The Management of Primary Carcinoma of The Urethra - Reza Mehrazin

July 18, 2021

In a presentation, followed by an educational discussion, from Reza Mehrazin, MD, the topic of management of primary urothelial carcinoma is discussed in depth. Dr. Mehrazin began his presentation with epidemiology and risk factors for this aggressive disease. He discussed the risk factor of advanced age (>60 years old) along with other less-known risk factors, such as chronic urethral irritation. Primary urethral carcinoma gender-influenced outcomes are discussed on the basis of anatomy and physiology, and the respective differences between each gender. Dr. Mehrazin discusses how even though females are less likely to develop primary urethral carcinomas, they can still show up in very aggressive forms. While treatment, usually as upfront systemic therapy, is a large piece of the puzzle, imaging (MRI and CT scans) and early detection are keys in the management of this cancer. When asked about patient follow-up, Dr. Mehrazin discusses his more - intense form of follow-up with annual urethroscopies to monitor symptoms. In his closing statement, Dr. Mehrazin discussed the lower prevalence of this cancer but warned of its highly aggressive nature.  

Biographies:

Reza Mehrazin, MD, Associate Professor of Urology, The Mount Sinai Hospital

Ashish Kamat, MD, MBBS, Professor, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, President, International Bladder Cancer Group (IBCG), Houston, Texas


Read the Full Video Transcript

Ashish Kamat, MD, MBBS: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I am Ashish Kamat, professor of urologic oncology at MD Anderson cancer center in Houston. And today I'm welcoming professor Reza Mehrazin, who is Director of Urologic Oncology fellowship at the Icahn School of Medicine in Mount Sinai in New York. Dr. Mehrazin has done work and published on the management of primary urethral carcinoma, which is a very important topic, even though it's a relatively small number of patients that we see with this disease process. So with that, Reza, I'll hand the stage over to you and take it from here.

Reza Mehrazin, MD: 
Hi, thank you for that introduction. So we'll just dive right into it. Okay. So primary urethral carcinoma is a rare malignancy with potentially devastating consequences for patients, for both treatment and mortality. The incidence is approximately 4.3 million for males, and about 1.3 to 1.5 per million for women. The risk factors, histopathology, and treatment have gender-based differences due to anatomic and embryological distinctions between the male and female urethra. However, in both genders, advanced age is a significant risk factor. Male, a primary urethral cancer is more common in African-Americans than Caucasians and the most common risk factors are chronic urethral irritations and stricture disease, which can be found up to 50% in men who have this urethral cancer. The anatomy and histopathology: I think this slide is very important for us to understand as treatments vary, depending on where the cancer of the urethra is originating from. The male urethra can be divided into anterior and posterior, which the anterior is consists of [inaudible 00:02:05], pendulous urethra and bulbar urethra, and the posterior urethra, which consists of the membranous urethra and prostatic urethra.
The anterior urethra is lined by a stratified squamous epithelium, which transitions to stratified and pseudostratified columnar epithelium. And the posterior urethra is lined with urothelium, which accounts for the majority of cases followed by squamous and adenocarcinoma.
Female: the cancer of the urethra is very rare; however, the urethral diverticulum in, which is commonly seen in women, can predispose them to having an adenocarcinoma. The female urethra is about four cm long usually. And within the distance of two third the distal urethra is lined by non-keratinizing stratified squamous epithelium. And the proximal third of the urethra is lined by urothelium. And as I said, the disease management and treatments, basically, it really depends where the cancer originated from along the course of the urethra. Diagnosis and diagnostic workup: these patients need cystourethroscopy, they need cytology exam under anesthesia, biopsy, and definitely a good cross-sectional imaging. Typically, I would say MRI, perhaps plays a better role here than a CT scan. These are two selective cases of two of my patients. On the left, you have a male proximal urethral tumor. And on the right, you have a female with a huge high-volume tumor with urethral diverticulum extending into the bladder.
There's a TNM staging. I think the audience here are familiar with the TNM staging for GU cancer. But one thing to point out, do you have the urethra for male and female versus TNF T staging for a prostatic urethral involvement, so those two are a little bit different that you need to be familiar with. This is an important diagram. It's a management algorithm that I actually adopted from the recently updated European guidelines. On the right side, you have the management algorithm for T3 higher or nodal disease, and also metastatic disease. Typically, these patients are managed by upfront systemic therapy and depending on their response and their performance status, then you can consider proceeding with surgery or radiotherapy. On the left side, it's a little bit more involved in terms of understanding how we should tackle these patients. The distal male urethra, which is again, [inaudible 00:05:14] layers and penile urethra is often curable with aggressive local control. And because of this, you can do a penile preservation therapies.
Tumor excision with distal urethrectomy, with or without partial Glansectomy, is acceptable for localized cancer. Those who have T2 or less with N0M0, while historically we've been kind of aiming for one cm negative margins, a five-millimeter negative margin is sufficient for cancer control in these patients. Patients who refuse surgery may be treated by primary XRT and these patients will have XRT. They should have prophylactic XRT to inguinal lymph nodes regardless of the clinical staging. That's different from those who have open excision of the urethral tumor, because if they have negative inguinal lymphadenectomy, typically we don't do inguinal dissections in patients, but again, if they're going for primary XRT, they should have XRT to the inguinal region as well to have local control.
Men with posterior or prostatic urethral involvement, this should be evaluated for asynchronous urethral cancer of the bladder and upper tracts. Patients with TA, TIS, or T1 disease, they can be managed with a complete TERP, followed by induction of BCG. Those who have T2 or stromal involvement, they should have new adjunct chemo followed by radical system prostatectomy, urethrectomy also pelvic lymphadenectomy.
In females for posterior urethra, again, these typically tend to be more aggressive. So surgical therapy involves anterior exent and because of low rates of local control and survival outcome, these patients should be treated with multiple allied treatments. They need systemic therapy, either upfront or adjunctly and sometimes radiotherapy should assist with the local control. Again, it's the multimodal therapies for these patients.
Follow-up: it's a rare disease, but because of the aggressiveness, we tend to follow these patients very closely with cystourethroscopy, cytology, and cross-sectional imaging. Unfortunately, the prognosis is poor, but again, we tend to follow these patients very closely every three to six months. This is just a summary of a prognosis. You have male and female urethral survival. So in five years, survival is 48% versus 32%. For 10 year survival, you have 43% versus 29% in female. And adenocarcinoma tends to have a worse prognosis compared to urothelial or squamous carcinoma. Thank you.

