Sam Chang: Hello everyone, my name is Sam Chang. I am a urologist at Vanderbilt University in Nashville, Tennessee. And we are very fortunate to have Dr. Marco Moschini from Milan, Italy. He's a full-staff urologist there, MD, PhD. And importantly, part of the young urologist group within the EAU that's examined the impact and the disease process of Lynch syndrome and the evaluation for upper tract urothelial carcinoma for these patients. This is a process and a genetic syndrome that's become increasingly recognized. And fortunately, we've received some guidance from our cohorts and our compatriots in Europe. So Marco, thank you very much for spending some time with us and we look forward to your presentation and what your group has put together in terms of evaluation for patients with Lynch syndrome.

Marco Moschini: Thank you, Dr. Chang. It's a real honor for me to present the results of our work. So everything I'm presenting today, it's a part of this paper that we published recently in European Urology Oncology. As you correctly said, it's a part of important collaboration in the young academic urologist, the urothelial section, and also from the, I want to site also the Global Society of Rare Genitourinary Tumors the GSRGT. So just to give some small points regarding Lynch syndrome, it's autosomal dominant disorder, it has germline mutation gene, the mismatch repair, which are it's important to recognize also for us urology, which are MLH1, MSH2, MSH6, and PMS2. And then there is somatic mutation in the microsatellite regions of the DNA that cause microsatellite instability, which cause a predisposition to multiple primary malignancies. It's important to say that not every mutation has the same risk of developing urological tumors.

If we consider the Lynch syndrome, 80% of the patients which has the syndrome will develop a tumor during their lifespan. The most common tumor are colorectal cancer, endometrial cancer, and the third point come upper urinary tract tumors. There are then other tumors which are less common for these kind of patients. Then I wanted to show you what does it mean for a patient with upper urinary tract tumor and Lynch syndrome. With this patient are not the same patient at the dose that we saw normally with a sporadic urinary tract tumor, they're normally younger. So the patient with Lynch syndrome and upper urinary tract tumor has a median age at the diagnosis of 60 years old and not 70 years old of age. The male female ratio are different. So for Lynch syndrome patient, approximately the same, the incidence for male female. And also the location of the tumor are different.

For the patient with the Lynch syndrome are more commonly tumor in the ureter compare with the renal pelvis location. And also the exposure of tobacco is less important in the Lynch syndrome patient than for the sporadic tumors. Then what to do to diagnose a patient with Lynch syndrome and upper urinary tract tumor. We have to stick firstly in clinical criteria. Because we still have to remember that 80% patient with upper urinary tract tumor has a sporadic disease that has nothing to do with Lynch syndrome. But we still have 10 to 20% of patients who has Lynch syndrome and we need to recognize that. So we will see later the clinical criteria for this. For the patient who fit the clinical criteria, we have to start with molecular testing, testing the microsatellite stability using a PCR. Then only for those who has a microsatellite stability, we can go further in the analysis and to use immunohistochemistry to test the loss of MMR proteins.

And only for those, we need to require genetic testing. Only for those who has this protein missing. It's very important and also cost-effective analysis. We don't need to do a genetic testing for all our patients. Then the clinical criteria for the diagnosis. This is an overview how it changed during the years. We had several concerns and there were several proposals. And at the end you can see what is now in the European Association guidance as a result. So for the [inaudible], which are the actual criteria for suspecting a Lynch syndrome in upper urinary tract patient. So the patient needed to be younger than 65 at diagnosis and has a personal history of a Lynch syndrome-related cancer. Or he need to have a relative younger than 50 with a Lynch syndrome-related cancer, or he needs to have at least two relatives with Lynch syndrome-related cancer, regardless the age of diagnosis.

Then this is what to do practically to your patient in your clinic when you have upper urinary tract patient. So still remember that just 10 to 20% as Lynch syndrome of this patient, all the rest are sporadic. So if your patient doesn't fit the clinical criteria, you have to do nothing. So it's a sporadic upper urinary tract tumor. If your patient fit the clinical criteria, then you have to start, as said, with a PCR testing the microsatellite stability. If it's low and still you have clinical suspicions, you can require further investigation. But normally you need to have high microsatellite stability. Then you need to screen MMR proteins using immunohistochemistry.

And only for those patients with a mutation, you need to do this thing. So you have to start with germline DNA sequencing for your patient, but also then you have to consider all the other risk that he has incurring in other cancers, especially colorectal, endometrial for women, and then you need also to investigate the family of the patients. Then the screening, it's already recognized for colorectal and endometrial cancer. Their society already decided that they need a colonoscopy every 2 years for colorectal cancer screening. And also they need an annual evaluation for the risk of endometrial cancer. Regarding upper urinary tract is still not clear. We have many data outside, all of these areas have very few patients and everyone are suggesting something different regarding the optimal follow up of Lynch syndrome patients.

I don't have an answer. Here we put in our paper what the majority of this research suggesting. What we are doing in our clinic is actually every two years a cytology and sonography. And then it depends on the symptoms. If the patient is developing hematuria, of course, we're going to investigate. Then, so in conclusion, these are my suggestion considering Lynch syndrome in upper urinary tract patients. But consider also upper urinary tract patients and Lynch syndrome patients. Then optimal criteria for diagnosis and follow-up strategies still need better define and better investigated. And for the future is where we're also investigating now, is that not every mutation has the same risk of developing urinary tract tumor. So in the future would be also important to consider the type of mutation and not just the Lynch syndrome regarding the importance of a close follow-up or even the risk of diagnosis of upper urinary tract in Lynch syndrome patient. Thank you very much for your attention.

