Clinical presentation, diagnosis, and staging of bladder cancer

INTRODUCTION — Bladder cancer is the most common malignancy involving the urinary system. Urothelial (transitional cell) carcinoma is the predominant histologic type in the United States and Europe, where it accounts for 90 percent of all bladder cancers. In other areas of the world, non-urothelial carcinomas are more frequent. Much less commonly, urothelial cancers can arise in the renal pelvis, ureter, or urethra. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)

The spectrum of bladder cancer includes non-muscle invasive (superficial), muscle invasive, and metastatic disease, each with its own clinical behavior, biology, prognosis, and treatment.

The clinical presentation, diagnosis, and staging of bladder cancer will be presented here.

The management of patients with bladder cancer, including specific recommendations based on the stage of disease, is discussed separately:

●Overview of bladder cancer treatment (see "Overview of the initial approach and management of urothelial bladder cancer")

●Non-muscle invasive bladder cancer (see "Treatment of primary non-muscle invasive urothelial bladder cancer")

●Muscle invasive bladder cancer (see "Radical cystectomy" and "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer")

●Metastatic bladder cancer (see "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract")

CLINICAL PRESENTATION — Patients with bladder cancer classically present with painless hematuria (grossly visible or microscopic), although irritative voiding symptoms (frequency, urgency, dysuria) can be the initial manifestation. The diagnosis is often delayed due to the similarity of these symptoms to those of benign disorders (urinary tract infection, cystitis, prostatitis, passage of renal calculi), and delays can lead to a worsened prognosis due to more advanced stage at diagnosis [1]. There is evidence to suggest that delayed diagnosis accounts for the poorer survival in females diagnosed with bladder cancer compared with males [2]. Furthermore, symptoms are often intermittent. In some patients, metastases will cause the initial symptoms. Incidental bladder cancer is rare at autopsy, suggesting that most cancers eventually become symptomatic [3].

Hematuria — The most common presenting symptom is hematuria, which is typically intermittent, gross, painless, and present throughout micturition. (See "Etiology and evaluation of hematuria in adults".)

Hematuria is typically due to benign causes in most patients and can be seen in up to 18 percent of adults [4-6]. However, the likelihood of bladder cancer increases when the hematuria is gross (visible) rather than microscopic [7,8], with an incidence of bladder cancer of approximately 2 to 5 percent among patients with microscopic hematuria [4,5,9,10] and 10 to 20 percent among those with gross hematuria [4,9,11]. The risk for bladder cancer is higher in males, older patients, and smokers.

For patients with microscopic hematuria, the American Urological Association (AUA) recommends diagnostic evaluation for bladder and other urothelial cancers using the following risk-based approach [12]:

●Low-risk patients – Low-risk patients include those who meet all the following criteria: females age <50 years or males age <40 years; never-smokers or those with <10 pack-years of smoking; 3 to 10 red blood cells [RBC] per high-power field [HPF] on a single urine analysis; no risk factors for urothelial cancer. (See "Etiology and evaluation of hematuria in adults", section on 'Risk factors for malignancy'.)

•These patients should be engaged in a shared discussion to have either a repeat urinalysis (UA) within six months or immediate cystoscopy and renal ultrasound (US).

●Intermediate-risk patients – Intermediate-risk patients include those who meet any of the following criteria: females age 50 to 59 years or males age 40 to 59 years; 10 to 30 pack-years of smoking; 11 to 25 RBC/HPF on a single UA; low-risk patients with no prior evaluation and 3 to 10 RBC/HPF on repeat UA; additional risk factors for urothelial cancer. (See "Etiology and evaluation of hematuria in adults", section on 'Risk factors for malignancy'.)

•These patients are referred to a urologist for cystoscopy and a renal US.

●High-risk patients – High-risk patients include those who meet any of the following criteria: any patient age ≥60 years; >30 pack-years of smoking; >25 RBC/HPF on a single UA; a history of gross hematuria.

•These patients should receive cystoscopy and cross-sectional imaging with computed tomography (CT) scan or magnetic resonance imaging (MRI) of abdomen and pelvis.

However, guidelines among expert groups differ. Recognizing a lower risk among younger females who do not smoke, the American College of Obstetricians and Gynecologists (ACOG) and the American Urogynecologic Society (AUGS) recommend that asymptomatic, low-risk, never-smoking females aged 35 to 50 years undergo evaluation only if they have more than 25 RBCs per HPF [13].

