Urinary Tract Cancers
Sumanta K. Pal
Hyung L. Kim
Robert A. Figlin
RENAL CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Renal cell carcinoma (RCC) constitutes 3% of adult malignancies. The worldwide incidence is increasing at an annual rate of about 2%, with approximately 58,000 new cases per year in the United States and 13,000 associated deaths. Men are affected twice as often as women. RCC is a tumor of adults, occurring primarily in those in their fourth and sixth decades. The incidence and mortality rates for blacks appear to be increasing in excess to those for whites in the United States.
B. Etiology. Approximately 70% of sporadic cases of clear cell RCC (the most common histologic variant) are associated with inactivating mutations of both copies of the Von Hippel-Lindau (VHL) tumor suppressor gene. This results in overexpression of hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF), leading to defective regulation of angiogenesis, which is of major importance in the pathophysiology of RCC.
1. Factors that increase the risk for RCC include the following:
a. Smoking
b. Urban living
c. Family history of renal cancer
d. Thorotrast exposure
e. Obesity
f. Genetic syndromes include
(1) Von Hippel—Lindau disease (associated with germline mutations of the VHL gene; 35% to 45% of these patients have RCC, mostly multiple and bilateral)
(2) Hereditary type 2 papillary RCC: associated with mutations in MET proto-oncogene
(3) Birt-Hogg-Dube (BHD) syndrome
2. Unproven factors that may increase the risk for RCC include polycystic kidney disease, diabetes mellitus, and chronic dialysis.
II. PATHOLOGY AND NATURAL HISTORY
A. Adenocarcinomas (historically named hypernephromas or Grawitz tumors) make up nearly all renal cancers in adults. They are typically round and have a pseudocapsule of condensed parenchyma and connective tissue. Bilateral tumors occur in 2% of sporadic cases, either synchronous or asynchronous.
1. The most common histologic types include clear cell (70%), papillary (10% to 15%), chromophobe (5%), and unclassified RCC (<5%). Sarcomatoid tumors can arise from any cell subtype.
2. These tumors originate from proximal tubular cells, invade local structures, and frequently extend into the renal vein. Metastasis occurs through the lymphatics and bloodstream. The most common sites of distant metastases are the lungs, liver, bones, and brain. Adenocarcinomas may present with metastases to
unusual sites, such as the fingertips, eyelids, and nose. A primary renal cancer may be diagnosed based on the characteristic histology of a metastatic deposit.
unusual sites, such as the fingertips, eyelids, and nose. A primary renal cancer may be diagnosed based on the characteristic histology of a metastatic deposit.
3. The natural history of RCC is more unpredictable than that of most solid tumors. The primary tumor has variable growth patterns and may remain localized for many years. Metastatic foci may have long periods of indolent or apparently arrested growth and may be detected many years after removal of the primary tumor.
B. Transitional cell carcinomas are uncommon tumors that arise in the renal pelvis and often affect multiple sites of urothelial mucosa, including the renal pelvis, ureters, and urinary bladder (see “Urinary Bladder Cancer,” Section II). These tumors usually are low grade but are being discovered late in the course of the disease. Transitional cell carcinomas occasionally have a peculiar disposition to spread over the posterior retroperitoneum in a sheet-like fashion, encasing vessels and producing urinary tract obstruction. Hematogenous dissemination occurs, particularly to lung and bone.
C. Rare renal tumors
1. Nephroblastomas (Wilms tumors) appear as large, bulky masses in children but rarely occur in adults (see Chapter 18, “Wilms Tumor”).
2. Lymphomas and sarcomas arising in the kidney have clinical courses similar to their counterparts elsewhere in the abdomen.
3. Juxtaglomerular tumors (reninomas) are rare causes of hypertension and are usually benign.
4. Hemangiopericytomas are renin-secreting tumors associated with severe hypertension and are occasionally malignant (15% of cases).
5. Oncocytomas (7%) are benign tumors originating from a subtype of collecting ducts.
6. Bellini tumors (collecting duct RCC, <1%) are aggressive cancers originating from collecting ducts.
7. Medullary cancer (<1%)
8. Benign renal adenomas. The existence of benign renal adenoma is controversial because it is not possible to determine malignant or benign biologic behavior only by histology on any lesion <3 cm in diameter.
