Bladder cancer is one of the most commonly diagnosed forms of cancer in the U.S. About 1 in 40 Americans born today will develop this cancer at some point in their lifetime, and a majority of these people will be males over the age of 60. Bladder cancer is the fourth most common cancer in American men, representing more than 6% of all cancers in males.
But while men are three to four times more likely than women to develop bladder cancer, the disease tends to be deadlier in females. Women are also more likely to be diagnosed with larger bladder tumors. Why? These are questions that medical researchers have puzzled over for years, but answers remain elusive. “We know that women are more likely than men to be diagnosed with advanced disease, but whether their cancer is biologically more active, or missed for a longer period of time, we don’t know,” says Dr. Janet Kukreja, an associate professor and bladder cancer specialist at the University of Colorado Cancer Center. These sex discrepancies are particularly striking because, for many other cancers—such as cancers of the head, neck, esophagus, stomach, liver, and pancreas—women tend to fare better than men.
Unanswered questions also haunt the research on bladder cancer in younger people. Here again, bladder cancers tend to show up more frequently in males than in females. And again, women tend to experience more aggressive and developed tumors than men. However, some of the most common risk factors for bladder cancer in older adults—a history of smoking, and also past exposure to dyes or pesticides—don’t seem to be factors when younger people develop bladder cancer. “It’s more common for younger patients not to have a history of smoking or other obvious [risk] exposures,” Kukreja says. “We often have no idea why they get it.”
Figuring out the causes of these age and sex disparities is an important area of bladder-cancer research. Finding answers could lead to improved treatments and outcomes.
Why women with bladder cancer fare worse
Some cancers—such as pancreatic cancer—can be difficult to detect because they cause few if any noticeable health effects. That’s seldom the case for bladder cancers, which often cause hard-to-miss symptoms. “Typically, patients see blood in their urine and that leads them to come in for evaluation,” says Dr. Yair Lotan, a urologist at the University of Texas Southwestern Medical Center in Dallas.
According to a 2014 study in the journal Cancer, hematuria (blood in urine) is the most common initial symptom of bladder cancer. That study found that in up to 35% of people who have blood in their urine—enough to turn their urine pink, red, or cola colored—cancer turns out to be the cause. Despite the strong association between bloody urine and bladder cancer, women who have blood in their urine may be less likely than men to be referred to an appropriate specialist. “If a man reports blood in his urine, he’s almost always going to be sent to a urologist,” Lotan says. “Women are more likely to be treated with antibiotics for a urinary tract infection.” Some analyses have found that women with bladder cancer who report blood in their urine are more than two times as likely as men to be initially misdiagnosed with a urinary tract infection. This happens in part because UTIs are more common in women than in men, and bloody urine is a primary symptom of a UTI. But it can be a costly mistake. “Bladder cancer is an aggressive disease, so any delay makes a difference,” Kukreja says. Even a month-long delay could have a significant impact on treatment and survival, she adds.
UTI misdiagnoses may partly explain why women with bladder cancer tend to experience worse outcomes than men. But they’re not the whole story. Research has found that after first noticing blood in their urine, women with bladder cancer go an average of 85 days before receiving a proper diagnosis. For men, the average wait is 74 days. Statistically speaking, that difference is significant. But it’s not large enough to fully explain the sex disparities in disease outcomes. Biology also seems to play a part. “There’s been some work on hormonal factors,” Lotan says. Specifically, some work has found that estrogen receptors in the lining of the bladder might play a role in the formation of cancer cells. Researchers have also found that male sex hormones (androgens) also seem to affect the development of bladder cancer cells. It’s possible that these sex-dependent biological characteristics change the activity of bladder cancers in ways that help account for the different incidence rates and outcomes.
There may also be some sex-related differences in the cancer itself. “When we talk about cancer, we usually describe it by its primary location,” says Dr. Nicholas Cost, a urologist and co-director of the surgical oncology program at the Children’s Hospital of Colorado. “While that’s one way to describe it, usually there are a number of different cancer types even within a single organ.” Put another way, bladder cancer is not one disease. Like other forms of cancer, it can come in many different subtypes—subtypes that may respond differently to treatment and that may be associated with better or worse outcomes. It may be that the subtypes of bladder cancer that develop in women are different from those that develop in men, and this may explain why women with the disease tend to fare worse. However, the research to date hasn’t been able to identify consistent sex-based differences in cancer mutations or other underlying characteristics that explain the difference in outcomes.
