Timothy N. Clinton, MD, and Stephanie A. Berg, DO, discuss gender differences in bladder cancer during Bladder Cancer Awareness Month.
Despite bladder cancer ranking among the top 10 most prevalent cancers in women, female patients are routinely diagnosed later and at more advanced stages than their male counterparts, largely because hallmark symptoms such as urinary frequency and urgency are often mistaken for urinary tract infections (UTIs), underscoring the need for more gender-specific approaches to diagnosis and treatment planning, according to Timothy N. Clinton, MD, and Stephanie A. Berg, DO.1
“This is an underrecognized topic, and I’m glad we’re shedding some light on it,” Clinton said in an interview with OncLive®. “At the
Clinton is an associate surgeon at Brigham and Women’s Hospital, as well as a surgical oncologist at Dana-Farber Cancer Institute, both in Boston, Massachusetts. Berg is a medical oncologist for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School in Boston, Massachusetts.
In a joint interview during Bladder Cancer Awareness Month, Clinton and Berg discussed what differentiates male and female patients with bladder cancer regarding presentation and diagnosis, female-specific interventions that are being developed, and future research directions in the space.
Clinton: A lot of these patients will start off in the urology sphere, and they can present with different findings. When we think about bladder cancer in general, we think of the patient who’s coming in with gross hematuria, with or without pain, [but] that’s not always the case. When it comes to gender differences in particular, although a lot of men may present with hematuria, whether it’s due to the tumor or prostate bleeding, a lot of times women are coming in without blood in the urine. This is why there tends to be a delay in diagnosis or recognition.
Presentation is really important when it comes to gender differences, because if you have a patient who has a strong smoking history but presents with irritative symptoms [such as] frequency or urgency, that may go unrecognized or be treated as a UTI. Oftentimes, this may represent bladder cancer in women. That’s the presentation we see in a lot of female patients.
Berg: As someone who trained in primary care and internal medicine, women simply get UTIs more often. They’re just more common in women. However, bladder cancer is not a common cancer in women; it’s more common in men. I agree with Dr Clinton that women will often have repetitive UTIs and experience delays, receiving more and more antibiotics without getting a urologic evaluation.
It is quite easy, in a sense, to prescribe antibiotics, and UTIs are very common. However, it’s the persistence of symptoms and also recognizing that this may be more than just a UTI, even in the absence of hematuria, that should prompt an earlier urology referral. In internal medicine and primary care, when we see blood in the urine, we tend to think infection first. It’s not quite as reflexive to send female patients to urology compared [with] male patients. I agree that women can experience more delays and, unfortunately, may present with more advanced disease. That has been shown in the literature as well.
Clinton: It’s important to note again that bladder cancer is more prevalent in men, which is part of why there may be less instinctive recognition in women [and] less of a reflex to consider bladder cancer or a bladder tumor, as opposed to a UTI or overactive bladder symptoms. Some of that is anatomy-related. Women are more susceptible to UTIs, which is why first-line providers will instinctively test and treat for that. Whereas in men, hematuria sets off red flags, because UTIs should be relatively uncommon in that population.
Beyond the anatomical differences, there are also voiding differences. Men more commonly retain urine, which means that if there are toxins associated with cigarette smoking or other environmental factors, those will tend to sit in the bladder longer. The prevailing thought is that this can induce mutational changes or cellular damage that leads to tumor development—hence why there may be a biological basis for the higher prevalence of bladder cancer in men.
Berg: Smoking is really the biggest [environmental risk factor] to emphasize, especially from a primary care standpoint, when thinking about who is high risk and when to refer. As a medical community, we are trying to raise more awareness around earlier screening. For example, sending any female patient with high-risk features to a urologist for an office cystoscopy, which is usually relatively straightforward to perform, is really important for diagnosing bladder cancer early rather than late.
Clinton: Awareness is probably the number 1 priority. Whether it’s through Bladder Cancer Advocacy Network [BCAN] or other foundations and support groups, getting the message out is critical. This increases the likelihood that primary care providers and internists will recognize the risk factors, signs, and symptoms more closely linked with bladder cancer in women.
While it may not be as prevalent in women, bladder cancer is still one of the top 10 most prevalent cancers in women, and it needs to be at the forefront of our minds when thinking about screening. Getting routine urinalysis in the primary care setting and then acting on risk factors—if you have a female patient presenting with frequency and urgency, repeatedly managed as recurrent UTIs, especially with a significant smoking history—that is the time for early intervention and urologic referral. We know that the sooner these tumors are identified, the better the outcomes.