D. Metastatic tumors. The kidney is a frequent metastatic landing site for many malignancies, mainly cancers of the lung, ovary, colon, and breast.
E. Paraneoplastic syndromes commonly occur with renal adenocarcinomas.
1. Erythrocytosis. Renal adenocarcinomas are associated with erythrocytosis in 3% of patients and account for 15% to 20% of cases of inappropriate secretion of erythropoietin. A left flank mass of RCC may be mistaken for an enlarged spleen resulting from polycythemia vera. The differential diagnosis of erythrocytosis is discussed in Chapter 34, “Increased Blood Cell Counts,” Section I. Tumor production of erythropoietin may identify a subset of patients responsive to immunotherapy with interleukin-2 (IL-2) and interferon-α (IFN-α).
2. Hypercalcemia, which occurs in about 5% of patients, associated with parathyroid hormone-like proteins. Hypercalcemia may also be associated with widespread bony metastases.
3. Fever caused by tumor occurs in 10% to 20% of patients.
4. Abnormal liver function (Stauffer syndrome) occurs in 15% of patients. Leukopenia, fever, and areas of hepatic necrosis without liver metastases are noted. The resulting elevated serum levels of alkaline phosphatase and transaminase are reversed after nephrectomy.
5. Hypertension associated with renin production by the tumor occurs in up to 40% of patients and is alleviated by removal of the tumor.
6. Hyperglobulinemia can result in elevated erythrocyte sedimentation rate.
7. Amyloidosis occasionally occurs.
III. DIAGNOSIS
A. Symptoms and signs. Symptoms other than hematuria usually indicate large, advanced tumors. The classic triad of flank pain, a flank mass, and hematuria occurs in <10% of patients with RCC. The combined picture of anemia, hematuria, and fever is rare, but suggestive of renal cancer. The widespread use of ultrasound, CT, and MRI changed significantly the typical presentation of RCC. More than three-fourths of all locally confined tumors are found serendipitously (as an incidental finding), and thus a substantial proportion of patients are symptom free at the time of diagnosis. Therefore, symptoms and signs (as listed below) become rare and currently are more characteristic in cases presenting with advanced disease.
1. Symptoms
a. Gross hematuria is rare.
b. A steady, dull flank pain occurs in a few patients. Colicky pain may develop if blood clots are passed into the ureter.
c. Weight loss may be a presenting feature in <15% of patients.
d. Sudden onset of a left-sided or a right-sided varicocele is rare and usually suggests invasion into the renal vein or inferior vena cava, respectively.
e. Leg edema is the result of locally advanced disease, which causes venous or lymphatic obstruction.
f. Fever, plethora, or symptoms of hypercalcemia or anemia may be presenting features.
g. Symptoms related to metastases, including bone pain or fracture, may occasionally be a presenting symptom.
2. Physical findings
a. A palpable flank mass is rarely present.
b. Fever occurs in about 15% of patients.
c. Pallor from anemia may occur.
B. Diagnostic studies
1. Urinalysis may reveal proteinuria and hematuria. All patients with macroscopic or microscopic hematuria of any degree must have a thorough urologic evaluation.
2. Routine studies
a. Complete blood count, LFT, and renal function studies
b. Hyperglobulinemia may be present in patients with RCC because acutephase reactant proteins are elevated.
c. Chest radiographs may reveal multiple, large, round (cannonball-like) metastatic deposits that are characteristic of metastatic genitourinary neoplasms.
3. CT scanning of the kidneys is most cost-effective method for evaluating a suspected renal mass and should be the first study for that purpose. Extension through the capsule is usually diagnosed correctly. CT does not detect minimal lymph node involvement.
4. MRI may be as accurate as CT. MRI images demonstrate extension of tumor into the renal vein and vena cava more reliably in preparation for surgery.
5. Ultrasonography with duplex Doppler may assist in imaging tumor thrombus in the inferior vena cava and in defining its extension. It cannot be used for local staging because regional lymph node involvement cannot be imaged.