Sam Chang: Marco, thank you so much. That was a great overview of the two different groups, those with Lynch syndrome, and that you need to keep up with upper tract possibility of development and then those with upper tract and evaluating them for Lynch syndrome. So let's start off with the scenario of the Lynch syndrome patient that you're evaluating for upper tract. You mentioned that at your institution, it's a urocytology and an ultrasound every other year, every two years. In thinking about that, do you consider also, you said symptoms of gross hematuria. Are there any other things that would make you do a more frequent evaluation? For instance, if the patient is younger or if the patient has a smoking history on top, are there other things that would drive you to do things more stringently?

Marco Moschini: Yeah, that's an excellent question. So as a background, I am telling you that we started our outpatient clinic for Lynch syndrome patients in our hospital as a request from our gastroenterologists. They used to have a huge program and they started to ask us, okay, we are following the patient for the GI tumors, but we don't know what to do for urothelial tumors. So we started at the very beginning to offer them every year cytology, sonography. And then actually have to say, we never diagnose upper urinary tract tumor. Because if you look for the Lynch syndrome patient, actually their risk of developing an upper urinary tract tumor during their lifespan is not that high.

So we start and then we tended to stratify then the follow up. And then as said, there is specific mutation with an increased risk of developing upper urinary tract tumors. And of course we also selected the smoker, because the smoker has also increased risk of the sporadic ones. But we don't know actually if the Lynch syndrome plus the smoker has a synergic effect or is just another risk factors. And another risk that we saw following the patient too strictly is to lose the patient. Because at the end, the patient doesn't want to come anymore if he has to come every year to do an ultrasound, and then it's always negative. And then at the end, the patient is like, maybe it is not so useful.

Sam Chang: Yeah. Excellent points. I mean, in terms of the real world of balancing, if you have too many visits set up, they're not going to show up. Exactly right. So you want to get that spot where you're screening effectively, but not over screening. In those patients then that you say have upper tract that maybe don't meet your criteria, but for instance, just a younger patient say in their fifties, don't have first degree relatives, don't have previous Lynch syndrome. Do you, in terms of questioning for evaluation, are there things that you routinely do? Do you always do an extensive family history? Do you always refer to genetic screening? What do you do for the younger patient that don't meet your criteria?

Marco Moschini: So also for this point, we started with a very enthusiastic feeling, proposing genetic testing to everyone because we wanted to find the Lynch syndrome patient. Then the reality was that insurance and the health system was not covering for those not filling the clinical criteria. And so if the patient has to pay out of his pocket for something that you tell him, okay, but you have to be honest, you tell him, listen, we have clinical criteria. You could have, but the risk is very low, then it is difficult that a patient accept to pay. Because it never happened, actually we started at the beginning, but then the patient said, okay, no, maybe if I have hematuria or if I start to have other tumors, then I will come back and we will see together.

Sam Chang: Yeah. I think that insight, because I love the table where you had all the different kinds of follow-up protocols, but everybody has just a few patients and they make a big deal about these few patients. But what you say regarding in reality, yes, we should recognize that we should be on the lookout for it. But to me, have every single patient have a huge genetic evaluation, today makes no sense. Now maybe years down the line everybody will be getting a whole genetic panel because, but right now I agree with you totally, that we should be aware. But the idea of implementing yearly screening and this and this, I think I agree with you is not really applicable to everyday practice for sure. So if you were to say where the next exciting step would be for identifying these patients or screening these patients, where do you think the next exciting step would be? Is it cheaper testing? Is it better screening? What do you think it'll be?

Marco Moschini: Well, we discuss with the young academic urologists in the last meeting, what should be the next step. From our point of view now was to create literature regarding this topic and to collect all together the data to show actually the outcome of this patient, the incidence of this patient, and to make them recognizable. Because I think that what we really can do for the patients is to make them not famous but recognizable. Because there are also cases that we see in the clinic with really like this Lynch syndrome patient with a lot of tumors and maybe none of their relatives were investigated for the Lynch syndrome.

So you can really save lives if you spread also to urologists this information. And you can do that by collecting the data and sharing the data, because it's a rare syndrome. So if every hospital work alone, then as a urologist in your life, probably you meet it not so many times. And then it is easy not to recognize it. But if you start to share the data, to collect the data and you make literature, you publish about that, then you are going to definitely save lives of patients because they will get recognized. So I think that's the next point that we need to do. The second then will be to stratify the mutation. So to know exactly where the mutation at and how it makes the upper urinary tract more or less frequent. So that's the second point.

Sam Chang: Yeah, I think two really excellent points in terms of everybody just has a few. And you can't learn a lot from just a few and I really applaud what the young academic urologists have done within the EAU to help actually combine their literature, their patient populations, and attempt to get a better picture of what's going on. And then if we can identify the specific mutations or pattern of mutational changes to help determine what we do, how we screen, how we even treat, who may have more successful treatment, who may have a higher chance for recurrence, those points I think are incredibly important. So, Marco Moschini, thank you so much for spending some time with us. We really appreciate all of your efforts, all of the EAU efforts. And I thank you again. I look forward to the next publication and the next work that your group does.

Marco Moschini: Thank you very much. It was a real honor to be here. Thank you again.