The importance of evaluating hematuria was illustrated by a study of 1930 patients, in which 61 percent had no abnormality diagnosed [9]. Abnormalities that were found included bladder cancer (12 percent), urinary tract infections (13 percent), medical renal disease (10 percent), stone disease (4 percent), kidney cancer (0.6 percent), and prostate cancer (0.4 percent) [9]. Bladder cancer was much more frequent in older patients, but seven patients with bladder cancer were younger than 40 years, including one with microscopic hematuria.

The point at which gross hematuria is noted during urination can be helpful in localizing its source:

●Hematuria occurring primarily at the beginning of urination is usually from a urethral source.

●Blood that is only noticed as a discharge between voidings or as a stain on undergarments, while the voided urine itself appears clear, indicates an origin at the urethral meatus or the anterior urethra.

●Terminal hematuria, with blood appearing towards the end of voiding, generally originates from the bladder neck or prostatic urethra.

●Hematuria occurring throughout voiding can originate from anywhere in the urinary tract, including the bladder, ureters, or kidneys.

Pain — Pain associated with bladder cancer is usually the result of locally advanced or metastatic tumors. Its distribution is related to the size and location of the primary tumor or its metastases:

●Flank pain may result when a tumor obstructs the ureter at any level (bladder, ureter, or renal pelvis). Although obstruction usually is associated with muscle invasive disease, large noninvasive tumors at the ureteral orifice may also cause symptoms. The pain is similar to that experienced with the passage of urinary stones, and may or may not be associated with hematuria. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)

●Suprapubic pain is usually a sign of a locally advanced tumor that is either directly invading the perivesical soft tissues and nerves or obstructing the bladder outlet and causing urinary retention.

●Hypogastric, rectal, and perineal pain can be signs of disease invading the obturator fossa, perirectal fat, presacral nerves, or the urogenital diaphragm.

●Abdominal or right upper quadrant pain may signal the presence of abdominal lymph node or liver metastases.

●Bone pain may indicate the presence of bone metastases.

●Significant and persistent headache or disordered cognitive function may suggest the presence of intracranial or leptomeningeal metastases.

Voiding symptoms — Voiding symptoms are most common in patients with carcinoma in situ (CIS) of the bladder and may result from a functional decrease in the bladder capacity, detrusor overactivity, invasion of the trigone, or obstruction of the bladder neck or urethra.

●Irritative voiding symptoms (eg, daytime and/or nocturnal frequency, urgency, dysuria, or urge incontinence) occur in approximately one-third of patients. The complex of dysuria, frequency, and urgency in particular is highly suggestive of bladder CIS. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

●Obstructive voiding symptoms are less common and may be due to tumor location at the bladder neck or prostatic urethra. Symptoms include straining, an intermittent stream, nocturia, decreased force of stream, and a feeling of incomplete voiding. On occasion, gross hematuria may result in "clot retention."

Constitutional symptoms — Symptoms such as fatigue, weight loss, anorexia, and failure to thrive are usually signs of advanced or metastatic disease and denote a poor prognosis. In rare cases, patients may have constitutional symptoms due to renal failure caused by bilateral ureteral obstruction. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)

PHYSICAL EXAMINATION — A complete physical examination should be performed in patients with bladder cancer, including a digital rectal examination in males and a bimanual examination of the vagina and rectum in females.

Although the physical examination is unremarkable in most patients, abnormal findings that can be seen include the following:

●A solid pelvic mass may be felt in advanced cases.

●Induration of the prostate gland can sometimes be felt on digital rectal examination if the bladder cancer involves the bladder neck and invades the prostate. An attempt to palpate the base and lateral walls of the bladder should be made, looking for induration or fixation.

●Inguinal adenopathy can be present, although the inguinal region is not a common site of node metastases.

●Nodularity in the periumbilical region can be seen in advanced lesions involving the dome of the bladder. This is often seen with urachal cancers, which typically are adenocarcinomas rather than urothelial tumors.

●Abdominal examination may reveal the presence of substantially enlarged para-aortic lymph nodes or hepatic metastases.