6. Scans for staging should be performed in the following situations:
a. Bone scan, if there is bone pain or elevated serum alkaline phosphatase levels
b. MRI of the brain, if there are signs of central nervous system abnormalities
7. Percutaneous biopsy of a renal mass has a controversial role and is also believed to be inaccurate in approximately 25% of the cases. This procedure should be restricted to patients with medical conditions that make surgery unduly hazardous and patients with metastatic disease for which a tissue diagnosis is necessary.
C. Renal cysts are usually classified using CT according to the chance of harboring malignancy (Bosniak classification). The following approach is recommended to evaluate potential renal cysts:
1. If a renal cyst is suspected or demonstrated and the findings are not strongly suggestive of cancer, ultrasound is performed to determine whether the mass is cystic. If a simple cyst or a fatty tumor is demonstrated, no further follow-up is usually indicated. If a hyperdense cyst is imaged, the patient should have follow-up studies.
2. Rarely, all imaging modalities are not diagnostic, and surgical exploration is indicated.
3. Bosniak cyst types 3 and 4 are managed in the same fashion as renal cancers.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. The current TNM staging system is shown in Table 13.1. A different system is used for cancers of the renal pelvis.
B. Prognostic factors
1. Pathologic stage is the most important prognostic indicator.
a. Tumor size >10 cm is associated with poor prognosis in comparison to smaller lesions.
Table 13.1 TNM Staging System for Cancers of the Kidneya | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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b. Venous extension. Renal vein or vena caval involvement is not associated with a hopeless prognosis if managed properly; 25% to 50% of patients survive for 5 years.
2. Histology. Sarcomatoid and unclassified patterns of RCC have a poor prognosis.
a. Nuclear grade correlates with survival across all tumor stages. Fuhrman four-tiered system is most commonly used; it takes into consideration nuclear size, nuclear shape, and nucleolar appearance.
b. Nuclear ploidy was proposed as a potential prognostic marker for survival. Nondiploid tumors are thought to harbor a less favorable prognosis.
3. Disease-free interval. The length of time between nephrectomy and the development of metastases affects the survival of patients with metastatic disease.
a. Nearly all patients who have metastases at the time of surgery or who develop metastases or local recurrence within 1 year of surgery die within 2 years if untreated.
b. Patients who develop metastases >2 years after nephrectomy have a 20% 5-year survival rate from the time metastases are recognized.
4. Integrated prognostic systems. The TNM system can be augmented with more complex systems that take into account various prognostic factors, such as Fuhrman nuclear-grading system and performance status to assess risk and the probability of survival with and without evidence of RCC. Such a system is shown in Figure 13.1.
V. PREVENTION AND EARLY DETECTION
The incidence of renal cancer might be reduced if tobacco-smoking habits could be controlled. Early detection depends on prompt attention to hematuria and other symptoms suggestive of these cancers.
VI. MANAGEMENT
A. Early disease
1. Surgery
a. Radical nephrectomy classically involves removal of all structures contained within Gerota fascia, including kidney, adrenal gland and superior ureter. Radical nephrectomy is generally used for large, locally advanced tumors. The adrenal gland can be safely spared when the tumor is in the lower pole or when a smaller tumor is clearly separate from the adrenal gland. A laparoscopic approach is generally preferred; however, an open approach may be necessary for tumors that involve adjacent structures such as the inferior vena cava.
b. Nephron-sparing surgery (NSS, partial nephrectomy) is the treatment of choice when it is technically feasible. Maximal preservation of renal function is an important goal of surgery since even mild renal insufficiency has been linked to cardiovascular disease and related morbidities such as myocardial infarction and stroke. Most tumors that are <4 cm in diameter are amenable to NSS. A minimally invasive approach using laparoscopy or robotics results in more rapid postoperative recovery when compared to an open approach. Although surgical resection is considered the standard of care, ablative procedures using cryotherapy or radiofrequency ablation can be considered for the smallest and most exophytic tumors.
c. Occlusion of the renal artery using angiographic techniques has been advocated for locally advanced tumors associated with increased vasculature. Occlusion procedures may limit blood loss and make the operation
technically easier. It may also provide palliation for symptomatic patients who are not candidates for surgery. However, renal artery occlusion will cause temporary pain, fever, and nausea.
technically easier. It may also provide palliation for symptomatic patients who are not candidates for surgery. However, renal artery occlusion will cause temporary pain, fever, and nausea.
