Ashish Kamat:  Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, a professor of urology at MD Anderson Cancer Center. And it's a pleasure to welcome a friend, colleague, and a true expert, Dr. Curtis Pettaway. Who is also at the University of Texas and is a professor of urology here. He's been active in the urologic oncology field for many decades and has evolved his practice into the thoughtful management of rare cancers. And even though urethral carcinoma really isn't a rare cancer per se, the occurrence in the urethra is certainly rare enough that we need his expertise.

So, Curtis, I want to thank you for joining us today and our audience, and sharing with us some of your clinical pearls. The stage is yours.

Curtis Pettaway:  Great. Well, thanks, Dr. Kamat. I really appreciate that and the opportunity to talk about a rare cancer. And today I'm going to talk about urethral carcinoma, and I'm going to focus more today on surgical concepts and surgical consolidation for locally advanced urethral carcinoma.

So we'll start off with a little bit of background. So this is a rare tumor and in a large review of the SEER database from several years ago, they collected about 1,600 cases from 1973 to 2002. And the incidence in males was 4.3 per million, and in females was about 1.5 per million. So this is really rare. And when we think about penile cancer, which occurs in men, let's say with about one per hundred thousand, this malignancy is about 10 times less common than penile cancer. So it is really rare.

Unfortunately, it can be quite lethal though. The median age in males and females is about the same, 59 to 60. And as in some other cancers, there is a racial predisposition in that African-Americans tend to have a higher incidence of certain types of histology. For instance, African-American females tend to have a higher incidence of adenocarcinoma affecting the urethra, and males have a higher incidence of squamous carcinomas.

When we think about the pathogenesis of urethral carcinoma... And now again, I want to focus on primary urethral carcinoma, and I want to differentiate that from a secondary involvement from the bladder, which is very common and Dr. Kamat is very familiar, with managing, I should say.

One of the underlying pathogenic themes here is inflammation. And when you look at the associated factors for urethral carcinoma in males and females, this really is highlighted. What do you see? In males, you see men with a stricture disease often, been dilated for many years, and then the stricture becomes very difficult to dilate. They get a biopsy and the diagnosis is made. There's a history of sexually transmitted disease often in these men, with HPV infection present in 25 to 30% of males and females. History of prior trauma is common in men with urethral cancer. In females, you think about chronic inflammatory conditions, caruncles, fibrosis, diverticula, sexual activity. And that's again, probably related to the predilection for HPV infection. So inflammation is a common theme in the pathogenesis of urethral cancer.

When we look at just some anatomic features, the urethra is about 20 centimeters long in a male, and it's divided up into a posterior part and an anterior part. The posterior part contains the prostatic urethra, the membranous urethra, and the bulbous urethra. The anterior part is the pendulous urethra and the fossa navicularis and the urethral meatus. And we can see that the lining at the filium changes as you move throughout the urethra. In the prostatic portion of the urethra, you have more of a euro filium, whereas in the membranous urethra you'll see urothelium. But you also, because of the influence of the periurethral glands, when you develop a carcinoma, this is where an adenocarcinoma theoretically can develop. And in the more pendulous urethra, you have a pseudostratified columnar, and as you go more distally, you see a stratified squamous. So the types of cancers you see reflect this. You see urothelial carcinoma, you see squamous carcinoma, you see adenocarcinoma, and you can even see other rarer variants, like melanoma.

In males, the most common location is in that posterior location. And you can see varying percentages here. And a slightly smaller incidence in the more pendulous and distal urethra, but in males, that bulbo membranous presentation is very common, with a rarer presentation in the prostatic urethra.

With respect to histology, really the most common histologies depend on the series. In single-institution series, you often see squamous carcinoma predominating. But when we look at population-based series, we see more of a urothelial histology being a more common variant.

