Urothelial Cancer: Diagnostic Evaluation

— Hematuria often the presenting sign

Illustration of a stethoscope with an electrocardiogram in a circle over a bladder with Urothelial Cancer
Key Points

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Urothelial cancer is the most common form of bladder cancer, but the term also encompasses cancers of the urethra, ureters, and renal pelvis. Rarer types of bladder cancer (representing less than 5% of bladder cancers) include squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and sarcoma.

Urothelial cancer is also sometimes called transitional cell cancer, but both terms are typically used interchangeably with bladder cancer.

About 80,000 new cases of bladder cancer and 17,000 deaths attributable to the disease were expected in the U.S. in 2022, according to American Cancer Society statistics. Approximately three to four times as many men as women develop bladder cancer -- mostly in those older than 55. Whites are more likely to be diagnosed with bladder cancer than Blacks or Hispanic Americans. In 2019, there were an estimated 712,644 people living with bladder cancer in the U.S., according to the National Cancer Institute.

Approximately 75% of bladder cancers are detected before they invade the detrusor muscle of the bladder, and are referred to as nonmuscle-invasive bladder cancer (NMIBC).

"The presence of microscopic or gross hematuria is often the first sign of bladder cancer," Paras Shah, MD, of the Mayo Clinic in Rochester, Minnesota, told MedPage Today. "Other early signs and symptoms include frequency, urgency, or pain with urination. In advanced stages of disease, obstruction of the ureters may occur where they drain into the bladder, resulting in lower back pain or flank pain localized to the side of the blockage."

The most common methods to evaluate for the presence of bladder cancer involve office-based procedures such as cystoscopy and urine cytology, as well as computed tomography (CT)-based imaging of the abdomen and pelvis. "Cystoscopy is the most sensitive and specific method for identification of bladder malignancies, but it is somewhat invasive and thus carries a slight risk for complications such as bleeding, infection, and pain," Shah noted. "These procedures are often prompted by the presence of blood in the urine or persistent irritative voiding symptoms in the absence of infection."

A formal diagnosis of bladder cancer is made only after biopsy is performed of suspicious masses noted within the bladder on cystoscopy or CT scan or if there is concern based on urine cytology.

Biopsy of the bladder tumor is performed endoscopically through the urethra by transurethral resection of bladder tumor (TURBT). Although other urinary biomarker tests exist, such as fluorescence in situ hybridization (FISH), and tumor marker tests such as bladder tumor-associated antigen -- also called complement factor H-related protein (CFHrp) -- ImmunoCyt/uCyt+, and NMP22 BladderChek, these tests lack sensitivity and specificity and thus have limited value.

What is the Value of Urine Cytology?

Urine cytology is typically part of the initial workup when a patient has visible blood in the urine, given its sensitivity for high-grade bladder cancer. In this instance, cytopathologic analysis of the sample under the microscope may reveal shedding of tumor cells from the bladder epithelium due to the dyscohesive nature of high-grade malignancy.

Results are reported as:

  • Negative for high-grade urothelial carcinoma
  • Atypical
  • Suspicious for high-grade urothelial carcinoma
  • Positive for high-grade urothelial carcinoma

Shah noted that interpretation of urine cytology can be highly variable, leading to heterogeneity in the way it's reported, which may limit its value. "For example, to one pathologist, the cells may be atypical, but to another the cells may look suspicious. There is a very broad spectrum of characterization," Shah said.

Moreover, the utility of cytology is primarily in the context of high-grade cancers due to their dyscohesive nature and propensity for shedding. This, however, is not a feature of slower-growing cancer. "The report may say negative for high-grade urothelial carcinoma, but that doesn't mean it's negative for bladder cancer," Shah said. "A low-grade bladder cancer is still a possibility."

Bladder cancer may also manifest itself in the form of microscopic hematuria, or blood that is not visible to the naked eye but is appreciated only under microscopic analysis. However, microscopic hematuria is a relatively common condition that may be a sign of a wide spectrum of urologic issues, both benign and malignant, and thus the ensuing urologic work-up is controversial, he explained.

The American Urological Association (AUA) defines microscopic hematuria as three or more red blood cells per high power field on microscopic evaluation of a single specimen. Anthony Corcoran, MD, of NYU Langone Perlmutter Cancer Center in New York City, noted that AUA recently endorsed a personalized risk-based strategy for evaluation based on factors including age, sex, smoking, and other urothelial cancer risk factors, and degree and persistence of microhematuria.

"It used to be that everyone with microscopic hematuria got a cystoscopy, but now the AUA is supporting risk stratification for cystoscopy based on these risk factors if the patient has 20 or fewer red blood cells per high power field," said Corcoran, who is also director of Urologic Oncology at NYU Langone Hospital - Long Island.

