Update Series (2026): Evaluating Abnormal Urine Cytology Without Clinically Demonstrable Urinary Tract Disease

The following episode is brought to you by the American Urological Association. This episode is part of a special series highlighting the A-Way Updates series volume 45. In this episode, we will be covering some of the key lesson points with Dr. Sherry Donet, one of the authors of Lesson 30, evaluating abnormal urine cytology without clinically demonstrable urinary tract disease. Now in this 45th installment, the A-Way Updates series is renowned for delivering high quality lessons to practicing urologists, fellows, and residents. All content is developed by internationally recognized experts in urology, making the A-Way Updates series the most professional and sought after self-study program available. Improve your practice and patient care by staying abreast of the latest treatments and surgical techniques in urology. For more information or to subscribe to the A-Way Updates series, please visit the A-Way University. Welcome to another episode of the A-Way University podcast. I'm Dr. Mark Gonzalgo, professor of urology and chair of the A-Way Office of Education. Today we're walking through update series Lesson 30, evaluating abnormal urine cytology without clinically demonstrable urinary tract disease. This is a stereo every urologist recognizes, you know, the cytology comes back positive, you do the workup, the guidelines call for, and everything is negative. Cestoscopy is clear, imaging is normal, and you have results that you need to explain to an often anxious patient. Joining me is the author of the lesson, Dr. Sherry Donet. Dr. Donet is an attending surgeon and professor of urology at Memorial Sloan Kettering Cancer Center in Wilk, Cornell Medical College, where she has been a leader in urologic oncology for the past 30 years. She is a 2026 recipient of an A-Way Distinguished Contribution Award for her critical contributions to improving the quality of care for patients with urologic cancers. Dr. Donet, welcome. It's really a pleasure to have you here today. Thanks a lot, Marik. I'm happy to do this and I'm really excited for people to have more access to this type of education. So let's orient our listeners. How is lesson 30 organized and how would you suggest they work through it? Well, the objectives of the lesson are to really just increase the awareness of the ideologies for a positive urine cytology when you don't have any demonstrable disease, and that would include an understanding of the causes for both false positive and false negative cytology results, gender-specific considerations requiring further diagnostic evaluation in an awareness of a non-urologic malignancies that might cause a positive urine cytology. And you know, in terms of importance, you know, obviously there's not a lot of direction that's providing the guidelines. Why was this important to include in the update series? Well, I think for the very reason that you said there's not a lot of, you know, guidance in the guidelines mostly because there's a paucity of data. But if you look at, you know, our experience in what data we do have about 17% of patients with high-grade urethelial carcinoma, we'll have a positive urine cytology at some point in time with no demonstrable disease, and the longest that we have someone with that is now 18 years. So they probably have carcinoma in cytos somewhere in the urinary tract, but you can't direct treatment until you find where it's coming from. So I think, you know, therefore, a better understanding of the possible ideologies will help physicians better direct gender-specific diagnostic workup, hopefully leading to earlier diagnosis and treatment for patients. I think it will help minimize the risk for false positives and false negative results. And it also provides some rationale for surveillance of the patients once the initial evaluation is negative, which currently the guidelines don't have much direction for that at all. You know, I think it's important to note, as we talk about cytology, you know, really making sure that the result when we get that back is actually trustworthy, right? And I think that there is a table in this lesson where it kind of goes out to explain some things that lays out recommendations on how to reduce false positives and false negative urinary cytology results, you know, what do most urologists already know here? And more usually, what do they tend to not know? Well, in my experience, I think most physicians seem to be aware of the inflammatory conditions that might cause false positives, like urinary tract infections, stones, cystitis, or a recent urinary tract manipulation. And some may even recognize that if the patient has urinary diversion, that that may also affect the urine cytology, but they seem to be less familiar with the importance of obtaining a good patient history, gender related anatomic issues that can affect the cytology, and gender related extrovescal recurrent sites, and also really processing urine cytologies. I mean, I'm surprised even at the fellows in the residents nowadays really don't have a good grasp of, you know, how they should prepare the cytology and what they should look for on the report. So in table one, in the AUA update, we try to give some common clinical causes for both false positives and false negatives, just to increase the awareness. So you can try to avoid these. We give a proper method for specimen collection and the interpretation of the quality of the report that you get back. And also, the information that you need as a physician to provide to the cytopathologist beyond just saying this is the patient has hematuria, or they have a history of bladder cancer in order to minimize the risk for getting false positives or false negative readings. Yeah, and I'd like to underline that last point you made, you know, off from the cytopathologist or reading cells without the clinical context that we have as urologists and the quality of that read really depends a lot on what you may be able to tell them, right? Things like prior introvescal therapy, prior radiation, recent instrumentation, all these factors are concernedly planned to the patient's treatment timeline and may change interpretation. Correct. And it does save you time because if you don't do that and then you get an abnormal reading back, then you have to call the cytopathologist and say, "Hey, I forgot to put on there. They've had radiation," or they had a prior cervical cancer, or, you know, different