Females. When we look at the urethra, much shorter, only four centimeters, and we have the posterior two thirds, and the anterior one-third. Again, the lining epithelium tends to be somewhat different depending on where you're at. In the posterior urethra, more urothelium, in the more distal urethra, more of a squamous epithelium. And again, with respect to malignancy, you see the same thing that you see in males. Urothelial carcinoma, certainly in the posterior portion, adenocarcinomas in the area of the sphincteric complex, and the more distal you go, you tend to get more squamous carcinomas.

Now with respect to females, what you see is that you often see a more distal presentation. So that's the more common location for females or involvement of the whole urethra. Again though, the urethra is only four centimeters long, so it's not uncommon to get involvement of the whole urethra. And with respect to histologic types, again, in single-institution series, you often see squamous carcinoma, but when you look at national databases like SEER or the National Cancer Database, you see more adenocarcinomas and you see more urothelial carcinomas. And adenocarcinomas often occur in association with the diverticulum. So they are much more common in women than they are in men.

What types of symptoms do we see? So in males, again, obstructive symptoms are very common. Again, you hear that history of a guy that's having more difficulty urinating. You know, he had a stricture a while back, and it's usually dilated, and now it's becoming more difficult to dilate, and they biopsy it, and they find something.

Irritative symptoms, hematuria, or spotting on the underwear, very common. These masses in the posterior urethra can get quite large. They could fistulize and you end up with kind of a scrotal inflammatory process, so they can present as an abscess. And again, in males, again, their presentation is mostly in the posterior urethra. So very common that there is a delay in presentation.

In women, you see irritative symptoms. Very common to talk about spotting on underwear. Obstructive symptoms with a large mass or diverticulum, hematuria, a vague pelvic pain, and median time to presentation in females is four to five months. Very common to have a history of chronic urinary tract infections from an infected tumor, that kind of thing. They get multiple courses of antibiotics and it just doesn't get better. So these are the kind of presentations you see in males and females.

So evaluation, of course, you're going to examine the patient and you may see something protruding out of the urethra. And again, many times you think of benign things like urethral prolapse, or polyps or caruncles, things like that. But you have to keep urethral cancer in the back of your mind. May present as a palpable mass. In a woman, it could be a diverticulum. Could be an abscess in either one, or you might feel induration from a tumor. And there are just some slides that you can see different protrusions from the male and female genitalia.

In terms of examining the inguinal region, again, just like penile cancer, really important to do a good inguinal exam. And what we note in urethral cancer is that palpable adenopathy in urethral cancer patients is almost always associated with metastasis to an inguinal node. In penile cancer, about 50% of the time that palpable adenopathy is due to inflammation or reactive condition. While in urethral cancer, if they have palpable adenopathy, it's almost always cancer.

So other important parts of the evaluation, looking in. So you're going to, of course, examine these patients with cystoscopy, and really the best exam is done under anesthesia so there's no discomfort, you really get to examine very thoroughly. And so typically we'll do a cystourethroscopy. We want to evaluate the whole urethra from the meatus on into the bladder. And of course, make sure that there isn't a coexisting bladder tumor, and this is really a secondary manifestation of the urothelial process going on in the bladder.

And often, I will map the urethra by taking various bites along the urethra to try to localize where the process is, and where it isn't. I'll do an exam under anesthesia to determine if there's a palpable mass, which often you can feel with the patient really relaxed.

In terms of the diagnostic study, these days, MRI has really become the gold standard, because it really gives us great soft tissue detail of the pelvic structures and allows for accurate staging, and also surgical planning. Of course, if they have an invasive lesion MRI, you would get a CT scan of the abdomen and at least a chest x-ray, if not a chest CT.

This slide shows the eighth edition staging for urethral cancer. And we can see here, we have non-invasive lesions like small papillary lesions or carcinoma in situ. Then we get into the more invasive lesions that invade the subepithelial connective tissue, or the lamina propria. And then in the urethra, T2 lesion invades either the corpus spongiosum in a male or the periurethral musculature in a female. A T3 lesion invades the corpora cavernosum in a male or the anterior vagina in a female.