Urine cytology has little diagnostic value when a patient presents with microscopic hematuria, especially given that the yield for low-grade cancer is low. "Cytology is not going to catch the low-grade tumor," Shah said. "Urine cytology is collected in the setting of microscopic hematuria mainly when patients persistently have microscopic amounts of blood in the urine and have otherwise undergone an exhaustive negative work-up, which includes imaging and cystoscopy. The likelihood of high-grade malignancy even in this setting generally remains low -- in part because of the absence of gross hematuria."

Beyond Urine Cytology: Imaging

For patients with microscopic hematuria, AUA recommends personalizing the diagnostic evaluation according to patient risk and involving shared decision-making. The evaluation generally involves cystoscopy and upper tract imaging in the form of either renal ultrasound (low-risk and intermediate-risk) or CT of the abdomen and pelvis (i.e., CT urogram) among high-risk patients.

For low-risk patients, Corcoran said, the choice of cystoscopy and renal ultrasound or repeat urinalysis in 6 months is discussed with the patient. Low-risk patients include those who are young, nonsmokers, have no family history of bladder cancer, and no occupational exposure to environmental carcinogens.

"In higher-risk patients [i.e., those who are male, have had prior radiation, are older, and have more severe urinary symptoms], I would encourage a CT scan and cystoscopy with the cytology, and for patients in the middle, I would typically do cystoscopy and an ultrasound," Corcoran said. The overwhelming majority of patients tolerate cystoscopy well, "and I think that patients would rather have peace of mind than something hanging over their heads."

For patients who present with gross hematuria, upfront urine cytology is often pursued as part of the evaluation, in addition to cystoscopy and imaging. The preferential imaging technique is a CT urogram as this offers a more comprehensive search for the source of bleeding, whether from the kidney, ureter, or bladder. Of note, although CT urography may demonstrate the presence of a bladder mass, cystoscopy is still generally performed to visually confirm its presence and better characterize the tumor.

Several imaging findings on CT urography for hematuria strongly suggest the presence of malignancy within the bladder. Features such as a discrete soft tissue mass within the bladder, filling defect within the bladder lumen on delayed phase imaging (i.e., an area within the bladder that is devoid of contrast), focal hyperenhancement of the bladder urothelium, urothelial thickening, or nodularity are all suggestive of a malignant process within the bladder and may represent the source of bleeding.

These findings are often still confirmed by subsequent cystoscopy. A visible tumor in the bladder prompts TURBT to establish a tissue diagnosis, assess the grade of the tumor, and evaluate the extent of disease -- specifically, the depth of invasion or the stage (which will be covered in a subsequent installment in this series).

These factors will ultimately influence treatment selection, since the majority of NMIBCs can be managed conservatively with intravesical instillations of chemotherapy or immunotherapy agents, whereas muscle-invasive tumors require more radical treatment such as bladder removal or radiation.

Other sites of disease may also cause gross hematuria, such as tumors of the kidney or the collecting system. Tumors within the kidney are most often identified by upper tract imaging, such as renal ultrasound or CT scan.

Similarly, tumors within the urinary collecting system, referred to as upper tract urothelial carcinoma, are also most often identified on upper tract imaging, particularly CT urography. These tumors may appear as filling defects on delayed phase imaging of the CT urogram, soft tissue masses within the ureter, or thickening of the ureteral lining with enhancement.

In many cases, swelling of the ureter (i.e., hydroureteronephrosis) upstream from the site of concern may also be present. Upper tract urothelial cancers, particularly those that are high grade, may also cause a positive urine cytology associated with the shedding of cancer cells into the urine.

Similar to the situation for bladder tumors, visualization and biopsy is typically necessary to confirm the diagnosis. This most often involves placement of a cystoscope through the urethra into the bladder and the subsequent insertion of a guide wire through the cystoscope into the ureter. A longer version of the cystocope, referred to as a ureteroscope, is inserted over the guide wire into the ureter and permits both visualization of the ureteral tumor and biopsy of the area of concern.

CT urogram will also provide partial staging information when a tumor is discovered in the bladder, ureter, or kidney, which aids in decisions about treatment. Additional workup with a positron emission tomography scan may be performed with ambiguous findings on a CT scan, such as slight enlargement of lymph nodes. However, this is usually not a first-line imaging test.

The role of many urine-based molecular tests in the diagnosis of bladder cancer is still evolving and thus their use is not routine for this indication.

The most common of these urine-based molecular tests is the FISH test, also referred to as UroVysion. As the name implies, FISH fluorescently labels the DNA of cells shed into the urine for abnormalities in specific chromosomes involved in bladder cancer pathogenesis, which are chromosomes 3, 7, 13, and 17. As such, it is less likely to be influenced by the subjectivity of pathologist interpretation, especially given that it is more agnostic to inflammatory changes that may make cells appear atypical.

"The FISH test is used mainly to assess response in patients with NMIBC receiving intravesical therapy such as Bacillus Calmette-Guerin," Shah said. "It can also be used to evaluate for the presence of bladder cancer in patients with an indeterminate urine cytology."