Ashish Kamat, MD, MBBS: 
Thank you very much. That was a very nice, concise summary of a rather difficult problem. If I could ask you a few questions mainly to highlight management issues for the audience: when you approach your patient that has say urothelial cancer, right, bladder cancer?

Reza Mehrazin, MD: Yes.

Ashish Kamat, MD, MBBS: 
And we know that there's primary urethral, but there's also secondary involvement of the urethra. What are some of the trigger or warning signs in a patient with either current or remote history of primary bladder cancer that would make you look at the urethra more carefully?

Reza Mehrazin, MD: 
Typically if they have a bladder neck or prostatic urethral involvements, those are the ones that you want to look at closely. Also, the history: if they tell you they have stricture disease, you want to have that in the back of your mind that you're not missing anything distally, i.e. the distal urethra. And even if you do a cystectomy, I tend to watch these patients. I do urethroscopy at least once a year, just to make sure that they don't develop recurrence within the stump and at the distal urethra. Does that answer your question?

Ashish Kamat, MD, MBBS: 
Yeah, absolutely. And that raises that important question, because there have been studies and groups that strongly advocate for urothroscopy of the urethral stump, and then others that state that if you just monitor the patient for symptoms, for example, spotting of blood in the underwear, that's more than enough. What's your sense as to is one preferable over the other, or it's just a purely a practice preference between the patient and the physician?

Reza Mehrazin, MD: 
I tend to do the urethroscopy and urethral washing because every year, a year and a half, I have one of my patients who I diagnose them with urethral recurrence. I have seen it personally, not just because they were referred to me. These are the patients that I followed. So I tend to do urethroscopy once a year on patients who I think that are at a risk of recurrence. If hey had the posterior wall tumor or lateral wall, obviously those are further down on my radar, but some of these patients, I tend to look out for them.

Ashish Kamat, MD, MBBS: 
Have you found that detecting the tumor based on urethroscopy and cytology gives you a different prognosis from waiting for those that may have say blood spotting on the underwear?