T4 lesions invade adjacent organs like the bladder, or the prostate, or the levator musculature. So, staging is very important and MRI plays an important role in that. We'll show you a couple of examples. So when you look at the natural history of urethral cancer, it is somewhat like penile cancer in that growth locally can be relentless. These are stage T2 to four tumors when we're talking about advanced disease. In males, they're often involving the posterior urethra, in females, involving either the proximal or whole urethra.

If we look at this MRI here, this is a T2 weighted coronal image of a male with urethral cancer. Here we see bladder, here we see prostate, here we see the UG diaphragm, and here is the posterior urethra. We see the corporal bodies have already diverged.

Now, normally in a T2 weighted image, the corpus spongiosum should light up white, like a Christmas tree. But you see this dark spot right here, this whole dark area impinging right on the GU diaphragm. And so this is invading the GU diaphragm, this is a T4 tumor in a male, and it's quite nicely delineated on MRI. So you really get an idea of the anatomic extent of the disease. So yeah, again in a male, they can invade the GU diaphragm. They can invade the levators, the rectum, the prostate. 

And then we see an MRI in a female.  So here we see this kind of enhancing mass here. It almost looks like it could be the bladder, but this is actually below the bladder. And this whole area is a large urethral tumor compressing the vagina. The rectum is down here, a little bit away from the levator musculatures and not involving the bone. This was a mobile large mass in a female. So again, these tumors can go grow quite relentlessly.

Now, what we see in terms of natural history is that about a quarter of males and females will present with regional adenopathy at the time that they're diagnosed. And the location of spread does correlate with the location of the tumor for the distal urethral, or distal pendulous urethral tumors in males and females. The inguinal nodes are the route of spread for the more proximal disease involving the bulbomembranous urethra, or the proximal urethra in males and females, involvement of the pelvic nodes is common.

Now, one of the things that I want you to remember is that in this disease, distant metastasis at presentation is not very common. So that tells you that if you can attack this tumor from an aggressive, local, regional approach, you potentially can cure the patient. If they recur though, if they recur, they often recur not only locally, but with distant disease; lung, liver, bone, lymph nodes, and brain. And so this is actually different than penile cancer, where you often get regional recurrences, but you don't get distant disease until you have an extremely large recurrence. So, distal metastases in penile cancer are much less common than they are in urethral tumors. So it's really important to focus in on the right treatment early on.

Now, a little bit of prognosis. When we look at prognostic factors, the things we think about are size, stage, location, and in some earlier series, this was shown very nicely in three series, one from Memorial, one from MD Anderson, and another one from India. We see the median survival, overall survival here with about over four years of follow-up is about 48, 50% overall. But when you look at stratifying high stage versus low stage, look at the difference between survival in high stage lesions, versus the corresponding low stage in the same series.

Same thing. When you look at proximal location versus distal location, and one of the things that I would hypothesize, and we'll talk a little bit more about this is that this location-dependent prognostic feature is likely related to our ability to control the disease locally, or the ease with which we can control the disease locally. So here are two series one from our own series here by Dr. Dinney at MD Anderson from a while ago, and then another one from Guido Dalbagni at Memorial. And what we see again, small numbers and these are all small series, but what you see is in the bulbo membranous urethra, look at the incidence of local recurrence. Over 50% in both series, whereas in the pendulous urethra in our series, it was only 8%. And up to a third in the series from Memorial. But consistently 50% or higher in the series from major cancer centers. So it is much more difficult to obtain local control in the more proximal tumors than it is in the distal tumors.

We see the same thing with respect to urethral carcinoma in females. Again, when we look at different prognostic factors, we see here anterior, posterior, or entire urethra, or low stage versus high stage, you see disease-specific survival higher in anterior tumors, higher in low stage lesions. Freedom from local recurrence, higher in anterior tumors, higher in low stage tumors. Same thing for metastasis-free survival.

