Jennifer A. Linehan, MD

Prostate cancer breaks down into four main groups, very low grade, low grade, intermediate and high grade. Many low-grade prostate cancers do not need to be treated and patients can go on active surveillance, and it doesn’t affect overall survival or quality of life. However, for cancers that need treatment, rather than turning to the tried-and-true radiation and prostatectomy routes first, as we used to, we now look for less invasive approaches that allow patients to maintain their quality of life, and especially, their continence and erectile function.

Focal therapies, like high intensity focused ultrasound (HIFU), have become the middle ground between active surveillance and more radical therapies like surgery or radiation. HIFU is for men whose cancer is localized, meaning it has not spread beyond the walls of the prostate, and whose doctors identify as good candidates. HIFU is used to burn away (ablate) the cancer without damaging the surrounding structures that control a man’s continence and erectile function.

HIFU has fewer side effects for patients than other focal therapies using energy sources including irreversible electroporation, cryotherapy, photodynamic therapy, focal laser ablation or laser interstitial thermotherapy, radiofrequency ablation, and focal brachytherapy. 

When we do the HIFU procedure, we do not make any incisions. We can perform HIFU and retreat if needed, again with HIFU, or radiation or surgery if the cancer ever returns. Multiple studies have shown HIFU’s effectiveness over the last 10 years. Men are treated in an outpatient setting, leave the hospital, typically with a catheter, and are generally back to their lives within a week.

Selecting HIFU over other innovative focal therapies for prostate cancer

There are other focal options I have explored for treating prostate cancer, including cryotherapy and brachytherapy, but the targeting of the tumors is done through cognitive fusion, and that can be difficult. 

With HIFU I can treat the tumor inside the MRI and deliver radiofrequency ablation. Another option is cryotherapy, but this often requires the patient to actually be inside the MRI machine and that can take up to 4 hours.

TULSA or Transurethral Ultrasound Ablation is a minimally invasive procedure that uses directional ultrasound to produce very high temperatures to ablate (destroy) targeted prostate tissue, similar to HIFU. However, the procedure is performed in an MRI suite and the probe goes into the urethra (versus the anus), which requires a cooling method. As most cancers are in the peripheral prostate, it makes more sense to treat transrectally, except when tumors are at the apex, then any focal therapy may have some issues reaching the tumor. 

Focal One, the most advanced HIFU technology which fuses MRI imaging and biopsy data, gives me the precise location of the tumor and allows me to create a contour around it and easily direct the HIFU energy to ablate it. The patient is going to get better results when we target the tumor in real time. For some patients, rectal access to the prostate cancer causes less symptoms like burning and dysuria.

To be very frank, while the energy source we deliver, HIFU, cryo, microwave or RFA (radiofrequency ablation) is central to tissue destruction, the technology we use to deliver it may be even more important: to deliver precise, focused treatment exactly where you want it to go, avoiding injury to the nerves, blood vessels, urethra and rectum.  

Urologists worry about any transrectal therapies, and the small risk of creating fistula tracks or other issues in the rectal wall. But the HIFU technology allows us to see where the rectal wall is by using a sensor to divert the ultrasound energy if we come too close. HIFU allows us to treat where we want and not where we don’t. I recall talking to my surgical oncology friend who uses HIFU for liver cancer because he can literally treat tissue that is next to the vena cava – the largest vein in the body -- without injury.

HIFU’s legacy is being able to treat prostate cancer with minimal side effects

HIFU’s legacy is that now we’re able to treat prostate cancer with minimal side effects to the patient because we can specifically target the lesion and not treat any other tissue, nerves or arteries, or anything that's in the vicinity of the prostate that's going to affect the patient's overall urinary function or erectile function. This makes a significant difference in the lives of the men we treat -- and their partners—or future partners. We can’t underestimate the value of preserving their quality of life as we treat their cancer.

Jennifer Linehan, MD, is a board-certified urologist and director of Urology Translational Research and an associate professor of Urology and Urologic Oncology at the Saint John’s Cancer Institute. She also practices general urology, including both male and female voiding dysfunction and treatment for kidney stones.

Articles

"HIFU allows us to treat where we want and not where we don’t," writes Jennifer Linehan, MD.

Why favor high intensity focused ultrasound for treating localized prostate cancer?



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 

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.

 What are the most common risk factors associated with developing low-grade UTUC?

[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].

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.

 What characteristics distinguish low-grade disease from high-grade disease?

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 

 mutation. In fact, we think that 60% to 75% of patients with UTUC have the 

 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?

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.

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?

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.

How concerning is progression from low-grade UTUC to high-grade disease?

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.

 What disease characteristics do you use to classify tumors as resectable or nonresectable?

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.

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. 

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



[One of] the most common risk factors for low-grade [upper tract] urothelial carcinoma (LG UTUC) [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].

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 

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. 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.

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.

[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, these patients are 100% going to recur. The tumor can grow, and if left untreated, that can flourish into high-grade disease.

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.

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.

Videos

In the first video of the series, Jennifer A. Linehan, MD, provides an overview of LG-UTUC including risk factors, signs and symptoms, and diagnosis as well as factors to consider regarding disease progression, recurrence, and which patients might be candidates for resection.  

Jennifer A. Linehan, MD

Articles

Why favor high intensity focused ultrasound for treating localized prostate cancer?

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

EP. 1A: Key Considerations in the Diagnosis and Treatment of Upper Tract Urothelial Carcinoma