Berg: Dr Clinton and I are both very active in the BCAN, and we’ve been involved in national guideline discussions as well. A big part of our work involves talking with primary care physicians about improved screening and awareness, particularly around the UTI misdiagnosis issue. That’s something we’ve both been vocal about, because we’re seeing later diagnoses and worse prognoses as a result. Emphasizing that point to primary care and really encouraging them to pursue the appropriate workup is something we’re all trying to do through advocacy networks and national awareness efforts, including conversations like this one.
Clinton: We’ve talked a lot about the presentation for female patients with bladder cancer, and I have to say there is often a lot of frustration and disappointment among these patients, because they feel they were repeatedly treated for recurrent UTIs. [They were] not necessarily dismissed, but they had to advocate for themselves. That’s important for patients to understand, but it’s also important for providers to ensure that timely recognition and assessment are built into the care pathway.
Depending on the stage and extent of disease, there are a lot of gender-specific considerations when it comes to treatment. For example, if someone has non–muscle-invasive bladder cancer [NMIBC] and is going to undergo intravesical therapy, I often try to minimize UTI-like symptoms during treatment, for instance by prescribing vaginal or topical estrogen to ease catheter placement and repeat cystoscopies. On the other end, if they have muscle-invasive disease and are considering radical cystectomy, there are important discussions around urinary diversion type and female organ-sparing surgery.
The other thing that comes to mind when talking about gender differences is fertility. This is largely a disease of older adults, so fertility isn’t always top of mind, but there is a subset of patients who are younger and may have fertility considerations. I believe it’s important to discuss future fertility desires with all patients. Additionally, for patients who are candidates for female organ-sparing surgery, I discuss menopause, specifically where they are in terms of perimenopausal symptoms and estrogen replacement.
Berg: I’d add that the psychological burden is real. Women can experience significant anxiety and depression in this context. Coming into the primary care office month after month with UTI symptoms, getting antibiotics each time, and not having an explanation, that accumulates. I agree that part of our job is empowering patients to advocate for themselves, while also working with primary care to lower the threshold for referral.
In primary care, we can order imaging like CT scans or MRIs before referring to urology. Frankly, the most efficient and diagnostic step is often an office cystoscopy with a urologist, especially in the setting of high-risk features. The data clearly support that recognizing this earlier, rather than continuing cycles of antibiotics, leads to better outcomes.
We typically think of bladder cancer as a diagnosis in patients in their 60s or 65 [years] and older, but we are seeing diagnoses in younger populations, patients in their 30s and 40s, and those patients may be dismissed longer because no one expects bladder cancer at age 38 or 42. We see it in testicular cancer and younger-onset prostate cancer as well, and now we’re seeing it in bladder and colon cancer, too. The environmental piece is still not fully understood, but we know something is happening beyond the traditional exposures we historically associated with bladder cancer risk.
Clinton: I’m not currently aware of a gender-specific national screening program, to my knowledge, the American College of Physicians has not established one. However, the American Urological Association [AUA] has been pushing for increased screening through urinalysis, although that hasn’t fully filtered down into primary care practice yet. The most actionable step right now is encouraging primary care providers to screen more proactively and make those urologic referrals early, especially in high-risk patients. There is a lot of work being done at the national level to bring this issue to the forefront, particularly given the trend toward younger diagnoses.
Berg: When it comes to clinical trials, I’m not aware of any trials specifically designed around gender differences at this time. However, given that bladder cancer is a relatively rare entity in women, there should be a strong push to recruit women into existing trials. This would help us understand whether there are biological differences that affect response to newer treatments, particularly the novel NMIBC therapies coming down the pipeline. The sequencing of these treatments will be very important, and if gender differences emerge, this will be a rich area for future research.
Some of the more gender-focused work that has been done to date has centered on surgical treatment, specifically cystectomy and female pelvic organ-sparing surgery, including the ovaries, fallopian tubes, uterus, and anterior vaginal wall. These decisions are driven by patient preference and tumor characteristics, but there has been a significant national push, particularly through the AUA, to spare these organs whenever appropriate, especially in younger patients with fertility concerns.
Finally, genetic testing is increasingly important. As we see more cancers diagnosed in younger patients, we should be recommending and, when appropriate, encouraging germline genetic testing and counseling. This has implications not just for the patient, but for their family members. In a rare disease entity like bladder cancer in women, especially in younger patients, we don’t want to miss an underlying genetic syndrome. There’s a lot of ongoing research in this area, and there’s a great deal more to come.