And when reviewing some of the older series, and then comparing the evolution of surgical technique over time, you can see that many times you have a large posterior tumor here, and certainly, it was attacked from two compartments, but it was often attacked in a discontinuous fashion. Now, the biology of these tumors is that it's not just what you see grossly here, is that obviously, they have microscopic extensions down into the perineum, maybe into the GU diaphragm, on the undersurface of the bone. And so attacking this from a two-compartment strategy, but leaving this central portion, or not doing an unblocked resection, potentially exposes you to recurrence in this area. And this is a very common site of recurrence in the perineum, or underneath the pubic symphysis.

Later series, basically utilize an En bloc resection technique, where you basically took kind of everything and almost did kind of a GU-ectomy with an En bloc dissection. And that's shown on this slide here, where actually they've taken the bladder here. Here's the prostate, here's the pubic bone. Here's the large tumor here, and here is the penis.

And so when we look at local control rates, again, small series, but they are quite different. In this top series where they use more of a discontinuous resection technique, smaller numbers, but local recurrence rates, 60%, similar to what we were seeing before. When we looked at more En bloc dissection with, or without radiotherapy, local recurrence was very significantly decreased. And so that's something that certainly is a part of contemporary resection of posterior tumors. And we'll talk a little bit down the road about how this has evolved with the integration of multimodal therapy.

Again, we've shown you some single-center series. What about on the population level? So this is a series that was published a while back by Farhang Rabbani. And he looked at male urethral cancer and looked at a variety of prognostic factors, including the role of surgery and other therapies. In this analysis, there were 453 patients. There were more patients in this, but this was focusing on the surgery side of things. And basically, he asked the question of whether surgery itself contributes to cause-specific survival, or enhanced caused specific survival. And here you see decreasing survival with increasing stage, and you can see how those with advanced stage disease did relatively poorly over time.

And when you compared strategies, here are the groups that had any kind of surgery, versus those that had no surgery at all. And obviously, there are a lot of biases implicit in these kinds of data. But what we can say in a multivariate analysis, surgery was an independent prognostic factor for enhanced cause cancer-specific survival, and radiation was not, in and of itself.

We see the same thing in a published series from SEER with female urethral cancer. 359 patients in this series, about 250 had some form of surgery. Some of the patients had surgery combined with radiotherapy, and then there were 96 patients who had no surgery. And then this looks at the radiation cohort here. Again, we see poor survival with an advanced stage of the disease, but those who had surgery, any form of surgery, with or without radiation therapy, did better than those that had no surgery at all. So two series showing this on a population basis. And again, in a multi-variate type of analysis, as best you can, surgery was an independent risk factor for survival, and radiotherapy was not associated with survival.

Now, what about management of the nodes in urethral cancer? Should we treat it just like penile cancer? And so the group from the University of Chicago, when Gary Steinberg was there, they looked at this question. They collected a series of 725 patients over about 10 years using the National Cancer Database. They compared 536 patients who had no lymphadenectomy, to 189 patients who did have lymphadenectomy. And it was strictly defined. They took only those patients that had lymphadenectomy within six months of diagnosis, and they could not have had any neoadjuvant type of therapy. So it's truly looking at the potential effects of surgery alone.

And so the first question they ask, if you have no evidence of palpable adenopathy, what is the incidence of finding cancer in those lymph nodes? Now, we know in penile cancer, for patients that tend to be higher risk, we do prophylactic inguinal lymph node dissection all the time and we find cancer in anywhere from 30 to 70% of those patients.

Well, what did he find? He found that in patients with urethral cancer in the national database, only 9% had cancer in the specimen. This implies that if someone has urethral cancer and has no evidence of palpable, visible adenopathy, that a prophylactic lymph node dissection very well may not be indicated. They also looked at the outcome of... One other thing I meant to mention there too, as well. What about the patients that did have palpable lymph nodes? You remember, before I talked about how it almost always is a sign of cancer? Well, they showed that here. In patients presenting with palpable adenopathy, 84% of the time, they had cancer in the nodes. So not often reactive, more likely metastatic.

And so when they looked at the survival again, of those patients who underwent a lymphadenectomy, versus those who did not have a lymphadenectomy, it again, after adjusting for a variety of factors, was an independent prognostic factor for overall survival. So again, with some data, we can say that lymph node management addressing the lymph nodes, especially in someone with palpable adenopathy, is an important thing in urethral cancer.