 Figure 13.1. UCLA Integrated staging system: risk group assignment for patients with metastatic renal cell carcinoma. To obtain a patient’s risk group, begin at the top of the decision box and progress downward using the AJCC N and M stages, Fuhrman grade, and ECOG performance status. ECOG PS, Eastern Cooperative Oncology Group performance status (see inside of back cover); Int, intermediate risk; Neph, nephrectomy. Modified from Zisman A, Pantuck A, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002;20:4559, with permission |
d. Contraindications to surgery include high surgical risk because of unrelated medical diseases. Since the emergence of targeted therapies, the role of surgery (“adjunctive nephrectomy”) in the presence of distant metastases is once again under investigation.
2. Observation is now recognized as an acceptable option for small renal tumors (e.g., tumor <4 cm) in patients who are poor surgical candidates or have a limited life-expectancy. Many of these small tumors are benign; however, even if they are malignant, most small tumors are indolent and progress slowly.
3. RT has no established role in the management of early renal cancers.
4. Chemotherapy has no established role in the management of early renal cancers.
B. Advanced disease
1. Surgery
a. Nephrectomy. For patients treated with immunotherapy, cytoreductive nephrectomy has been shown to extend survival. However, immunotherapy has been largely replaced by a growing number of targeted therapies such as sunitinib and sorafenib. Therefore, ongoing clinical trials are revisiting the role of cytoreductive nephrectomy in patients treated with targeted therapies. Until these trials are completed, cytoreductive nephrectomy remains a well-accepted adjuvant to systemic therapy for patients with good performance status.
b. Resection of metastases. In select patients, metastatic lesions can be surgically resected for curative intent. Metastectomy is most likely to be curative in patients with a single metastatic lesion and in patients with a solitary recurrence identified more than 2 years after the definitive nephrectomy. Prior to performing metastectomy, a thorough metastatic workup is mandatory.
2. RT is used to palliate symptoms from metastases to the central nervous system and bone. Gamma knife radiotherapy is effective for control of brain metastasis.
3. Pharmacotherapy
a. Targeted Agents: Six molecularly targeted therapies are currently approved for the treatment of advanced RCC. These can be broadly divided into two categories: (1) vascular endothelial growth factor (VEGF)-directed therapies and (2) inhibitors of the mammalian target of rapamycin (mTOR). VEGF-directed agents include the monoclonal antibody bevacizumab, and the small molecule tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, and pazopanib. mTOR inhibitors currently approved for RCC therapy include everolimus and temsirolimus.
Each of these agents is supported by phase III data which can guide their clinical utilization. For instance, sunitinib and bevacizumab (with interferon-α, IFN-?α) were evaluated in treatment-naïve patients with advanced clear cell RCC. In contrast, the pivotal trial of pazopanib was performed in patients who were either treatment-naïve or cytokine-refractory. The majority of patients (82%) treated in the phase III evaluation of sorafenib were also cytokine-refractory. Given these reports, the National Comprehensive Cancer Network (NCCN) has rendered a category 1 recommendation to sunitinib, pazopanib, and bevacizumab/IFN-?α, for the first-line therapy of advanced clear cell RCC. Pazopanib also carries a category 1 recommendation for patients with cytokine-refractory disease, as does sorafenib. A category 1 recommendation by NCCN is based on a high level of evidence (e.g., randomized controlled trials) with uniform NCCN consensus.
The pivotal trials for everolimus and temsirolimus assessed distinct populations. Patients in the phase III evaluation of everolimus had advanced clear cell RCC and had been exposed to previous treatment with sunitinib and/or sorafenib. In contrast, the pivotal trial of temsirolimus principally included treatment-naïve patients with poor-risk disease. Uniquely, eligibility was not limited to those patients with clear cell RCC, and patients with treated brain metastases were allowed to enroll. The agent now carries a category 1 recommendation from the NCCN for patients with poor-risk disease.
