Bladder cancer: Men at risk

Genitourinary malignancies are a worry for men. In adolescents and young adults, testicular cancer is the main concern. One of the unappreciated benefits of growing older is that cancer of the testicles becomes rare — but as men outgrow that risk, they face the problem of prostate cancer. With these well-publicized diseases to head their worry list, it's easy for men to overlook bladder cancer — but that would be a mistake. In fact, about 53,000 American men will be diagnosed with the disease this year alone, and over 10,000 will die from it.

Bladder cancer is the fourth most common internal malignancy in American men; it is also one of the 10 deadliest cancers, and it saps our strapped economy of almost $3 billion a year. But there's good news, too. Early diagnosis can nip the disease in the bud, and new treatments are improving the outlook for patients with advanced disease. And when it comes to good news, you'll also be glad to know that you can take simple steps to reduce your risk of getting bladder cancer.

Who gets bladder cancer?

Men, mostly. The disease is almost three times more common in men than in women. Caucasian men have double the risk of African Americans. Age is another major risk factor; the disease is uncommon before age 60, but its prevalence increases steadily as the years pile on.

Causes

All cancers are caused by varying combinations of genetic and environmental factors. In the case of bladder cancer, scientists are just discovering genes that increase risk. The list already includes oncogenes that stimulate malignant transformation of cells (TP63 and EGFR are examples for bladder cancer), and tumor suppressor genes that can mutate and lose the ability to fulfill their normal role of fighting cancer cell growth (TP53 and RB1 are examples for bladder cancer). Research is sure to uncover additional genetic factors, but that won't negate the critical role of environmental causes.

Accounting for almost half the bladder cancer deaths in men, cigarette smoking is the most important cause of the disease. Many of the toxins that enter the body when smokers inhale are absorbed into the bloodstream, and then excreted by the kidneys into the urine. Because urine dwells in the bladder for hours before it is expelled, the bladder lining is subject to prolonged contact with carcinogens (cancer-causing substances). Cigarette smokers are more than twice as likely to get bladder cancer as nonsmokers; heavy smokers are at greater risk than light smokers, but the risk gradually diminishes in people who kick the habit, even if they've smoked for many years.

Various industrial toxins can also injure the cells that line the bladder, eventually producing cancer. In the past, workers in the rubber, paint, electric, and textile industries were at substantial risk, but contemporary workplace safety regulations have greatly improved matters. In certain parts of the world, such as the Nile River delta, parasitic infections account for many cases of bladder cancer. Other relatively uncommon causes include prolonged therapy with cyclophosphamide (Cytoxan) and overuse of the pain killer phenacetin. Radiation therapy for prostate cancer appears to increase risk for bladder cancer years later. Although extremely high doses of artificial sweeteners may cause bladder cancer in animals, there is no evidence that they do so in humans. Other dietary factors, however, may play a role (see "Prevention").

Tobacco smoke and other toxins cause bladder cancer by damaging DNA and altering gene structure and function. Genetic abnormalities have been detected on several chromosomes of malignant bladder cells, and scientists are already using this information to develop new diagnostic tests (see "Diagnosis," below).

Symptoms

The most common symptom of bladder cancer is gross hematuria, blood in the urine that is visible to the naked eye. Another finding that often leads to the diagnosis is microscopic hematuria, red blood cells in the urine that are too few in number to be visible but can be detected during laboratory analysis of a urine specimen. In either case, the bleeding can be consistent or intermittent; although visible bleeding is always alarming, the amount of blood does not predict the severity of disease. And although urinary bleeding should always raise the possibility of bladder cancer, other conditions are often to blame. In fact, kidney stones and infections of the prostate, bladder, or kidneys are even more common causes of blood in the urine; less often, kidney cancer, prostate cancer, trauma, sickle cell anemia, and other conditions are responsible.

Although bladder cancer is usually painless, the disease can sometimes cause urinary burning, increased urgency, or increased frequency. Men who develop these symptoms in the absence of a urinary tract infection should always be checked for bladder cancer. And in the uncommon cases of widespread disease, the first symptoms of bladder cancer can be belly, back, or bone pain, or weight loss.

Diagnosis

Two elements are involved in establishing a diagnosis of bladder cancer: ruling out other common causes of hematuria, and identifying the bladder tumor itself. The first task depends on a urine culture to exclude bladder or kidney infections and a digital rectal exam, usually with a prostate-specific antigen (PSA) test, to check for benign prostatic hyperplasia and prostate cancer. Imaging studies can help by ruling out other diseases and evaluating the bladder itself. Although ultrasound can still be useful, conventional x-rays have been largely replaced by helical CT scans, which can detect kidney stones, kidney cancer, and even larger bladder cancers, especially if they extend beyond the bladder wall itself.

