ACR Appropriateness Criteria®

Clinical Condition: Follow-up Imaging of Bladder Carcinoma

Variant 1: Superficial TCC - no invasion or risk factors.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: Invasive TCC with or without cystectomy.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 3: Superficial TCC – no invasion with risk factors.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

Transitional cell carcinoma (TCC) of the bladder accounts for 95% of all bladder cancer in the United States. It is the second most common genitourinary malignancy and the fifth leading cause of cancer deaths in American males over 75 years of age. In 2006, approximately 61,420 new cases were expected to occur. Bladder cancer occurs about four times more commonly in men than in women and with double the frequency in whites compared to African Americans. According to the American Cancer Society, "An estimated 13,060 deaths will occur in 2006. For all stages combined, the 5-year relative survival rate is 82%. When diagnosed at a localized stage, the 5-year survival rate is 94%; 75% of cancers are detected at this early stage. For regional and distant stages, 5-year relative survival rates are 48% and 6%, respectively. Beyond 5 years, survival continues to decline, with a rate of 75% at 10 years and 70% at 15 years after diagnosis." Patients who have been diagnosed and treated for TCC require follow-up evaluation, which is usually based upon the type of treatment as well as accurate initial grading and staging of the tumor.

The purposes of follow-up imaging evaluation are to detect new or previously undetected tumor, to detect recurrent or metastatic disease, and to monitor the effects and/or complications following urinary diversion surgery. Recommendations for tumor surveillance can be based on the classification of patients into three groups; 1) those with superficial bladder cancer but no additional risk factors and treated by local therapy; 2) those with superficial bladder cancer with additional risk factors but still treated by local therapy; and 3) those with invasive bladder cancer, usually treated with cystectomy.

In patients with newly diagnosed TCC, the median time to the first recurrence is 31 months. Subsequent recurrences present with increasing frequency.

The likelihood of recurrent or metastatic disease increases with the presence of one or more of the following risk factors:

1. Depth of invasion - Most TCCs of the bladder (75 to 85%) are superficial. Although the risk of recurrence is approximately 75%, most remain superficial, with only 10% to 15% progressing to invasive carcinoma. There is evidence to indicate that cancers that invade the lamina propria (stage T1) should not be regarded as superficial. High-grade stage T1 tumors may progress to invade muscle in 30% to 50% of cases. When this occurs, the prognosis is as poor as it is for those presenting initially with invasive cancer. More than 50% of patients who are treated locally for invasive cancer manifest distant metastases, and they usually die of their disease within 2 years.
2. Tumor size - Various studies have shown that tumors greater than 3 cm have up to a 35% chance of progression, and tumors greater than 10 grams are also associated with a poor prognosis.
3. Grade - Progression from grade I to III in patients without interval intravesical chemotherapy, cystectomy, or radiation therapy has been associated with an increased incidence of invasive disease and a decreased 5-year survival. In one study, fewer than 10% of grade I tumors but as many as 50% of grade II tumors and more than 80% of grade III tumors were found to be invasive at the time of initial diagnosis. In another study, the 5-year survival of patients with grade I tumors was 94%, but only 40% for patients with grade III tumors.
4. Adjacent or remote bladder mucosal changes - If there are adjacent or distant changes of atypia or dysplasia, there is a significant chance of progression to muscle invasion (more than 30% within four years of diagnosis). Carcinoma in situ (CIS), in patients with low-grade, low-stage lesions may be associated with progression to muscle invasion (greater than 80% within 4 years of diagnosis).
5. Multiplicity of foci - The finding of multiple tumors is seen in approximately 30% of cases and is associated with a recurrence rate that is almost one-third higher than it is in patients with single lesions. This finding is generally associated with a shortening of the average time until recurrence. Two of three patients with single lesions but nine of ten with multiple lesions developed recurrent carcinoma. In a randomized clinical trial evaluating the prognostic factors associated with recurrence of T1 cancers, the number of tumors (worst for those with three or more) at the time of presentation was most important followed, in order of importance, by the number of recurrences (significantly greater chance of future recurrence for those patients with more than one recurrence per year) and the size of the largest tumor (worst for those over 3 cm).
6. Upper tract obstruction has been associated with a decreased 5-year survival rate. Patients with bilateral hydronephrosis had a 5-year survival of 31%, compared with 45% for those who had unilateral involvement and 63% for those with no hydronephrosis.
7. Lymphatic invasion in the lamina propria is a very poor prognostic sign, and most patients so affected die within 6 years. Solid (nonpapillary) lesions have a greater tendency for lymphatic invasion.
8. TCC involvement of the prostate - When TCC of the bladder is associated with involvement of the prostate (and it has been observed in 29% to 43% of cystectomy specimens), particularly with stromal invasion, there is a substantially increased risk of urethral recurrence. Sixty-seven percent of men with urethral recurrence had prostatic TCC in cystectomy specimens. Urethral recurrence can be expected in only 1% to 4% of cases when there is no TCC in the prostate. Those patients who are not candidates for cystoprostatectomy with urethrectomy are best followed up with urethral washings. Urethroscopy is performed in those having positive cytologic results.
9. Laboratory tests and chromosomal abnormalities - A number of laboratory tests have been used to prognosticate tumor progression. These include tests for Thompson-Friedenreich (T) antigen expression, lectin-binding carbohydrate structures, ABH blood group antigens, oncofetal protein expression, and epidermal growth factor receptors. According to one study, "these tests have not been adopted into clinical practice to influence treatment decisions in individual patients." Chromosomal abnormalities in tumors (marker chromosomes and a large proportion of aneuploid tumor cell lines) have also been used to predict tumor recurrence or progression.