INITIAL EVALUATION

Overview — The presence of otherwise unexplained hematuria may represent urothelial cancer in individuals until proven otherwise. Nevertheless, many causes are benign, such as hematuria from enlarged prostates, urinary tract infection, cystitis, prostatitis, and passage of renal calculi. The goal of the diagnostic evaluation is to determine the diagnosis, site, and extent of cancer, and the presence or absence of muscle invasive disease. However, the extent and need for evaluation is based on risk for bladder cancer. (See 'Clinical presentation' above.)

●A full urologic evaluation of the entire urinary tract is indicated in such patients unless there is clear evidence of glomerular bleeding (eg, red cell casts, proteinuria, dysmorphic red cells [particularly acanthocytes], and in patients with gross hematuria, a smoky brown color). (See "Etiology and evaluation of hematuria in adults", section on 'Glomerular versus nonglomerular bleeding'.)

If evaluation is pursued, it should consist of cystourethroscopy and an evaluation of the upper tracts, since urothelial malignancy can be multifocal, with one or more lesions anywhere from the renal pelvis to the proximal urethra.

●Radiographic imaging of the upper tract aims to detect disease in the kidney, renal pelvis, or ureter. The choice of imaging study should balance risk of disease with concerns about radiation exposure and nephrotoxicity of contrast agents. For patients at low and intermediate risk of disease, renal ultrasound (US) balances the likelihood of disease with toxicity of other imaging modalities. For patients at high risk for disease, imaging can consist of either a computed tomography (CT) scan of the abdomen/pelvis with urography with oral and intravenous contrast or intravenous pyelography (IVP) plus nephrograms or renal US to evaluate both the collecting systems and the renal cortex. IVP is rarely used and has been largely replaced by CT. Magnetic resonance imaging (MRI) may be used in patients with allergy to iodinated contrast and poor kidney function. (See 'Hematuria' above.)

Urinalysis — The urinalysis should include a microscopic and gross examination as well as a dipstick chemical test. Nonrefrigerated urine should be examined within 30 minutes of collection. (See "Urinalysis in the diagnosis of kidney disease".)

The average individual excretes approximately 30,000 red blood cells (RBCs) per hour, which equates to approximately one RBC per high-power field (HPF) on microscopic examination. Hematuria is usually not considered significant unless there are more than three RBCs per HPF. RBC morphology may also suggest the etiology of the hematuria; cells of glomerular origin are often dysmorphic or formed in casts, indicating intrinsic renal disease, while normally shaped RBCs are more likely from an extrinsic source such as calculi, tumor, obstruction, or infection. (See "Etiology and evaluation of hematuria in adults".)

Urine color can be affected by its concentration, ingestion of certain foods or drugs, or the presence of bacteria, and can be confused with hematuria.

Urinary pigments that can mimic hematuria include the following:

●Betalain contained in beets (beeturia)

●Phenazopyridine, a urinary analgesic

●Vegetable dyes

●Urates

●Free myoglobin or hemoglobin

●Serratia marcescens

●Phenolphthalein, which used to be a common component of many over-the-counter laxatives

On occasion, dipstick analysis will be positive for blood, but microscopic examination fails to show RBCs. This can occur when myoglobin is present in the urine, since it is chemically similar to hemoglobin. This can also occur when the RBCs are lysed and in the presence of hemoglobin occurring in the course of hemolysis.

The specific gravity of a specimen is important to note because of its influence on the stability of white blood cells or RBCs. For example, when the urinary flow rate is high and the urine is very dilute, RBCs are lysed and therefore will not be present on microscopic examination, even in the presence of pathology. (See "Urinalysis in the diagnosis of kidney disease".)

Cystoscopy — Cystoscopy is the gold standard for the initial diagnosis and staging of bladder cancer. This procedure is done in the office with a flexible cystoscope and only has minimal risks, such as bleeding and infection. Risk of infection is minimal using sterile techniques. In the United States, this is typically done with white light; fluorescence cystoscopy has been available in Europe and was approved in the United States in 2010 for use in the operating room and in 2018 for office cystoscopy. However, the indication for fluorescence cystoscopy has been for cancer surveillance and not for evaluation of hematuria. (See 'Fluorescence cystoscopy' below.)

Our approach is as follows:

●Any visible tumor or suspicious lesion seen at the initial (diagnostic) cystoscopy should be either biopsied or resected transurethrally to determine the histology and depth of invasion into the submucosa and muscle layers of the bladder.