Most often, the diagnosis of bladder cancer depends on cystoscopy. It's usually an office procedure that uses a thin, flexible fiber-optic tube, the cystoscope. After administering a local anesthetic, the urologist inserts the scope through the urethra into the bladder. He can visualize and photograph the bladder, and he can insert tiny instruments through the scope to obtain biopsies of the bladder wall, the most important step of all.

Cystoscopy is the gold standard for the diagnosis of bladder cancer, but it is invasive. As a result, researchers are developing tests to diagnose bladder cancer by checking urine samples. The oldest test is urine cytology, the microscopic evaluation of cells in voided urine using a technique similar to female Pap tests. Unfortunately, while the Pap test is an excellent way to diagnose cancer of the cervix, urine cytology is much less accurate for the diagnosis of bladder cancer. Newer tests depend on finding tumor markers — abnormal genes or their protein products — in the urine. Several tests are available, including the two bladder tumor antigen (BTA) tests, the nuclear matrix protein 22 (NMP) test, and several fluorescent-staining tests. Like urine cytology, these methods are more likely to detect larger, more advanced cancers than small, early tumors. At present, these tests appear more useful to help keep track of patients already diagnosed with bladder cancer than to establish an initial diagnosis.

Follow-up is important because bladder cancers often develop at multiple sites and because these tumors tend to recur. Most urologists perform follow-up cystoscopies every three months for the first two years after successful treatment of superficial bladder cancer, then every six months for two years, then once a year indefinitely. It's an effective strategy, but as doctors gain confidence in urinary tumor markers, they may be able to substitute noninvasive testing for at least some cystoscopic exams. In any case, because patients with bladder cancer are at risk for upper urinary tract tumors, they should also have imaging tests, such as CT scans, every year or two.

Anatomy and staging

From top to bottom — from the structures that collect urine in the kidneys to the upper two-thirds of the urethra, where urine exits from the body — the urinary tract is lined by a special tissue called the uroepithelium, or transitional epithelium. In the United States and other industrialized countries, nearly all bladder cancers arise from the cells of this thin, membranous tissue. The transitional epithelium is only a few cells thick; cancers that are diagnosed when they are still confined to this superficial layer respond very well to simple treatment — but cancers that penetrate to deeper tissues are much more problematic. Fortunately, about 70% of bladder cancers are discovered when they are still superficial.

A membrane called the lamina propria lies just beneath the epithelium. Below that lies the much thicker muscular layer, which provides the contractile force that empties the bladder. The bladder muscle itself is divided into superficial and deep zones. The adjacent structures are called perivesicular tissues; beyond lie separate organs such as the prostate, lymph nodes, and bones.

If bladder biopsies show that cancer has penetrated beyond the superficial epithelial layer, doctors will perform other tests to see how far it has spread. CT scans of the pelvis, abdomen, and chest are widely used; MRIs can also help, and positron emission tomography (PET) scans are being investigated. Bone scans may detect tumors that have metastasized to the skeletal system. And every patient should have simple blood counts and tests of kidney and liver function.

Using the results of these tests, doctors will use the TNM (tumor, node, metastasis) system to stage bladder cancer.

Staging is all-important because it determines the treatment and outlook of bladder cancer.

Treatment

The treatment of bladder cancer depends on the stage of the disease and whether the tumor cells appear low-grade or high-grade and potentially aggressive.

Most cases are diagnosed early, before the tumor has invaded the bladder muscle (stages Ta, Tis, and T1). The mainstay of treatment for these superficial cancers is surgical removal of all visible tumors. This can be accomplished with transurethral resection of the bladder tumor (TURBT), which allows the urologist to work on the inside of the bladder through a cystoscope. In some cases, the urologist will instill a chemotherapy drug such as mitomycin C immediately after the TURBT.