Now, urethral cancer clearly has evolved. And we knew that with monotherapy, with chemotherapy, with radiation, with surgery alone, in the longterm with advanced cancer, we weren't curing a lot of patients. So began to look and began to see some series where they began to integrate in multimodal strategies. And here's a very nice series from the group in Boston, where they integrated in chemoradiation in an effort to preserve genitals, reserving surgery only for those patients who perhaps relapsed, or failed. And this is truly a series of advanced patients. Most of them were T3, T4. Many were N2, squamous histology was a prominent feature in this study.

And when we look at the long-term follow-up from this study with a median follow-up of about three years, complete clinical response was high with 79%. Unfortunately, so was disease recurrence. And so most of these patients had to be salvaged with subsequent surgery. So even in a situation with induction chemoradiation, we saw that surgery was still required. And with surgical salvage in that setting, the five-year disease-specific survival was actually pretty good, it's 68%.

Now of the long-term survival, as you'll see down here, half of them required some form of urethral reconstruction. And so with respect to an induction chemoradiation approach, they can respond. But in essence, you almost should look at it as almost as a neoadjuvant type of strategy, where surgery is going to be needed down the road in most of these patients.

What about induction chemotherapy? This is a series that was published from our center about seven years ago and basically looked at the characteristics and survival of patients with advanced urethral cancer who were referred for chemotherapy.

So what did we see? Variety of different histology, squamous carcinoma, adenocarcinoma, urothelial. Advanced patients, a significant number were N positive or M positive. Primary tumors were large, T3 or T4. And chemotherapy was directed towards histology where urothelial patients often got like dose-dense MVAC. Squamous carcinoma often got paclitaxel, ifosfamide, cisplatin, the TIP regimen, or cisplatin, gemcitabine, ifosfamide. And then the adenos got something like 5-fluorouracil, leucovorin platinum. So generally everybody received, saw some form of platinum.

So what did we see here? Well, the complete impartial response rate was over 70% in this series of patients that were referred for chemotherapy. And fortunately, what we saw is that no patient actually, I mean, a very low likelihood of progressing on therapy. So chemotherapy was able to be given safely and many of the patients responded.

20 patients had no distant metastasis. And so induction chemotherapy with then planned surgical strategies could be evaluated in 20 of the patients. The median survival of this group was about 26 months, with 50% alive at 42 months, or half. And look at the local recurrence rate, only 15%. Again, I showed you a number of series where the local recurrence rate in these advanced patients was easily 50%. Local recurrence here, only 15%, so that was certainly encouraging. And four out of the nine patients with lymph node metastasis were free of disease at greater than three years. So this was very encouraging for us.

Looking at an international registry. And so this is really nice in that there's an international registry of urethral cancers that have been collected by Dr. Gakis, and they've published several papers. This paper basically dealt with their experience of advanced disease and peri-operative therapy. And they looked at neoadjuvant chemotherapy as an induction strategy, or chemoradiation, or initial surgery with, or without, adjuvant therapy.

And again, numbers are really small here, but what they saw again, in selected patients, patients undergoing neoadjuvant therapy and then surgery, neoadjuvant chemotherapy, and surgery; excellent survival of three years. Similarly, with neoadjuvant chemoradiotherapy, excellent survival. Patients with surgery alone didn't do as well. And then surgery with adjuvant therapy did relatively poorly. And when they looked at predictors of survival, receipt of neoadjuvant therapy, again became the predictor associated with survival. So again, these types of data suggest that a neoadjuvant approach in advanced disease potentially is a good way to go.

With respect to surgical concepts nowadays, again, with patients receiving induction chemotherapy or chemoradiation, we're seeing a therapeutic effect in the primary tumor, which allows us again to save the bladder, allows us to not have to resect the pubic symphysis. We still pay attention to En-bloc strategy. Here, you see an En-bloc prostatectomy, urethrectomy with En-bloc excision of a portion of the GU diaphragm here.