Cystoscopic and Virtual Cystoscopic Surveillance

Recommended surveillance for patients treated for superficial bladder TCC includes cystoscopy every 3 months for 2 years, then every 6 months for 2 years, and then yearly thereafter. There has been interest in developing virtual cystoscopic or cystographic techniques using magnetic resonance imaging (MRI) and computed tomography (CT) both for problem solving in cases that are suboptimal for standard cystoscopy (narrow-necked diverticula) and as a way to avoid the patient discomfort associated with standard cystoscopy. One study demonstrated CT cystography to have a 100% sensitivity in identifying 0.5 cm masses and a sensitivity of 95% for all patients in detecting neoplasm with an accuracy of 88%. Another study examined MR cystography (multiplanar reconstructions) and cystoscopy demonstrating a combined sensitivity and specificity of 90.7% and 94.0% respectively. Multiplanar MR reconstructions (cystography) alone demonstrated sensitivity of 92.3% and specificity of 91.1% and MR cystoscopy demonstrated sensitivity of 90.7% and specificity of 90.4%. Both CT and MR cystoscopy provide views comparable to standard cystoscopy.

Urinalysis and cytologic evaluation should be performed at the time of each cystoscopy. Positive cytologic findings are followed by examination of the remaining bladder or upper tracts. There has been interest in developing quantitative tests to complement or even replace urinary cytology in follow-up of bladder carcinoma. One study demonstrated 85% sensitivity in detecting recurrent bladder cancer using the NMP22 marker detection device versus 41% sensitivity for traditional cytology, suggesting that it may substitute for urinary cytology. Additional studies demonstrate similar sensitivities for detecting bladder cancer with various molecular markers and some of these studies suggest that, due to its sensitivity, immunohistochemical testing may increase the time period between cystoscopies or even replace cystoscopy.

Intravenous pyelography (IVP) was once the most common imaging modality used to evaluate the urothelium of the upper collecting system. CT urography has begun to supplant IVP as its use becomes increasingly widespread. Although some suggest an upper urinary tract imaging study such as these every one or two years, most believe that, in the absence of risk factors, urine cytologic evaluation and cystoscopy are sufficiently accurate, especially since the risk of upper-tract TCC in all patients treated for bladder carcinoma is only about 2%–5% and the mean interval between initial treatment of bladder tumor and detection of subsequent upper-tract cancer is 70-80 months. This low risk may not be sufficient to justify routine upper-tract screening, in spite of the fact that not all recurrences give positive cytologic results or are associated with hematuria.

In a study limited to patients who had their initial bladder cancer treated with radical cystectomy only, the mean interval between cystectomy and detection of upper tract tumors was approximately 40 months (range 8-100). Surveillance of the upper tracts is appropriate in patients with positive urine cytologic results or every one to two years in patients with the following risk factors (usually post-cystectomy):

1. Carcinoma in situ (CIS) - When found in the cystectomy specimen, patients had a 9% to 13% incidence of upper tract TCC, with a correlation between the extent of the CIS and the risk of upper tract TCC.
2. Urethral CIS - When present, the likelihood of upper tract TCC increases to 20 to 30%.
3. Multiple tumors.
4. Recurrent tumors.
5. Tumors involving the ureteral orifices.
6. Tumors arising in bladder diverticula as a result of later detection and earlier transmural tumor extension.

If a documented recurrence is invasive, the patient is then staged.

If CT urography cannot be done if there is incomplete visualization or nonvisualization of the collecting structures, evaluation can be supplemented with retrograde pyelography or, in those patients with ileal conduits, replaced by loopogram. CT urography is also promising in those patients with urinary diversions and may provide additional diagnostic information as it provides examination of the entire abdomen and pelvis unlike a standard loopogram. A preliminary study demonstrated that CT urography with 3D rendering depicted both normal and abnormal postoperative findings in patients with urinary diversions. The addition of digital radiography enhanced visualization of the urinary collecting system to a statistically significant degree. Antegrade pyelography is uncommon but occasionally performed for diagnosis when the above techniques fail or if the collecting system is directly accessed to perform urine cytology or nephroscopy.

Modern imaging techniques have led to more accurate tumor staging and detection of recurrences. These results in stage migration as patient with "...silent or early metastases, [move] from lower into higher..." TNM (tumor, nodes, metastases) categories. When CT is used to evaluate patients following cystectomy, the pelvis is the most common site of recurrence. In these cases, the CT should include evaluation of the abdomen and perineum so that unsuspected, isolated abdominal metastases and recurrent perineal tumor will not be missed. Most metastases are detected within the first 18 to 24 months following surgery. Bladder cancer deaths occur within 2 years of the initial diagnosis in over 80% of cases. The most common sites of metastatic TCC are lymph nodes, liver, lung, bone, and adrenal glands.