A final noteworthy difference between men and women has to do with the risk factors for bladder cancer. Even when researchers have controlled for environmental exposures, such as tobacco use, they’ve found that the sex-based differences in incidence persist. “Even women who smoke for 30 years still have one-quarter the risk of men, and we haven’t been able to narrow down why,” Lotan says.
It’s clear that men and women experience bladder cancer differently. Experts are still nailing down why this happens.
Read More: The Latest Breakthroughs That Could Help Bladder Cancer Patients
Bladder cancer in younger adults
Bladder cancer is very rare in people age 20 or younger. Far less than 1% of bladder cancer patients fall into this age group, and the prognosis for these pediatric patients tends to be better than for adults.
“What we’ve found is that a majority of tumors are low-grade indolent tumors,” says Dr. Jonathan Epstein, a professor of pathology, oncology, and urology at the Johns Hopkins University School of Medicine. These are the lowest-risk category of bladder cancers, he explains, and young people with these tumors rarely die as a result of the disease. In many cases, the tumor is surgically removed and no other treatment (such as chemotherapy) is needed.
Epstein says it’s unclear why kids develop these cancers. He and his colleagues have looked for links to a parent’s smoking history or occupational exposures, as well as inherited genetic factors, but they haven’t found any associations. “It’s basically just bad luck,” he says.
To a lesser extent, some of these same patterns show up in younger adults—those under the age of 50—who develop bladder cancer. For example, some work suggests that these cancers are more indolent, meaning slow to spread, than bladder cancers in older adults. There’s also some evidence that survival rates are better in this age group than in older patients. However, a lot of the research in this area has turned up conflicting results. “Tumors in younger patients may be less aggressive, but it’s very hard to know because the incidence rate in this age group is so low,” says Lotan. He says there are other, non-cancer factors that could better explain any apparent discrepancies between younger and older bladder-cancer patients.
For starters, it’s possible that younger, healthier adults are diagnosed at earlier stages than older adults, which could lead to better outcomes. Younger patients may also receive different treatments than older adults who are dealing with other health issues, and this could lead to improved survival figures. “If a patient is 85 and their life expectancy is in the range of one to five years, we may treat them less aggressively than we would a patient in their 40s or 50s,” Lotan says. And so, at this point, it’s hard to say if bladder cancers in younger adults are truly milder.
It’s also been difficult for researchers to establish strong ties between bladder cancer and smoking or other environmental risk factors in adults under 50. “With an older patient who smoked for 30 years, it’s a lot easier to find these associations,” Lotan says. “With younger patients, we’re often puzzled why they get it.”
Read More: What It’s Like to Participate in a Clinical Trial for Bladder Cancer
Catching bladder cancer sooner
Cancer screening is seldom straightforward. The benefits of catching a cancer early must be carefully assessed and weighed against the costs—in dollars, in time, in resources—of performing thousands of potentially unnecessary screening exams. While there’s some evidence that screening people with known risk factors for bladder cancer could be beneficial, this is not currently standard practice. That means it’s important for people not to ignore the symptoms of bladder cancer—symptoms that may be missed or misinterpreted in women, younger adults, and those who are statistically less likely to develop the disease.
“Early detection is really important,” Kukreja says. The job of identifying bladder cancer lies primarily with a person’s physician or care team, she says, but there are things people can do to ensure their cancer is spotted as soon as possible.
For starters, don’t ignore signs of blood in your urine. “Blood in urine is never normal, so you need to see a physician,” she says. While a handful of things—urinary tract infections, kidney stones, even intense exercise—can lead to bloody urine, no one should put off seeing a doctor if they develop this symptom. “It always warrants attention,” she adds. Other bladder cancer red flags include pain or burning during urination, peeing more than usual, or having trouble peeing. Again, all of these symptoms are more likely to be caused by a UTI or some non-cancer issue, but that doesn’t mean you should ignore them. “Until you see a provider, you can’t tease out what’s going on,” she says.
While these are helpful safeguards, it’s worth repeating that bladder cancer is less common in women than in men, and it’s rarer still in young people and adults under the age of 50. Experts
are working to learn more about how this cancer behaves in these atypical groups. But plenty of unanswered questions remain.
More Must-Reads From TIME