If a superficial bladder cancer has characteristics that suggest a high likelihood of recurrence, additional treatment is needed. Aggressive treatment and follow-up is particularly important for carcinoma in situ, (stage Tis, "flat tumors") which has the propensity to recur and spread. Most often, that treatment involves immunotherapy. Bacillus Calmette-Guerin (BCG) bacteria, which were developed over 80 years ago as a vaccine against tuberculosis, are injected into the bladder, where they boost the body's own tumor-fighting immune cells. An alternative is intravesical (within the bladder) chemotherapy: a watery solution of a chemotherapy drug, such as mitomycin C, is instilled in the bladder. In either case, a typical program involves weekly treatments for six to eight weeks followed by intermittent maintenance treatments for up to two years. Chemotherapy can begin immediately after TURBT, but BCG should be delayed for at least two weeks to allow the surgical sites in the bladder to heal. Both treatments can cause an increase in urinary frequency, urgency, and burning, sometimes with bleeding. Occasionally, BCG bacteria can spread to other organs, requiring antibiotics. Many American urologists favor BCG immunotherapy; interferon alpha is an alternative immunotherapy agent.

Superficial bladder cancers that do not respond to local therapy require more aggressive treatment. The same is true of invasive tumors that have penetrated into or through the muscular layers of the bladder wall (stages T2 and T3). The standard treatment for these tumors is radical cystectomy, surgical removal of the entire bladder and nearby lymph nodes; in men, the prostate and seminal vesicles are also removed, and erectile dysfunction is the rule. Some patients benefit from supplementary chemotherapy.

Until recently, patients with radical cystectomies required an ileal conduit to collect urine in a plastic bag worn on the abdominal wall. Although most patients adjust remarkably well, new surgical techniques can make life even better by using a portion of the patient's intestinal tract to construct an Indiana pouch that can be emptied through the skin by periodic self-catheterization. And skilled urologists can even use intestinal tissue to construct an artificial bladder (orthotopic neobladder) for some male patients, allowing them to urinate quite naturally. Still, some men who are unwilling or medically unable to undergo radical cystectomy may also get good results from combined therapy with limited surgical removal of the tumor, followed by radiation therapy, often with chemotherapy; an experienced medical center is the key to successful bladder-sparing therapies. Chemotherapy and radiation can help control widespread bladder cancer; although metastatic bladder cancer is rarely curable, treatment can achieve prolonged survival.

Prevention

Despite important advances in the immunotherapy of superficial bladder cancer and the surgical therapy of invasive disease, prevention is the best treatment of all. And here, too, progress is evident.

The first step, of course, is to quit smoking. It's an obvious necessity that will also reduce a smoker's risk of heart attacks, lung cancer, and many other major diseases. But in the case of bladder cancer, the benefit accrues slowly, taking several years or longer; ex-smokers should remain extra vigilant about warning symptoms during this time.

The second step is to review your work history for possible exposures to cancer-causing chemicals. Benzene and various arylamines are high on the list. And since bladder cancer develops slowly, usually becoming apparent at least 25 years after exposure, continued awareness is appropriate long after the exposure itself.

The third step is to improve your diet. Although the details vary, studies from the University of Washington, the University of California, the Roswell Park Cancer Institute, and Harvard agree that a high intake of fruits and vegetables appears to reduce the risk of bladder cancer, while a high-fat diet seems to increase risk. The Harvard study singled out broccoli and cabbage as protective; researchers at Roswell Park agree that cruciferous vegetables may help, but they singled out uncooked vegetables. The Washington investigation found protection from a dietary pattern rather than specific foods, but it found fruits particularly helpful and fried foods particularly harmful, increasing risk 2.2 times. A 2010 study also implicated red and processed meat as risk factors.

The final protective measure is to drink more fluid. It seems intuitive that a high urine volume will dilute toxins in the urine and increase voiding frequency, both of which should protect the vulnerable bladder cells from carcinogens. But intuition can be misleading, and two small European studies reported mixed findings: French investigators did not demonstrate any benefit from a high fluid intake, but Spanish scientists reported that coffee appeared protective. A large American study, however, was more optimistic. A 1999 Harvard study of 47,909 male health professionals showed that dilution may be a solution to the bladder cancer conundrum. All the men were free of cancer when the study began in 1986. Over the next 10 years, the researchers kept track of each man's consumption of 22 different types of beverages as well as the occurrence of bladder cancers. When the results were analyzed, the men who drank the most (averaging about 2 quarts a day) were 49% less likely to develop bladder cancer than the men who drank the least (averaging less than 1 quarts per day). Although water was particularly beneficial, all types of beverages contributed to protection, including alcoholic and caffeinated beverages, which had been cited as possible risk factors in some earlier studies. All in all, men can decrease their risk of bladder cancer by 7% for each additional 8 ounces of fluid they drink each day. In a sense, then, the bladder is like so many other parts of the body: the more it's used, the healthier it stays.