●In patients who presented with a positive urine cytology and whose initial cystoscopy showed no visible tumor (or suspicious lesion) within the bladder, biopsy of apparently normal appearing urothelium, prostatic urethra, and selective catheterization of the ureters/renal pelvis with urine specimens for cytology from the upper tract is required.

For patients with documented high-risk disease confirmed on a diagnostic transurethral resection of bladder tumor (TURBT), repeat resection may be indicated to eliminate the risk of understaging. This issue is discussed elsewhere. (See "Overview of the initial approach and management of urothelial bladder cancer", section on 'Transurethral resection'.)

Procedure — The procedure begins with a bimanual examination under anesthesia (EUA) to determine whether or not a palpable mass is present, and if present, whether or not it is mobile. An EUA during cystoscopy is effective for identifying locally advanced disease, which may present as gross extravesical extension, invasion of adjacent organs, or pelvic sidewall involvement. If a mass is felt, the bimanual examination is repeated after the resection to see if it is still present and to differentiate between clinical stage T2 and T3b disease (table 1). (See 'Staging' below.)

The cystoscope is then inserted into the bladder, and urine is obtained for cytology if patients have irritative symptoms. A bladder wash specimen obtained by irrigating the bladder with sterile saline provides the highest sensitivity for detection of cancer. The bladder is inspected visually, and a detailed description of the size, number, appearance, location, and growth pattern (papillary or solid) of all lesions is recorded. This information serves as a reference for subsequent cystoscopic examinations. The status of the uninvolved mucosa is also noted.

The size, stalk, and configuration of the cancer can be predictive of muscle invasion [14]. In general, low-grade, noninvasive tumors are papillary with a narrow stalk. High-grade, invasive tumors frequently can appear sessile, solid, or nodular. Carcinoma in situ (CIS) is a high-grade, noninvasive tumor, which can appear as a flat velvety lesion and can arise in patches. CIS sometimes involves large parts of the urothelial lining.

Fluorescence cystoscopy — Fluorescence cystoscopy uses an intravesical photoactive protoporphyrin (such as 5-aminolevulinic acid [5-ALA] and hexyl aminolevulinic acid [HAL]), which accumulates preferentially in neoplastic rather than normal tissue. The photoactive substance enhances the visual difference between normal and neoplastic tissue after illumination with blue light of the appropriate wavelength [15]. The HAL is instilled one hour prior to cystoscopy.

Randomized trials have confirmed that fluorescence cystoscopy detects more tumors (both papillary and CIS) than white-light cystoscopy. This improved tumor identification results in better patient management. The safety profile of fluorescence cystoscopy is excellent. The improved early detection and treatment of tumors need to be balanced by a slightly higher false-positive rate (mainly due to inflammation and scarring), the requirement for a special lens system, the need to instill the photosensitizer one hour prior to cystoscopy, as well as the higher cost. The clinical results with fluorescence endoscopy are discussed elsewhere. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Enhanced imaging techniques'.)

Urine cytology — Cytology is commonly used as an adjunct to cystoscopy to detect CIS and upper-tract malignancies. The underlying concept is that cells in the urinary tract that are proliferating rapidly will be exfoliated. However, urine cytology has a relatively poor sensitivity, particularly for low-grade tumors. This was illustrated by a meta-analysis that included 18 studies with 1255 patients [16]. The overall sensitivity was 34 percent, with sensitivities for grade 1, 2, and 3 tumors of 12, 26, and 64 percent, respectively.

Lower-grade tumors have fewer morphologic alterations that may lead to the loss of intercellular attachments and adhesiveness. Thus, they may not exfoliate as easily as higher-grade tumors. When they are exfoliated, low-grade tumors are shed in large papillary fragments with uniform size, minimal alterations in nuclear to cytoplasmic ratio, and small or absent nucleoli. Higher-grade tumor cells tend to be more isolated in loose clusters and elongated with marked pleomorphism, increased nuclear to cytoplasmic ratios, and variable nucleoli size.

False-positive results are rare with urine cytology (specificity >98 percent in most studies) [16]. Thus, any positive cytology should be assumed to represent malignancy. If no disease is evident in the bladder, the upper urinary tracts and prostatic urethra should be thoroughly evaluated. Enhanced cystoscopy with fluorescent cystoscopy or narrow band imaging can be helpful in these cases to improve detection of CIS. If no lesion is discernible, selective ureteral and renal pelvis washings may be performed; however, the diagnostic accuracy of these procedures is debated because of possible contamination from the bladder. (See "Malignancies of the renal pelvis and ureter" and 'Fluorescence cystoscopy' above.)