things like that. And it adds the workload to you as well. Right. So assume now that the result is real, okay, and the remainder of the standard workup is negative. Where does the lesson tell us to go next? Because I think, you know, there's a nice figure, figure four in the lesson that's really an algorithmic approach to the workup of this case of unresolved positive urine cytology. And as you've noted, in terms of gender-specific, you know, algorithm that's built separately for male and female patients. So can you tell our listeners how this was constructed and why that particular split matters? Yes. So figure four, what we did is basically use the backbone of the AUA guideline algorithm, which is very good. But then we split it into the gender differences to add other diagnostic things that need to be taken in the consideration based on the different genders. For instance, the current guidelines, you know, already recommend transurestral biopsy of the prosthetic urethrin males when the bladder and upper tracts are normal, but they give no further evaluation for females outside of the basic algorithms. And so this affects both males and females in two ways. One, in males, the recommended transurestral approach for biopsy of the prostate might risk missing a stromal invasion of the prostate that can either occur by direct extension of tumor through the floor of the bladder or the bladder neck directly into the prosthetic stroma. And that might not be visualized, you know, on cystoscopy or picked up by the transurestral biopsies. Or even it is more rare, but we have seen primary adenocarcinoma of the prostate where it's shedding cells and it contaminates the urine specimen and you get a false positive that way. You actually have adenocarcinoma of the prostate rather than urethelial cancer. And so for this reason, if the standard transurestral biopsy is the prostate or negative, you know, that the AUA recommends, then we recommend considering doing dedicated imaging of the prostate with MRI to look at any abnormal areas, especially at the base of the prostate near the bladder neck and seminal vesicles and to consider directed needle biopsies of the prostate as well. And then if all of that's negative, then you can feel more comfortable and then say, okay, I'm going to watch you for a little bit longer. For females, it's a little bit different story. I think most people think about, you know, vaginal involvement of urethelial cancer, usually in patients who have invasive disease, but there's actually quite a few reports of patients in the literature who've never had invasive bladder cancer who then get urethelial cancer involving the vagina, the cervix, the labia, clitoris, and so forth. And so I think that probably occurs by different methods. It could be by pagetoid spread, just like urethelial cancer does in the urethelial other places. And also women anatomically, the urethra can be seen. back in the vaginal vault. You've probably seen that. Some people, the urethra is right at the opening and some it could be set back a centimeter or two. And this allows for vaginal reflux of urine during voiding and urethelial cancer is a highly sedable cancer. So they don't necessarily have to have an invasive tumor to have urethelial cancer in the GYN tract. And also, I think in females, you know, the bladder neck and urethra are common sites to miss tumor, probably often because most people introduce the sister scope with the trocar in it. So you don't even visualize urethra and then it counts on you remembering to do it on the way out and to palpate the urethra. And then also the vaginal contamination of the void is cytology can occur when patients have non-urologic either GYN or recalmolignancies because women sit to void. So it sells fallout of vagina into the specimen and can cause false positive that way. So currently the AUA guidelines don't give any recommendations in women for evaluating the bladder neck or urethra with biopsies. You know, so I think, you know, a lot of times women will have red areas around the bladder neck. I think we should consider doing TOR biopsies in that case, you know, and also consider doing a cold cup biopsy of the urethra, you know, beyond this vincter because sometimes when it involves the vagina, just doing a bim annual exam may not catch it because if they just have carcinum in situ or or a papillary tumor in the vaginal vault, you may not, you may not feel it on bim annual exam. So you actually need to do something more to be able to find that. And then also to remember to refer patients to either, you know, you're gynecologist or the colorectal service to evaluate them for a primary GYN or colorectal malignancy and/or Paget's disease, which I don't think I you know, mentioned that in the AUA update, but extra mammary Paget's disease can also affect the urinary tract. And it's a great summary and very good points. And this algorithmic approach for a male and female patients is very nicely summarized and certainly can help guide us to what to do. And, you know, we know though that actual cases and situations tell us why it matters, right? This is where we see patients present in our clinic. And the lesson actually closes with four of these types of cases based on real patients. Can you briefly go through what some of these cases are designed to teach for our listeners? Yeah, so we these are all real patients as you mentioned. And so I tried to pick, you know, four patients that hit on different points. The case one emphasizes the risk factors for prosthetic urethral and stromal urethelial recurrence so that you'll know by getting the patient's urethelial history. Okay, this this patients at risk for having prosthetic or stromal invasion. And in fact, high risk non-evasive cancers in men about 39% of them will develop a prosthetic urethral or upper tract recurrence, you know, by 15 years. So it's important to know that natural history of the disease. We also review the various mechanisms of invasion of the prostate. And there's a nice illustration in there just to illustrate that for you. And I think it makes it easier to understand. There's also we go through methods for biopsy and the prosthetic urethral that are beyond doing the just the trans urethral t-war sampling to try to get a better sample. And we also look at the utility for dedicated imaging like MRI of the prostate if needed. The second case emphasizes the methods to help differentiate urinary and gynecologic sources for a positive urine cytology in women. So