More extensive experience with VEGF-directed therapies and mTOR inhibitors has suggested class effects associated with these agents. For
instance, VEGF-directed therapies appear to cause hypertension, proteinuria, hand-foot syndrome, impaired wound healing, and myelosuppression. In contrast, mTOR inhibitors have been associated with impaired metabolic profiles (i.e., hyperglycemia, hypertriglyceridemia, etc.), mucositis, and rash.
instance, VEGF-directed therapies appear to cause hypertension, proteinuria, hand-foot syndrome, impaired wound healing, and myelosuppression. In contrast, mTOR inhibitors have been associated with impaired metabolic profiles (i.e., hyperglycemia, hypertriglyceridemia, etc.), mucositis, and rash.
b. Immunotherapy. The role of immunotherapy for kidney cancer has decreased and is being supplanted by rapid progress with antiangiogenic agents. Nonetheless, IL-2 remains the only potentially curative treatment in selected patients with metastatic RCC.
(1) IL-2 administered alone in high-dose regimens produces a response rate of 15% to 20% in good-risk patients and durable remissions lasting for more than a decade in 10% of patients. Significant morbidity and 4% mortality associated with high-dose IL-2 make this therapy very difficult and applicable to only small minority of patients. IL-2 administered in lower dosages or in combination with IFN produces inferior response rates when compared with high-dose IL-2 in randomized trials. Recent data from the Renal SELECT study underscore a dearth of clinical or biologic criteria that identify patients who yield benefit from this modality.
(2) IFN-α as a single agent has modest antitumor activity in the setting of RCC, with a response rate of approximately 15%. With the emergence of effective targeted therapies, IFN-α is used primarily in clinical trials evaluating possible synergistic effects in combination with antiangiogenic agents.
c. Future strategies in the treatment of RCC include redefining the role of nephrectomy in advanced cases in the era of targeted therapies, the development of novel immunotherapeutic strategies (i.e., vaccine based therapy or PD-1 inhibition), and the development of biologic tools to risk stratify patients with both localized and advanced disease.
URINARY BLADDER CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Bladder cancers constitute 4.5% of all cancers in the United States. The disease is 2.5 times more frequent in men than in women and is most frequent in industrial northeastern cities. The average age of onset is the sixth to seventh decade. The incidence doubles in men >75 years of age versus younger men.
B. Risk factors and carcinogens
1. Occupational exposure is associated with 20% of cases. Historically, aniline dye workers were afflicted 30 times more than the general population. Aromatic amines and related compounds are the most abundant bladder carcinogens today. These are chemical intermediates of anilines, rather than the aniline dyes themselves. Leather, paint, and rubber industry workers also appear to have an increased risk for bladder cancer. Proven chemical carcinogens in these industries are 2-naphthylamine, benzidine, 4-aminobiphenyl, and 4-nitrobiphenyl.
2. Schistosomum haematobium infection of the bladder is associated with bladder cancer, particularly with squamous cell histology, in endemic regions of Africa and the Middle East.
3. Smoking increases the risk for bladder cancer fourfold in a dose-dependent fashion. Of men who die of bladder cancer, 85% have a history of smoking.
4. Pelvic irradiation increases the risk for bladder cancer fourfold.
5. Drugs. Cyclophosphamide unequivocally increases the risk for bladder cancer. Other drugs that have been implicated in animal studies but not proved in humans are phenacetin, sodium saccharin, and sodium cyclamate.
II. PATHOLOGY AND NATURAL HISTORY
A. Pathology
1. Histology. Of bladder cancers, 90% are transitional cell carcinoma (TCC), and 8% are squamous cell types. Adenocarcinomas, sarcomas, lymphomas, and carcinoid tumors are rare.