Urine cytology specimens must be properly collected and stored in order to maintain a high level of diagnostic accuracy. Catheterized specimens can denude normal surface epithelial cells; coalescence in papillary groups may be misinterpreted as low-grade transitional cell carcinoma (TCC). Voided specimens with prolonged exposure to concentrated urine or specimens from females that are contaminated with vaginal, cervical, or endometrial cells can also be misinterpreted. Cytology specimens should be processed promptly, as cells will degrade after 10 to 15 minutes at room temperature. One study showed a lower diagnostic yield with voided urine specimens when compared with bladder washings [17]. Chronic urinary tract infections, inflammatory conditions, stone disease, recent instrumentation or intravesical therapy, and bowel substitutions for the bladder (eg, ileal conduits or orthotopic neobladders) can create degenerative cellular changes and atypia, which can be misinterpreted. (See "Urinary diversion and reconstruction following cystectomy".)

Urine-based markers — Multiple urine-based tumor markers have been developed because of the low sensitivity of cytology and the need for a noninvasive diagnostic tool to supplement cystoscopy. These urine biomarkers are discussed in detail elsewhere. (See "Urine biomarkers for the detection of urothelial (transitional cell) carcinoma of the bladder".)

Urine-based tumor markers have been developed that are based on differential expression of tumor-related proteins, DNA, RNA, methylation changes, or cellular markers [18,19]. The pooled sensitivity of urine-based tumor markers ranges from 50 to 80 percent, and specificity ranges from 70 to 90 percent, depending on the analysis [18,19]. The sensitivity of markers and cytology correlates closely with stage and grade.

Most urine-based molecular markers are more sensitive than urine cytology in the detection of urothelial cancer, especially for low-grade tumors, but the specificity of molecular markers is inferior to that of urine cytology. These urinary markers may enhance risk stratification and shared decision-making over only clinical factors [20]. However, their routine use is not recommended by the American Urological Association (AUA) guidelines on management of hematuria [12].

None of these markers has sufficient sensitivity to replace cystoscopy in the assessment of an individual suspected to have bladder cancer, and their clinical use has not been recommended by consensus panels. There is potential benefit for surveillance in patients with a history of urothelial cancer by reducing the frequency of cystoscopy. There is evidence that use of markers such as a fluorescent in situ hybridization (FISH) assay or RNA panels [21] may help management of patients with atypical findings on cytology or cystoscopy [22,23]. Furthermore, urine markers may help in predicting outcomes for patients being treated with intravesical immunotherapy, but this awaits validation [24]. (See "Urine biomarkers for the detection of urothelial (transitional cell) carcinoma of the bladder", section on 'Gene expression panels'.)

One issue with markers is the finding of a positive marker with normal cystoscopy. These findings have been termed "anticipatory" positives, and some studies suggest they detect cancer prior to visualization [25].

Additional clinical trials are necessary to determine the incremental benefit of markers and the cost-effectiveness of their use.

Urinary tract imaging — Imaging studies may be used to define the location and extent of tumor as well as to detect sites of multifocal disease. CT scan is replacing IVP as the procedure of choice, but IVP remains an appropriate alternative where CT is not readily available.

Computed tomography scan — CT, with and without contrast, is the preferred study for all patients with bladder cancer, regardless of stage [26]. CT scans should include both the abdomen and pelvis, and should include delayed images to identify defects in the collecting system. CT may demonstrate extravesical extension, nodal involvement in the pelvis or retroperitoneum, visceral, pulmonary, or osseous metastasis, and tumor involvement or obstruction of the upper urinary tract.

Although CT provides better visualization of tumors than US, it may miss tumors <1 cm in size, particularly those in the bladder trigone or dome, and it cannot differentiate depth of bladder-wall invasion (ie, mucosal versus lamina propria or muscularis propria).

Although a thickened bladder wall on CT suggests the presence of muscle invasive disease, tissue is required for diagnosis. In contrast, CT is approximately 80 percent accurate in differentiating locally advanced tumors involving extravesical adipose tissue or surrounding structures from less invasive tumors (image 1) [27]. An important caveat is that in most instances, CT is performed after a transurethral resection, which complicates its interpretation. It may be difficult to distinguish inflammatory or iatrogenic edematous changes from true extravesical tumor extension.

