Upper tract transitional cell carcinoma: Diagnostic and therapeutic considerations

Around the Practice is a monthly urologic virtual tumor board featuring live case review from multidisciplinary experts, presented by Urology Times® in partnership with LUGPA. On January 20, 2021, a panel convened to discuss cases involving an incidentally discovered renal mass as well as upper tract transitional cell carcinoma. What follows is an edited portion of the panel’s conversation regarding the upper tract transitional cell carcinoma case.

The panelists included moderator Raoul S. Concepcion, MD, FACS; Jason M. Hafron, MD; Joelle Hamilton, MD; and Jeremy D. Handel, MD.

Raoul S. Concepcion, MD, FACS

CONCEPCION: In this case, the patient is a 64-year-old White male who presents with a 3-day history of asymptomatic gross hematuria, no voiding complaints, and no history of stones. He was a 2-pack/day smoker for 25 years, and his medical history is otherwise noncontributory. He has a history of colorectal cancer with both his younger brother and father.

The exams are unremarkable. Cytology is nondiagnostic. Office cystoscopy is negative for any type of bladder lesions. The provider conducted an upper tract work-up per guidelines. CT imaging showed a big filling defect in the left renal pelvis. Dr Hamilton, is there a role for genetic testing in this patient?

HAMILTON: Yes, there is. The first thing that comes to mind is Lynch syndrome. Lynch syndrome occurs when there is a germline mutation in mismatch repair genes, resulting in loss of mismatch repair proteins MLH1, MSH2, MSH6, or PMS2, which can be detected by immunochemistry [IHC]. An abnormal test of any of these 4 proteins on IHC suggests possible Lynch syndrome.

Joelle Hamilton, MD

Up to 15% to 20% of patients with Lynch syndrome will develop an upper tract urothelial cancer. The urologist can refer a patient to a genetic counselor or a medical oncologist to discuss germline testing if the immunohistochemistry stains suggest presence of Lynch syndrome or if the family history suggests Lynch syndrome. Genomic sequencing of the tumor can be done to assess for the presence of [microsatellite instability–high], but the IHC stains are a more cost-efficient and accessible test.

Regarding the patient’s family history, he likely fulfills the Amsterdam Criteria detailed in the National Comprehensive Cancer Network guidelines (brother and father with colon cancer). If the patient’s brother received a diagnosis of colon cancer prior to age 50, the patient would fulfill the Amsterdam Criteria for further evaluation of Lynch syndrome, which will frequently be covered by the patient’s insurance.

The most cost-effective and available form of testing is IHC of the original pathology. When Lynch syndrome is suspected by the family history as per the Amsterdam Criteria, genetic counseling can be done regarding germline testing. A third and less cost-efficient way is genomic sequencing.

CONCEPCION: Dr Hafron, from a diagnostic approach and a therapeutic approach, please walk us through how you would manage this patient.

Jason M. Hafron, MD

HAFRON: My first step would be to do a ureteroscopy and take a biopsy of the lesion. You need to get tissue. Radiographic images are no longer adequate for any surgical resection. I typically biopsy with a basket. Tissue is king, and with a forceps biopsy, you really don’t get good tissue. I will also do a selective cytology. I think that’s critical, as well, to further stage the disease. And then I think the issue of pathology becomes very important. It’s a new way to look at these lesions because with the advent of newer chemoablative agents, specifically Jelmyto [mitomycin-containing reverse thermal gel], there is potential now for nephron-sparing approaches for treating these lesions.

Historically, we would only consider nephron-sparing procedures for patients with bilateral disease, solitary kidneys, or acute or chronic renal insufficiency. But now, we’re starting to see that there is an option for nephron-sparing surgery patients with low-grade disease. Low-grade disease typically represents about 30% of patients who present with upper tract masses. The tissue is very important, and the grade of the tissue is very important.

The grade of the tissue in upper tract correlates much better with invasive disease. High-grade in upper tract is considered invasive and I personally consider it to be systemic disease. That’s different from bladder, because we know we can get high-grade lesions in the bladder that are noninvasive. High-grade disease is a different disease. If you find a patient with low-grade disease and their tumor is less than 2 cm and they have low-grade selective cytology, you really should consider nephron-sparing approaches.

I think there’s a major educational deficit in urology. Not all tumors in the upper tract require a nephroureterectomy; 30% of these patients potentially qualify for nephron-sparing treatment. The critical aspects are the evaluation and the work-up. You really have to make sure that they’re truly low-grade disease.

CONCEPCION: For this particular case, access should be relatively straightforward, but oftentimes, because we’re generally using flexible ureteroscopy, there can be access problems, whether it be because of a body habitus, torturous ureter, ureteral stricture. What if this was a filling defect, say in a minor calyx, where you cannot get deflection of the scope with your biopsy forceps? Dr Handel, what is the role of percutaneous access to get tissue?