2. Sites of involvement. The majority of TCCs are linked to carcinogen exposures such as smoking. Carcinogens in urine are believed to produce a fieldchange in the urothelium that predisposes to formation of bladder cancer. Therefore, TCC can develop in any part of the urinary collecting system including the kidney and ureter; however, the bladder is the most common site for TCC because it functions to store urine and has the greatest contact time with urinary carcinogens.
3. Types of bladder cancer
a. Single papillary cancers are the most common type (70%) and the least likely to show infiltration.
b. Diffuse papillary growths with minimal invasion
c. Sessile cancers are often high grade and invasive.
d. Carcinoma in situ (CIS; flat intraepithelial growth) appears either the same as normal mucosa or as a velvety red patch.
4. The panurothelial abnormality or field defect. Bladder cancer appears to be associated with premalignant changes throughout the urothelial mucosa. This concept is suggested by the following observations:
a. Up to 80% of patients treated for superficial tumors develop recurrences at different sites in the bladder.
b. Multiple primary sites are present in 25% of all patients with bladder cancer.
c. Random biopsies of apparently normal areas of mucosa in patients with bladder cancer frequently show CIS.
d. Depending on the reported series, patients with bladder CIS also have ureteral CIS (10% to 60%) and urethral CIS (30%).
e. About 40% of patients presenting with carcinoma of the renal pelvis or ureter develop tumors elsewhere in the urinary tract, usually in the bladder.
B. Natural history
1. CIS of the bladder is multifocal and can affect the entire urothelium. CIS is a high-grade malignancy. Up to 80% of patients with untreated CIS develop invasive bladder cancer within 10 years after diagnosis; the disease is lethal for most of these patients.
2. Low-grade superficial carcinomas have a better prognosis than CIS. Although the recurrence rate is 80%, low-grade, superficial carcinomas do not metastasize. However, 10% of superficial carcinomas may progress to high grade, invasive tumors with potential for metastasis. More than 80% of patients with both superficial cancers and CIS progress to invasive disease.
3. High-grade or invasive tumors are associated with adjacent areas of CIS in 85% of cases. Squamous cell cancers and adenocarcinomas are usually high grade and have an aggressive clinical behavior. Other uncommon and very aggressive histologic variants include sarcomatoid cancer, small cell carcinoma, and micropapillary tumors.
4. Mode of spread. Bladder cancers spread both by lymphatic channels and by the bloodstream. High-grade lesions are more likely to metastasize. Of patients with distant metastases, 30% do not have involvement of the draining lymph nodes. Distant sites of metastases include bone, liver, lung, and, less commonly, skin and other organs. Uremia from ureteral compression by a large pelvic mass, inanition from advancing cancer, and liver failure are the usual causes of death.
5. Iatrogenic tumor implantation. High-grade bladder cancer cells exfoliated by cystoscopy, brushing, transurethral biopsy, or resection were reported to seed other areas of the bladder. Mucosal sites damaged by inflammation or instrumentation appear to be most receptive to such implants.
6. Associated paraneoplastic syndromes
a. Systemic fibrinolysis
b. Hypercalcemia
c. Neuromuscular syndromes
d. Leukemoid reaction
III. DIAGNOSIS
A. Symptoms and signs
1. Symptoms
a. Hematuria occurs as a presenting feature in 90% of patients.
b. Bladder irritability occurs in 25% of patients. Hesitancy, urgency, frequency, dysuria, and postvoiding pelvic discomfort may mimic prostatitis or cystitis. These symptoms occur in patients with CIS as well as in those with tumors that are large, extensive, or near the bladder neck.
c. Pain in the pelvis or flank is associated with locally advanced disease.
d. Edema of the lower extremities and genitalia develops from venous or lymphatic obstruction.
2. Physical findings. The patient is carefully examined for metastatic sites. It is mandatory that a bimanual examination is performed by the urologist through the rectum each time the patient is put under general anesthesia or having a cystoscopy done. The importance of the bimanual examination cannot be overemphasized. It supplies pertinent information concerning local extension of the disease not obtainable by current imaging modalities.
