The Evolving Treatment Landscape of Low-grade Upper Tract Urothelial Carcinoma

EP. 1B: Low-grade Upper Tract Urothelial Carcinoma: Disease Overview

In this companion article, Jennifer A. Linehan, MD, from the John Wayne Cancer Institute in Santa Monica, California, shares expert insight into factors affecting LG-UTUC diagnosis and treatment.



For patients with low-grade upper tract urothelial carcinoma (LG-UTUC), one of the most common forms of bladder cancer in the United States, recent advancements and research updates have provided additional factors for patients and providers to consider for optimizing outcomes. In this new Urology Medical Perspectives series titled The Evolving Treatment Landscape of Low-grade Upper Tract Urothelial Carcinoma, leaders in the management of bladder and urinary tract malignancies discuss key factors affecting the diagnosis and treatment of LG-UTUC. In the first interview of the series, Jennifer A. Linehan, MD, provides an overview of the disease landscape and offers expert perspective on factors affecting recurrence and progression.

Urology Times®: What are the most common risk factors associated with developing low-grade UTUC?

LINEHAN: [One of] the most common risk factors for low-grade urothelial carcinoma [is] a history of bladder cancer, either low- or high-grade. Patients [who] have known Lynch syndrome have a risk of low-grade UTUC. Patients who are smokers, have a history of smoking, or [have other] risk factors such as exposure to aniline dyes [or] aristolochic acid exposure over time [are at-risk]. Patients who may be working with certain chemicals such as chemicals you would stain wood with or paints or those types of exposures [are also at-risk].

Urology Times®:What is the incidence of low-grade UTUC?

LINEHAN: The incidence of low-grade UTUC is about 30%. So 5% to 10% of all of the urothelial carcinomas are of the upper tract, and of that 5% to 10%, 30% are low-grade. This number is increasing, and I think it's more because our imaging and our way of monitoring patients has improved. It's hard to say if that's the actual incidence or if we're just finding more low-grade epithelial UTUCs.

Urology Times®: What characteristics distinguish low-grade disease from high-grade disease?

LINEHAN: There are imaging characteristics as well as some pathologic markers that will distinguish low-grade from high-grade disease. When you're examining patients and have them undergoing imaging, you may be looking in the bladder, up in the kidney, [or] up in the ureter. Any patients [who] have very large tumors, especially tumors greater than 2 cm; patients [who] have characteristics of the tumor invading the kidney or surrounding tissues on imaging; patients [who] have lymphadenopathy and large lymph nodes—even though it's within the pelvis near the bladder—[all have] signs to me that this could be a high-grade versus a low-grade cancer. From a molecular perspective, patients [who] have higher-grade disease have a higher predisposition [to] the FGFR mutation. In fact, we think that 60% to 75% of patients with UTUC have the FGFR3 mutation.

Urology Times®: What are the typical signs and symptoms of low-grade UTUC when a patient presents to your clinic? What tests or procedures are involved in diagnosing low-grade UTUC?

LINEHAN: Most of my patients with low-grade UTUC have presented with hydronephrosis on imaging and microscopic hematuria. Occasionally, I will also see gross, painless hematuria. Some patients will just come in with flank pain, and obviously, there'll be abnormalities on imaging that will lead me into that diagnosis. Then, of course, we perform ureteroscopy and find if it's low-grade or high-grade.

In my practice in diagnosing low-grade UTUC, I usually get imaging with the CT (computed tomography) urogram. You can also do MR (magnetic resonance) urogram, which I've been doing more in the era of contrast shortage. I think the only thing you're losing there is [that] you may not be able to see some stones. Either a CT urogram or an MR urogram—I think both are equally good, depending on your institution. I do urine cytology in the clinic; [however], for upper tract disease, especially if it's low-grade, the value of finding something is probably minimal. I think urinalysis is always important. You want to see how much microscopic hematuria is there. Then, of course, [for] any patients [who] can't have contrast for whatever reason, [such as] renal function or contrast allergy, I think retrograde pyelogram is always a good test to see if there's a filling defect within the collecting system.

Urology Times®:If a patient is confirmed to have low-grade disease, what are the most concerning complications that can result if they don't receive effective and timely treatment?

LINEHAN: When I'm treating a patient with low-grade UTUC, there are a couple of concerning factors for me that I want to make the patient aware [of in order to] have a good discussion about [them]. First, I think every urologist is always worried about missing some high-grade urothelial carcinoma in the tumor as well. I think making the diagnosis is most important. I always tell my patients that they have to understand that—even when there is no high-grade disease, even with low-grade UTUC—the risk of recurrence is high. There are some studies that report up to as high as a 76% recurrence rate for low-grade UTUC. [It is important to] understand that the recurrence rate is high; that while these cancers may not be dangerous in the setting of metastasis, they can harbor higher-grade cancers that we may not have found yet; and that the work-up is probably the most important combining pathology with biopsies as well as cytology when I'm doing ureteroscopy.

The cancer [may be] undertreated, for example, if I have a tumor that's in the lower pole of the kidney, and for some reason, I just can't get the scope around the bend into the lower pole. [If] I feel like I [couldn’t] laser it completely, [or if] I feel like I wasn't able to extract the tumor with a basket and then cauterize the tumor where I'm clearly aware that I may be leaving some disease behind, tumors in these patients are 100% going to recur. The tumor can grow, and if left untreated, that can flourish into high-grade disease.

Urology Times®:How concerning is progression from low-grade UTUC to high-grade disease?

LINEHAN: Concerning recurrence as well as progression of low-grade UTUC, recurrence is clearly my biggest concern. In patients, [I] make sure that I've adequately treated the tumors that are there. I know these patients [who have tumors with] a high likelihood [of recurring], so I'm going to monitor them closely, perhaps even do ureteroscopy every 3 months to make sure I've treated the tumor if I'm not using surgery plus some adjuvant treatment. As far as progression, I base that on the size. If I see very large tumors up in the collecting system, even if my biopsies are negative, if the tumors are greater than 2 cm, [such as] 3 or 4 cm, I'm always concerned that these could be harboring some high-grade disease. While that's not exactly considered progression, I think that's always some concern. For patients [who] have smaller tumors that are sitting in the ureter or sitting in the collecting system, especially if they're under 1 cm, there's a very low risk of progression to high-grade disease.

Urology Times®: What disease characteristics do you use to classify tumors as resectable or nonresectable?

LINEHAN: When I classify tumors of the upper tract as resectable versus nonresectable, I think of that in 2 settings. I think of the patients who have low-grade disease who have larger tumors or tumors in areas of the kidney or the ureter that I can't completely resect. Then I also think of patients with high-grade disease where the tumors may be extensively outside the kidney, invading other organs and even perhaps have some lymph node involvement. In this setting, if we're talking specifically about low-grade [disease], those are tumors that are in the area of the kidney where I just may not be able to get my flexible ureteroscope, where I may not be able to laser, where I may not be sure that I've taken care of everything. [The] tumors may [also] be [too] large. [If] I go in, do ureteroscopy, start to remove the tumor [with the] laser, and all of a sudden, it's getting really bloody, [and] I can't see anymore, [then] I have to come back another day. If I come back to treat a tumor 1, 2, [or] 3 times, those are the patients [for whom] I'm really worried that I'm dealing with more unresectable disease.

Transcript has been edited for clarity.