Jeremy D. Handel, MD

HANDEL:I’ve never heard of this being done specifically. But if there was a unique situation with extenuating circumstances, and no other option was available, I could conceive of a way to do this. To be clear, this would be beyond the normal scope of practice. I can think of 1 case where I actually did get access for a ureteral mass, and then I ended up doing a biopsy.

When we look at percutaneous nephrostomy access, one of the ways we assess cases is dilated versus nondilated. When we’re doing a nephrostomy access for something that has a nondilated collecting system, like a surgical injury or some type of leak or fistulous communication. It is far easier to access in obstruction, where they have a dilated calyceal system.

When we’re trying to get nephrostomy access into a decompressed system, it’s like trying to slide a needle between 2 pieces of paper deep into the belly. That can be pretty challenging. We have several ways to approach that. One is what we call tandem technique, where we intentionally stick a 21-gauge needle centrally knowing full well it won’t be our definitive access. We use it to distend the collecting system. That allows us to visualize and then stick a safe place that we can upsize to a more definitive access.

Another option is to give Lasix and contrast intravenously. There’s a sort of cocktail that is used to provide visualization of the collecting system for access, to give you transient opacification, or just [intravenous] contrast to opacify it.

Once you get access in the collecting system, you would have to maneuver toward the lesion under fluoroscopy. This is the kind of case that involves discussion with the urologist, and maybe even having both the urologist and radiologist in the room at the same time, with retrograde access, to make sure the right spot is being biopsied.

In this particular case, it’s a nice-sized calyceal system. Obtaining access wouldn’t be a problem. But if it’s not dilated, that could be tricky; just simply getting access can be a very tricky procedure.

CONCEPCION:Dr Hafron, let’s say pathology comes back with low-grade disease. What are the current therapies that are approved for the management of low-grade upper tract urothelial cancer?

HAFRON: Currently, Jelmyto is the only approved therapy. One of the biggest publications that came out of 2020 was the OLYMPUS trial (NCT02793128) that led to fast-tracked FDA approval of Jelmyto.

This is a chemoablative drug that is instilled as a liquid, but is heated by body temperature to a gel form, delivering about 6 hours of mitomycin in that area. The OLYMPUS trial evaluated Jelmyto in patients with tumor size of 15 mm or smaller. Impressively, 59% of patients had a complete response.

I’ve had a handful of patients that we’ve treated with Jelmyto, and I think it’s going to really improve our care and save a lot of kidneys so that we don’t always have to go to radical nephroureterectomy. We potentially can decrease our recurrence rates with this and potentially minimize progression to invasive disease.

In addition, Steba Biotech is conducting a phase 3 trial of padeliporfin (TOOKAD VTP) evaluating that agent for low-grade upper tract urothelial cancer (NCT04620239). The science behind this is fascinating. Basically, the agent is based on algae and is a systemic infusion. After infusion, once the target tissue is exposed to light, this will cause necrosis of the lesion.

What’s critical when using Jelmyto is that these patients still have to be monitored; they still have to have regular ureteroscopy and imaging. Additionally, there was a 44% urethral stenosis rate reported in the OLYMPUS trial. Dr Surena Matin, who presented long-term data from the OLYMPUS trial at the 2020 Society of Urologic Oncology annual meeting, said that he’s transitioning to placing nephrostomy tubes for instilling Jelmyto, hoping that that will decrease the ureteral stenosis rate. I think we’re probably going to transition to using nephrostomy tubes to instill it was well.

CONCEPCION: Dr Hamilton, what if the pathology comes back as high grade? What is the role of either adjuvant or neoadjuvant therapy?

HAMILTON: I do always like to have sufficient tissue on pathology so that I can have a detailed discussion and shared decision-making with the patient as to whether cisplatin is of benefit to them. What we do know from a meta-analysis is that adjuvant cisplatin increases cancer-specific, disease-free, and overall survival.¹ There is also a clinical trial evaluating neoadjuvant gemcitabine-cisplatin versus
gemcitabine-carboplatin; however, it recruited very poorly, and the data for that trial are not out yet (NCT02412670).

But when you pool all the data together, there is benefit in overall survival and cancer-specific survival. It is difficult to get patients through, but I have treated patients in the neoadjuvant setting.

Concepcion is director of the Comprehensive Prostate Center and clinical associate professor of urology at Vanderbilt University School of Medicine, Nashville, Tennessee.

Hafron is a partner at the Michigan Institute of Urology, PC; an associate professor of urology at the William Beaumont School of Medicine, Oakland University; and the director of robotic surgery at Beaumont Hospital Royal Oak
in Michigan.

Hamilton is an oncologist with Urology Clinics of Alabama in Homewood.

Handel is a vascular and interventional radiologist at Beaumont Hospital Royal Oak.

Reference

1. Leow JJ, Chong YL, Change SL, et al. Neoadjuvant and adjuvant chemotherapy for upper tract urothelial carcinoma: a 2020 systematic review and meta-analysis, and future perspectives on systemic therapy. Eur Urol. 2020;S0302-2838(20)30532-7. doi: 10.1016/j.eururo.2020.07.003