B. Diagnostic studies
1. Routine studies
a. CBC, LFT, and renal function tests
b. Urinalysis
c. Chest radiograph
2. Cystoscopy is the cornerstone procedure for diagnosing bladder cancer. Biopsy is performed of abnormal areas. Biopsies of normal areas at random are performed to search for CIS. Cystoscopy is followed by bimanual pelvic examination under anesthesia in both men and women. Cystoscopy is indicated for patients with the following clinical features:
a. Any gross or microscopic hematuria and a normal upper urinary tract imaging (except female patients with a single episode of acute bacterial cystitis who are <40 years of age and do not smoke)
b. Unexplained or chronic lower urinary tract symptoms
c. Urine cytology that is suspicious for cancer
d. A history of bladder cancer
3. Urography. An intravenous pyelogram (IVP) is useful for imaging the upper urinary tract in patients with unexplained hematuria, or cystoscopic or cytologic evidence of tumor in an attempt to search for primary sites in the ureters or renal pelvis. It is advisable to perform an IVP before cystoscopy, because if a poorly visualized upper system or nonconclusive filling defect is imaged, retrograde pyelography may be performed using a ureteral catheter inserted during the same cystoscopy session.
4. CT urography (CTU). CT scanning of the abdomen and pelvis typically includes three phases: a noncontrast phase, an early postcontrast phase, and the pyelographic phase. During the noncontrast phase, abnormal
calcifications (i.e., urinary stones) can be identified. The early postcontrast phase obtained minutes after IV administration of contrast serves to discern renal lesions and to differentiate between abnormal lymph nodes and normal anatomic structures. During the pyelographic phase, the contrast material is observed as it is excreted into the collecting system, allowing the identification of abnormal filling defects within the collecting system. Owing to its higher resolution and diagnostic accuracy, CTU has largely supplanted IVP as the imaging modality of choice for the upper urinary tract.
calcifications (i.e., urinary stones) can be identified. The early postcontrast phase obtained minutes after IV administration of contrast serves to discern renal lesions and to differentiate between abnormal lymph nodes and normal anatomic structures. During the pyelographic phase, the contrast material is observed as it is excreted into the collecting system, allowing the identification of abnormal filling defects within the collecting system. Owing to its higher resolution and diagnostic accuracy, CTU has largely supplanted IVP as the imaging modality of choice for the upper urinary tract.
It is important to obtain a CTU in any patient with hematuria, a history of bladder cancer, or positive cytology. CTU is also useful for staging invasive bladder cancer or upper tract TCC. Abnormally enlarged lymph nodes and visceral metastasis can be observed by CTU. Local invasion into pelvic organs or tumor infiltration into the perivesical fat can also be observed. CT is not reliable for the detection of local invasion, however.
5. Urine cytology detects about 70% of bladder cancers that are subsequently diagnosed by cystoscopy. Cytologic evaluation should not be the primary diagnostic method for patients suspected of having bladder cancer. Urine cytology is useful for the following purposes:
a. Following patients with a history of bladder cancer
b. Screening symptom-free patients who are exposed to environmental carcinogens
c. Evaluating patients with chronic irritative bladder symptoms before cystoscopy is done
6. Bladder tumor markers. Bladder tumor antigen (BTA), nuclear matrix protein 22 (NMP-22), telomerase activity, fibrin degradation products assay, and others are being tested to replace or decrease the frequency of cystoscopy, to serve in follow-up of TCC patients, and to assist in screening and evaluation of hematuria. Some of these tests are promising, but the current standard care for a patient with hematuria or history of TCC remains cystoscopy.
7. Fluorescent in situ hybridization (FISH). Because bladder cancers are associated with typical chromosomal aberrations, their detection in the urine is an accurate and noninvasive modality of TCC detection. The current commercially available FISH test (UroVysion) uses four chromosomal probes to detect an abnormal number of chromosomal copies (CEP17, CEP3, and CEP7) and a single locus-specific indicator probe (9p21). FISH has a sensitivity of 81% and a specificity of 96%, far better than those of cytology.
8. Scans. Bone scans should be performed in patients with bone pain or elevated serum alkaline phosphatase or transaminase levels.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. The current TNM staging system is shown in Table 13.2.
B. Prognostic factors.
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