Computed Tomography

CT is recommended at 6, 12, and 24 months for follow-up of patients with minimal muscle invasion (T2) who either elect cystectomy or other types of therapy without cystectomy, since most recurrences become evident within the first 2 years after surgery. There is a different recommendation for follow-up of patients treated with a bladder-preserving surgery. In these patients with transurethral resection of localized muscle-invasive TCC and follow-up combined neoadjuvant chemotherapy and radiation therapy, CT scans of the abdomen and pelvis are performed at 3 months after completion of radiation therapy and then every 6 months or "as otherwise indicated."

Magnetic Resonance Imaging

MRI of the bladder may be used to evaluate of superficial bladder tumors. CT provides limited visualization of the depth of tumor invasion within the bladder wall. MRI, even without intravenous contrast enhancement, has been noted to be "superior to clinical staging" and to allow distinction between advanced T3a tumors and the less invasive T1, T2, and early T3a lesions. One study demonstrated staging accuracies of 85% and 82% in differentiating superficial from muscle-invasive tumors and organ-confined from non-organ-confined tumors, respectively. Additionally, the accuracy of pathologic lymph node detection was 96%. Overstaging occurred in 32% of cases. Another study reviewed 71 patients using gadolinium-enhanced endorectal surface coil and reported an 83% overall staging accuracy. Muscle invasion was diagnosed with 87% accuracy, 91% sensitivity, and 87% specificity.

Although more costly than CT, MRI is more accurate in differentiating between T3b and T4a, between T4a and T4b, and between marrow and no marrow infiltration. MRI performed with ferumoxtran-10 (ultrasmall superparamagnetic iron oxide) contrast demonstrated accuracies in pathologic lymph node detection of up to 92% and sensitivities of up to 96%. These improved techniques for detecting new, recurrent, or metastatic tumors in patients with proven invasive TCC have sometimes been associated with decreased morbidity, although not with increased curability.

Ultrasonography

Abdominal and transurethral ultrasonography (US) have had "limited success" in the evaluation of bladder cancer for determining its local extent. Transabdominal US has "important limitations," particularly for tumors that are flat, smaller than 5 mm, or near the bladder neck and when there has been both understaging and overstaging. However, using transrectal US (TRUS), it is possible to detect almost all lesions in the region of the bladder neck and dome, as well as a number of small tumors (<5 mm). Some evidence suggests that there is improved bladder tumor staging when TRUS is used in conjunction with MRI. TRUS has also been effective for monitoring tumor response or recurrence following neoadjuvant chemotherapy.

Chest Radiography

Chest radiography (PA and lateral) to search for occult metastases should be obtained at 6, 12, 18, and 24 months and then yearly for up to 5 years following cystectomy. A lung lesion suspected on chest radiography may be appropriately followed by a CT scan of the chest for improved definition.

Positron Emission Tomography

Currently, there is a limited role for positron emission tomography (PET) imaging in the assessment of bladder cancer. According to one study, "It has a high positive predictive value and can be used for problem solving in patients with indeterminate findings on conventional imaging." Another study used PET in 12 patients with histologically proven bladder cancer. "The study demonstrated a true-positive rate of 66.7% and a false-negative rate of 33.3%. PET was able to identify 100% (17/17) of distant metastases (lung, bone, and remote lymph node) as well as 66.7% (2/3) of local pelvic lymph nodes." Therefore, "fluorine-18 fluorodeoxyglucose (FDG-PET) might be useful in detecting perivesical tumor growth or distant metastasis in patients with advanced bladder cancer, and for the early detection of recurrent cancer following therapy, although a major remaining pitfall is the intense FDG accumulation due to excretion in the urine."

Likewise, a review of PET imaging in patients with bladder, prostate, and renal cancer concluded that ¹⁸F-FDG is unsuitable for imaging bladder tumors because of its high urinary excretion, although there may be a role in detection of recurrent disease. A study correlating ¹⁸F-FDG-PET and CT results in the same patients reported sensitivity, specificity, and accuracy of 60%, 88%, and 78%, respectively, in nodal and metastasis staging, suggesting improved distant metastatic and locoregional node staging. Preliminary studies show that ¹¹C-choline PET when compared with CT promises slightly increased accuracy of lymph node staging (63.0% vs 88.9%, p <0.01) and may avoid false-positive lymph nodes due to reactivity when compared with CT. In addition there is negligible urinary excretion of ¹¹C-choline.

Summary

Routine imaging follow-up is NOT indicated for patients with superficial TCC and no invasion of the lamina propria or additional risk factors. Patients with superficial TCC require careful observation and IVP or CT urography every 1-2 years IF any of the following risk factors for recurrent tumor are present:

1. Tumor size greater than 3 cm or 10 grams
2. Higher than grade I tumor, or
3. Adjacent or remote bladder mucosal changes or dysplasia or CIS. Additional imaging may be necessary if there are positive urine cytologic findings, hematuria, or abnormal cystoscopy.

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