it reviews the recurrence patterns following patients that have, you know, women that have urethelial cancer and they've had in a vesicle therapy, you know, where to look for the positive cytology. And it also reviews methods for localizing a positive urine cytology in women. So because there is this reflex void and then you have to consider ways to determine, okay, is this coming from the vagina or is this coming from the bladder or upper tracts? The third case reviews upper tract evaluation beyond just doing a CT uregram and the utility of enhanced cystoscopy if you have it available in detecting a cold carcinoma in situ as well as looking at the utility of random bladder bobsies in the setting of a normal cystoscopy. And it also goes through risk factors for intramural tunnel recurrence, which I think a lot of people don't think about. And this is something that you can sometimes detect by knowing what the risk factors are. So you'll know maybe I should your readers go that intramural tunnel because they can have carcinoma in situ there. And that will be missed on CT uregram because it, well, you won't have hydrogen afrosis until you get a tumor big enough to cause it. So we want to be able to catch that earlier. So it goes through the risk factors. And I can addition to that cystoscopy when you're just doing your systematic cystoscopy. I always watch for the efflux from each uregram as part of the exam because I can't tell you how many times I've either had a polypoid tumor shoot out during the efflux and then go back in afterwards or I see a little trail of, you know, blood or urine and blood come out in the urine from the orifice that you might not have seen if you weren't watching. And it's not enough to cause gross hematuri that you can see but you can see it if you watch. And the last case kind of goes through how to reconcile a discordant urine cytology and pathology findings in women. So, you know, for example, if I have somebody with low grade disease and all of a sudden they have a positive urine cytology. If you understand the natural history of urethelial cancer, you know that that's a pretty rare event and that maybe you should look for other sources for the positive cytology. And it also goes through methods to try to reduce the risk of missing urethral cancer in women which as we all know is usually diagnosed late, you know, in late stage because people tend to miss the signs and/or don't do a physical exam. They just, you know, get cytologies and don't examine them. And lastly and and, you know, but not least, we go through the importance of not ignoring if the pathologist reports that there's human papaloma virus in the in the urine cytology, both in men and women. So in women, then, you know, they need to be sent for a pap smear because they may have a cervical cancer or a risk for that. And in men, you would want to see if they have a sexual partner in that partner, you know, female partner probably needs to go have a pap smear if they don't have a recent one to make sure that they don't have cervical cancer. And that's something that I don't think, you know, that we're taught very much anymore. So certainly very interesting for different types of cases, right, for different ways that the same abnormal result can be potentially challenging for us to deal with. Now before we close, I'd like you to share with our audience the bigger picture, right? And share your final thoughts with us on why should a urologist make time to read this particular lesson. Well, I think an unresolved urine cytology, both in patients with a prior diagnosis of urethelial cancer, and also in patients that you're going to evaluate for gross hematuria, or maybe they have persistent irritative voiding symptoms that, you know, are not consistent with BPH. Those cases can be diagnostically challenged. And I think it's something that most urologists are going to face at some point in their practice. So it's good for you to know and think about these things. Also, the goal of the update is to give both the urologist and physician extenders, which we're all using more and more nowadays, a practical evidence-based strategy to manage patients with unresolved urine cytology findings to also increase their awareness of the role that gender differences may play, both in the source of the urine cytology and the diagnostic tools that they might employ to adjudicate it. And then, finally, to increase awareness of the importance of getting a proper urine specimen collection, doing a thorough physical exam, and doing a thorough endoscopic exam, you know, that those play and diagnosis, because, you know, cystoscopy, you know, there's really not a standard way of teaching it, and you probably have seen people before too, where they go in and out in 30 seconds, and they're done. And, you know, colonoscopy, they've actually done studies, you know, that show that you need to spend eight or nine minutes and pull out, or you'll miss, you know, 20 percent or more of tumors. That study's never been performed with cystoscopy, and it's something that we should all keep in mind. So I, I think the main thing to do is to have a system that you go through and just do each, you know, area of the bladder and a systematic point and watch the e-flux from the ureters and so forth. You know, I think this is great. You've made really compelling arguments for a lesson that addresses a problem that most of us have encountered, and few of us may have a systematic approach, right, to management of this. Dr. Donald, thank you for joining us today. Oh, you're most welcome, and thank you for having me. You know, you've given our listeners a clear map of lesson 30, the fundamentals of psychology collection and interpretation that we talked about in Table 1 of Lesson, the expanded gender-specific algorithm that was in Figure 4, and four real cases that show exactly how the scenario behaves in clinical practice. To our listeners, this episode was really more of a guide, not a substitute. The detail is in the lesson, and I think it's worth your time, so I'd encourage you to read an update series lesson 30 in full, and to spend particular time with Table 1 and Figure 4, which are the tools you'll actually reach for the next time a positive psychology isn't resolved. For more educational content, visit AUANET.org/University. I'm Dr. Mark Gonzago, and on behalf of the AUA Office of Education, thank you for your commitment to lifelong learning and to the patients who depend on your expertise. Until next time. [Music]