The sensitivity of CT for identification of nodal involvement is relatively low (false-negative rate 68 percent, false-positive rate 16 percent) and requires a needle or excisional biopsy for confirmation [28].

Intravenous pyelogram — An IVP can visualize both the bladder and upper urinary tracts. IVP is an appropriate choice for patients with microscopic or gross hematuria or suspected urothelial cancer [9,29]. IVP is more sensitive for detection of small lesions of the ureter or renal pelvis, while CT scan and renal US are better tests for the evaluation of renal parenchymal disease. Ideally, if IVP is obtained, it should be done prior to TURBT to avoid misinterpretation of postoperative changes. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)

IVP may not be appropriate in patients with renal insufficiency, diabetes mellitus, or other conditions due to the risk of acute renal injury. IVP may also not be appropriate in patients with a history of allergies to radiocontrast agents, although prophylactic corticosteroids and antihistamines may be useful. In patients in whom the ureters and renal pelvis are poorly visualized by IVP, retrograde pyelograms may be performed during cystoscopy. (See "Prevention of contrast-associated acute kidney injury related to angiography" and "Prevention of contrast-associated acute kidney injury related to angiography", section on 'Epidemiology' and "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography", section on 'Prevention'.)

The cystogram phase of the IVP detects 60 to 85 percent of large bladder tumors, but smaller tumors are missed more frequently. Both the cystogram phase and the post-void film should be examined for filling defects (image 2), which are usually irregular, frond-like, or nodular, and persistent from film to film. Filling defects may be the result of parietal tumor implantation, the uneven jagged contours of papillary fronds, or obstruction of a ureter with proximal dilation. The classic urographic findings of an upper tract TCC are a meniscus-shaped ureteral filling defect known as the "goblet" or "Bergmann" sign and the "stipple sign," produced by contrast being trapped in the fronds of a papillary tumor.

Approximately 50 percent of patients with a filling defect in the renal pelvis or ureter will have associated hydronephrosis, hydroureter, or nonvisualization of the kidney secondary to obstruction [30]. Invasive bladder tumors may cause distal ureteral obstruction and secondary hydronephrosis. Although the lack of this finding does not rule out invasive disease, its presence signals an invasive cancer in over 90 percent of cases and extravesical disease in 70 percent [31] for unilateral and 90 percent for bilateral hydronephrosis [27]. Nonvisualization of the kidney is usually seen in advanced disease and is frequently associated with invasion of tumor into the renal parenchyma. Stenosis is also a specific sign of infiltrating disease and is more commonly seen in the ureter (image 3).

Magnetic resonance imaging — MRI is as reliable as CT for staging of invasive or locally advanced disease and may be better at evaluating tumors at the base and dome of the bladder. Gadolinium-enhanced MRI may be superior to CT to detect superficial and multiple tumors, extravesical tumor extension, and surrounding organ invasion [32-36].

Although MRI is useful for patients with contrast dye allergy, it is difficult to tolerate by claustrophobic patients and cannot be used in patients with pacemakers or other metallic foreign bodies. Open MRI imaging may be better tolerated, but image resolution is poorer due to the smaller magnet used with this modification in imaging.

Ultrasound — US is not very useful for the diagnosis or staging of bladder cancer. US can confirm the presence of a soft tissue mass, but usually cannot determine depth of invasion, extravesical extension, or nodal status. US may be useful in evaluating the upper tracts for renal parenchymal disease, hydronephrosis, and to differentiate a non-radiopaque stone from a soft tissue mass by differences in echogenicity [37]. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)

Imaging for metastatic disease — Once the diagnosis and clinical stage of bladder cancer are established, other imaging studies may be useful to evaluate for metastatic disease.

Guidelines recommend imaging of the chest for all patients with muscle invasive bladder cancer, but they do not specify the type of scan, so both chest radiographs and CT scan are acceptable. Bone scan and imaging of the brain are reserved for symptomatic patients. Positron emission tomography (PET)/CT is typically only used in patients with suspicious lymph nodes, but it is not commonly used.