Reza Mehrazin, MD: 
I can tell you, I was able to diagnose them personally. I don't know, but obviously the ultimate prognosis would be different if I waited till they had spotting, but those few that I have diagnosed myself, I treated it. I can tell that they have they've had no further issues and had no recurrence within that cavernosum or spongiosum. so we were able to control it locally.

Ashish Kamat, MD, MBBS: 
Okay, good. These are important points. Now, when it comes to the treatment of, let's say prostatic urethral carcinoma, there's varying schools of thought, and you outline it well about the role of BCG intravesical instillation versus radical cystectomy. Are there signs or little clues other than the actual TUR stage that you use to determine which patients should have cystoprostatectomy and which patients might benefit from intraluminal therapy?

Reza Mehrazin, MD: 
It's always concerning to give BCG for prostatic urethral because the contact time is not as much, but I always tell my patients, no one's really thrilled to lose the bladder. So everyone tries to find a way to give it a chance. Obviously, T2 is different. You do upfront cisplatin a new ajament if they're eligible. And then you just do a prostatectomy. T1 is always concerning. If they have a variant histology, you want to be a little bit more aggressive and proceed with cystoprostatectomy and urethrectomy. In my opinion, TI, TIS, those patients, you can certainly give it a chance with a maximal TUR and BCG. I have seen patients that they have responded well, but at the same time, I've had plenty of patients that didn't respond to TUR that we had to proceed with cystectomy.

Ashish Kamat, MD, MBBS: 
Yeah, no, it's a difficult question. And I agree with you. Doing a complete TUR is important for staging as well, because you don't want to miss, let's call it, an invasive tumor. And if you clear out the prostatic urethra, as much as you can, and then you do BCG on the penetration, and, obviously the BCG granulomas that we see in the prostate are a lot higher in those patients and hopefully the anti-tumor efficacy as well, but that's a concern.

Reza Mehrazin, MD: Yes.

Ashish Kamat, MD, MBBS: 
And thanks for raising that. Switching now to the distal urethral tumors, again, in patients on whom you could do a partial [inaudible 00:14:03] or urethrectomy, etcetera. That's obviously something that you would recommend as you mentioned, but what about the patient in whom a partial is not feasible and of course you have to do maybe a complete or total urethrectomy but don't want to really take out the bladder and there's no role at that particular point. What's your preferred way of dealing with the urethral opening, so to speak?

Reza Mehrazin, MD: 
You can consider doing a urethrectomy, close the bladder neck, and then do a catheterizable channel. You can always do that. Again, they usually tend to have their own issues, but I think you're only left with that option. If you don't want to do a cystoprostatectomy or anterior exent, then you just have to divert urine out by creating a catheterizable channel and maybe even put a suprapubic catheter. But I'm not aware of any other options here. I was very experienced with this.

Ashish Kamat, MD, MBBS: 
Well, just like you said, and that raises a difficult proposition with the patient because they are at risk of having a more proximal tumor recurrence or development. And then if you close off the channel and make it so that you can't actually have a good periodic access to the water to do surveillance, you're potentially putting them at risk there as well. So that's always a discussion that we had with the patient per se. Obviously, if the sphincter is intact, then you can take it down to the sphincter and leave the rest in place. That's an option for the patients, and some have selected that, but that's the minority of patients once you have had an honest discussion as to the biology and the risks and all that. So, thank you so much for taking the time and spending [crosstalk 00:16:05].

Reza Mehrazin, MD: 
Thank you. Of course. Thank you for your time. I appreciate it.

Ashish Kamat, MD, MBBS: We obviously could go on and chat for much longer, but in the interest of time, let me sort of give you the closing minute. And if you want to share some high-level thoughts with the audience in closing, that'd be great.

Reza Mehrazin, MD: 
Yeah, it's an aggressive disease, urethral cancer, and it's rare. Urologists will come across these in your practice. Patients who have urethral stricture disease and have a family history or to have a social history of smoking, these are the ones that you should not overlook. Cytology, if needed, has to be sent, a biopsy should be done. If a female presents with a urethral diverticulum, I suggest getting an MRI for your valid, with the scope and do a cytology. And these patients should be treated at the tertiary centers, high-volume centers, involvement of medical oncologists, the urologic oncologists, and radiation oncologists, multi-disciplinary approach to be able to maximize their survival.

Ashish Kamat, MD, MBBS: 
Great. Thank you again for taking the time, stay safe and stay well.

Reza Mehrazin, MD: 
Thank you very much.
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