a workup, including cross-sectional imaging, ureteroscopy, and biopsy, and care should be taken to accurately assess and document tumor size, multifocality, and grade.

Urologists should be familiar with Lynch syndrome, as we've spent several slides today discussing its association with upper tract urothelial carcinoma, and risk stratification of these patients is vitally important, with low versus high-risk disease dictating treatment options and prognosis.

Thank you very much for your attention. We hope you enjoyed this UroToday discussion of the AUA upper tract urothelial carcinoma guidelines.