Because bladder tumors often occur in older adults, a general medical evaluation is also essential to document significant comorbid conditions, which might interfere with appropriate treatment regimens (ie, ability to tolerate general anesthesia, prolonged surgery, chemotherapy). (See "Preoperative medical evaluation of the healthy adult patient".)

Lung lesions — Chest radiographs are used for the initial evaluation and for periodic monitoring in patients at risk for pulmonary metastasis, although they are insensitive for lesions <1 cm. Metastatic lesions are typically non-calcified soft tissue densities. CT may be preferred over chest radiographs if patients are at "higher risk," such as muscle invasive disease, and it is definitely indicated if abdominal imaging reveals abdominal or lymph node metastases.

Bone scan — Radionuclide bone scans to detect bone metastases are recommended only in patients with invasive or locally advanced tumors and either skeletal symptoms or unexplained elevations in serum alkaline phosphatase. Increased uptake is a nonspecific finding, which may be due to degenerative change, trauma, and previous fracture sites, as well as metastatic disease. Plain radiographs, CT, or MRI of suspicious areas may be necessary to confirm a metastasis.

Positron emission tomography — PET has limited value and does not yet have an established role in patients with localized bladder cancer due to urinary excretion of 18F-fluorodeoxyglucose (FDG) [38].

Preoperatively, PET/CT is a promising tool to detect metastatic disease, especially in high-risk disease where the CT or MRI remained inconclusive on distant metastases. In a study of 55 patients with bladder cancer, integrated PET/CT improved the preoperative tumor, node, metastasis (TNM) staging compared with CT alone in 15 percent of patients [39].

PET may have a larger role in detecting disseminated disease in patients who are locally advanced. In another study, 46 patients were evaluated with PET scans [40]. Sensitivity for metastases to adrenal, bone, kidney, lymph node, and soft tissue were all 80 percent or greater.

HISTOLOGIC GRADE — The World Health Organization (WHO) and the International Society of Urological Pathology (ISUP) have established a consensus classification system for urothelial (transitional cell) neoplasms, in which urothelial cancer is classified as low grade and high grade. Typically, invasive urothelial cancers are high grade. (See "Pathology of bladder neoplasms", section on 'Classification'.)

STAGING — Stage is the most important independent prognostic variable for progression and overall survival for invasive bladder cancer. The eighth edition (2017) of the tumor, node, metastasis (TNM) system is used to stage bladder cancer.

Comprehensive pathologic staging requires cystectomy (with lymphadenectomy). However, clinical staging can be applied for those patients who will undergo neoadjuvant therapy. For patients with non-muscle invasive cancer (Ta, T1, Tis), stage is determined by transurethral resection of bladder tumor (TURBT) and bladder biopsies.

Clinical staging — Clinical staging is based on information derived from bimanual examination and imaging studies as well as pathology results from the cystoscopic biopsy or TURBT. However, the initial pathology obtained from cystoscopy specimens does not always accurately reflect the pathologic stage based on radical cystectomy.

The limitations of clinical staging are illustrated by a study of 778 consecutive patients with bladder urothelial carcinoma who were treated with radical cystectomy and pelvic lymphadenectomy [41]. Pathologic upstaging occurred in 42 percent of patients. This included patients thought to have non-muscle invasive disease who had muscle invasion in the pathologic specimen and those thought to have organ-confined clinical stage in whom non-organ confined tumor was identified (≥pT3N0, or any pT and N positive (table 1)). Pathologic downstaging occurred in 22 percent of cases.

The detection of lymph node metastases with imaging is poor. Approximately 20 to 30 percent of patients who undergo cystectomy with clinically node-negative disease by computed tomography (CT) criteria have pathologic positive nodes at lymphadenectomy [42,43].

Pathologic staging — The standard staging system is the TNM system, which is based on pathologic studies of cystectomy specimens (table 1) [44]. This staging system is applied to urothelial carcinoma, squamous cell carcinoma, undifferentiated carcinoma, and adenocarcinoma arising in the bladder.

Tumor (T) stage —  (figure 1)

●Ta lesions – Ta tumors are exophytic (papillary) lesions that tend to recur, but these are relatively benign and generally do not invade.

●Tis – Carcinoma in situ (CIS) or flat tumors.

●T1 lesions – If a tumor invades the submucosa or lamina propria, it is classified as a T1 tumor.