And then from that standpoint of view, with these types of responses, we're often able to dissect the specimen off the corpora and especially posterior, where they already are diverging. And so we can often save the penis with a good response. And so we see a patient here who's maintained his penis. He underwent closure of the bladder neck with an appendicovesicostomy. He catheterizes through here. And then now he's even undergone a penile prosthesis, so he is sexually active. So we are seeing some very gratifying results with respect to this approach, and also some impact on the quality of life as well, which we need to actually measure.

So, in conclusion, this is a rare cancer. And what I would say is that these patients need to be managed in a multi-disciplinary fashion. We need many tools because local regional control is paramount. If we win the battle there, the patient has the potential to have long-term survival. But if we don't, and they recur, distant metastasis is common at that recurrence presentation.

So En bloc surgical resection with negative margins is the principle we want to achieve. It can be facilitated by chemotherapy or chemoradiation as an induction strategy. It's associated with the highest rates of local control and survival. With respect to the inguinal lymph nodes, they certainly should be addressed in somebody with clinically or radiographically involved nodes. And when you look at the NCCN, and I would even say the EAU guidelines that were recently published, they certainly reflect these data that I've shown you today.

So thank you, Dr. Kamat, and the UroToday team, for allowing me to present this topic of surgical consolidation and concepts in this advanced rare urethral carcinoma. Thank you.

Ashish Kamat:  Thank you, Dr. Pettaway. Curtis, I have to say, every time I listen to you I learn a lot, and today was no exception. I mean, your encyclopedic knowledge of this rare cancer is very impressive. And honestly, you covered all the points and the discussion points that I was going to ask you about, and I'm scratching my head to try and figure out what to ask you at this point.

Now, I really think our audience is really, really going to learn a lot from your lecture. And fortunately, the format that we have, they can go back and look at the slides.

Curtis Pettaway:  Oh, good.

Ashish Kamat:  But at the high level, if you're looking at the person out in the community that sees these patients, clearly, as you mentioned earlier, these patients should be ideally referred to a center of excellence where they have multimodal therapy. You know, again, MD Anderson is one of those, but any large cancer center. However, if there's an access issue for the patient, which we see nowadays with COVID-19, of course, but even otherwise, in your mind, what is the primary treatment modality? In other words, if the patient and their treating physician have to choose one, two, three, stepwise, what would be your high-level pearls for that physician?

Curtis Pettaway: Yeah, well, I think that many physicians have access to radiotherapy and have access to chemotherapy. And I think that these surgical procedures are very challenging. And so from that standpoint of view, regimens are published, they're rare. But I think just presenting it, and talking to your region oncologist and your medical oncologist about this tumor, and the potential to downsize the tumor with either chemotherapy or chemoradiation as an initial strategy. So that you get to see a little bit about the biology of the tumor. If the patient is receiving chemotherapy or chemoradiation, and you see the tumor is shrinking, and that takes a little bit of time for that to occur, you can be planning for surgical resection, if it is not feasible for a referral.

If there is an avenue for referral, then certainly, by all means, refer them because obviously, the surgical volume is important too, in this cancer, as it is in all cancers.

So I think that in low stage disease, by all means, surgery first is a very reasonable strategy, but for advanced-stage disease, I really think we should be thinking about induction therapy for downsizing the disease and facilitating the achievement of negative surgical margins and lower local recurrence rates.

Ashish Kamat:  Those are great points. And as you mentioned, I do want to highlight that there is no dress rehearsal with this cancer, as with many other cancers.

Curtis Pettaway:  Right.

Ashish Kamat:  The first attempt at local-regional control, as you've put there, is paramount, and it's not something to be taken lightly.

So, Curtis, again, I want to thank you for taking time off from a busy schedule and spending time with us and our audience. I mean, this is really invaluable for our listeners that are trying to get as much knowledge as they can without attending the large meetings that we normally have in person. We truly appreciate this. Stay safe and stay well.

Curtis Pettaway:  Thank you. I really appreciate it. And thank you all very much.