●T2 lesions – In T2 lesions, invasion into muscle is present. For T2 tumors, cystectomy is considered "standard therapy." When muscle invasion is present, the probability of nodal and distant metastases is increased. The 2017 TNM staging system divides muscle-infiltrating (T2) disease into superficial (T2a) or deep (T2b) invasion, with disease still confined within the bladder [44].

●T3 lesions – T3 tumors extend beyond muscle into the perivesical fat. CT or magnetic resonance imaging (MRI) scans may help to identify disease that has spread outside the bladder. T3 stage is stratified between T3a (microscopic) and T3b (macroscopic).

●T4 lesions – The TNM system differentiates tumors extending into adjacent organs (T4) from those extending into perivesical fat (T3). Tumor invading the prostate, vagina, uterus, or bowel is classified as T4a, while tumor fixed to the abdominal wall, pelvic wall, or other organs is T4b. Urothelial tumors may grow into the prostate along the prostatic ducts; these are noninvasive lesions with a good prognosis when resected. Alternatively, they may directly invade the prostatic stroma, which indicates a worse prognosis [45].

The most important prognostic determinant that is derived from staging is whether the tumor is organ confined (≤T2) or non-organ confined (≥T3). The accuracy of available methods for determining the degree of muscle invasiveness preoperatively is modest. Even in experienced hands, the correlation between depth of invasion, as assessed by cystoscopic evaluation and TURBT, and the pathologic examination of the bladder at the time of cystectomy is only approximately 70 percent. One study highlighted several features associated with a high risk of T3, T4, and/or node-positive disease, including detection of a three dimensional mass on examination under anesthesia (EUA), hydronephrosis, lymphovascular invasion, and aberrant histology (eg, micropapillary, neuroendocrine) [46].

Nodal (N) disease — The TNM system categorizes nodal disease based on the number and size of the involved nodes. It also accounts for metastases to specific sites.

In the 2017 TNM staging system, a single lymph node metastasis in the true pelvis is considered N1 disease, multiple nodes in the true pelvis are classified as N2 disease, and nodal involvement of the common iliac nodes is classified as a secondary lymphatic drainage area (N3) rather than metastatic disease. Lymph node sampling should include excision of an average of >12 lymph nodes [44].

Patients with nodal metastases but without disseminated disease may be treated with cystectomy or combined-modality approaches. (See "Radical cystectomy" and "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer".)

Metastatic (M) disease — The presence of disseminated metastases (eg, lung, liver, bone) portends the need for systemic therapy. Despite significant advances, the long-term prognosis is poor for most patients. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Bladder cancer diagnosis and staging (Beyond the Basics)" and "Patient education: Bladder cancer treatment; non-muscle invasive (superficial) cancer (Beyond the Basics)" and "Patient education: Bladder cancer treatment; muscle invasive cancer (Beyond the Basics)")

SUMMARY

●Clinical presentation – Patients with urothelial bladder cancer typically present with painless hematuria. The presence of unexplained hematuria in adults requires evaluation that is based on risk of malignancy. This risk is influenced by patient age, sex, presence of gross or microscopic hematuria, and tobacco exposure. (See 'Clinical presentation' above and 'Hematuria' above.)

●Diagnostic evaluation

•Cystoscopy – Cystoscopy is the initial procedure for both the diagnosis and management of urothelial malignancy. Cystoscopy is used to establish the diagnosis, assess whether or not muscle invasion is present (figure 1), and provide initial therapy for non-muscle invasive lesions. (See 'Cystoscopy' above.)

•Urine cytology – Urine cytology is widely used in combination with cystoscopy to assess for the presence of carcinoma in situ and to evaluate for the presence of upper urinary tract lesions. (See 'Urine cytology' above.)

•CT imaging – Computed tomography (CT) is the preferred imaging procedure to assess the local extent of disease and to further examine the renal pelvis and ureters. (See 'Urinary tract imaging' above and "Malignancies of the renal pelvis and ureter".)

●Staging – Stage is the most important independent prognostic variable for assessing the probability of progression and survival. The standard approach is the tumor, node, metastasis (TNM) staging system, which requires cystectomy (table 1). For patients who will undergo neoadjuvant therapy, clinical staging is appropriate. (See 'Staging' above.)

●Treatment – An overview of the treatment of bladder cancer is presented separately. (See "Overview of the initial approach and management of urothelial bladder cancer".)