Contributors of Campbell-Walsh-Wein, 12th edition
Sumit Isharwal, Max Kates, Trinity J. Bivalacqua, Joseph Zabell, Badrinath R. Konety, Thomas J. Guzzo, John P. Christodouleas, David J. Vaughn, Neema Navai, Colin P.N. Dinney, Anton Wintner, Douglas M. Dahl, Guarionex Joel Decastro, James M. Mckiernan, Mitchell C. Benson, Eila C. Skinner, Siamak Daneshmand, and Khurshid A. Guru
Epidemiology
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In the United States 81,400 patients will be diagnosed with bladder cancer (BlCa) in 2020, and 17,980 will die from their disease.
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The average age of diagnosis is 73 years in the United States with approximately 9 of 10 patients diagnosed after the age of 55 years.
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Although BlCa is more than three times as prevalent in men, women are more likely to be seen initially with more advanced tumors and less favorable prognosis.
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BlCa is most common among white Americans, with an incidence rate 1.5 times that of African Americans, twice that of Hispanic Americans, and six times that of Native Americans.
Economic impact
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BlCa is the most expensive cancer to treat per patient over a patient’s lifetime.
Risk factors
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Genetics – The most-studied genes associated with BlCa are N -acetyltransferase 2 and a deletion of glutathione S-transferase µ. Both of these genes are associated with the ability to metabolize aromatic amines and thus play an important role in the subset of individuals with environmental carcinogen exposure.
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Hereditary – Patients with Lynch syndrome are at increased risk of developing urothelial cancer. This increased risk is primarily found among the mismatch repair gene MSH2 mutations carriers.
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Tobacco – This is the main known cause of BlCa and accounts for 30%–40% of all urothelial carcinomas. Aromatic amines are the primary carcinogens in tobacco smoke that lead to cancer.
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Occupational Risk – Particularly at-risk occupations that work with aromatic amines include tobacco, dye, and rubber workers; hairdressers; painters; and leather workers. Those who work with polycyclic aromatic hydrocarbons are also at risk, including chimney sweeps, nurses, waiters, petroleum workers, and seamen.
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Medical Conditions – Patients with neurogenic bladder and spinal cord injuries who have chronic indwelling catheters are at a modestly increased risk of developing squamous cell carcinoma of the bladder. Malignant potential of bladder exstrophy has been well documented, with adenocarcinoma accounting for >90% of cases and squamous cell and urothelial carcinoma account for the remaining 10%.
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Schistosomiasis – Schistosomiasis remains a major contributor to squamous cell carcinoma of the bladder in many tropical countries.
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Radiation Exposure – External beam radiation therapy for cervical cancer and prostate cancer is associated with higher incidence of BlCa with estimated latency period of 15–30 years.
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Chemotherapy – Cyclophosphamide that has been shown to cause BlCa and phosphoramide mustard is the primary mutagenic metabolite.
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Environmental Pollution – Exposure to arsenic in drinking water has been associated with the development of BlCa. The mechanism of arsenic-mediated carcinogenesis is thought to be multifactorial, including oxidative stress, epigenetic effects, and alterations in DNA repair.
Presentation and workup
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Painless gross hematuria is present in 85% of patients with newly diagnosed BlCa, and microscopic hematuria is present in nearly all patients.
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Irritative voiding symptoms (e.g., frequency, urgency) also may be signs of BlCa, particularly carcinoma in situ (CIS).
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Workup includes a history and physical examination, cystoscopy, upper tract imaging, urine culture, and urine cytology in patients with gross hematuria.
Diagnosis
The gold-standard test for the diagnosis of BlCa is cystoscopy followed by biopsy/resection of tumor. Increasingly, blue light cystoscopy and narrow band imaging (NBI) are being used as adjuncts to cystoscopy in identifying occult malignancy.
Pathology
Staging and grading
BlCa are staged using 8th edition of Tumor Node Metastasis/American Joint Committee on Cancer (TNM/AJCC) ( Table 20.1 ). Clinical stage reflects findings in transurethral resection of bladder tumor (TURBT) as well as radiologic and physical exam findings with bimanual exam at time of TURBT. Pathological staging is based on surgical resection of the bladder via partial or radical cystectomy and pathological evaluation of pelvic lymph nodes. BlCa are graded using the 2004 World Health Organization/International Society of Urologic Pathologists (WHO/ISUP) grading system.
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High- and low-grade cancers are often considered essentially separate diseases based on disparate genetic development, biologic behavior, and management strategies.
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The most important risk factor for progression is grade.
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CIS is a precursor as well as a risk factor for progression, invasion, and metastasis.
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Deep penetration into the lamina propria, especially if involving muscularis mucosae, increases the risk of recurrence and progression.
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Hydronephrosis often indicates muscle invasion.
| Defination of Primary Tumor (T) | |
| T Category | T Criteria |
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Ta | Non-invasive papillary carcinoma |
| Tis | Urothelial carcinoma in situ : “flat tumor” |
| T1 | Tumor invades lamina propria (subepithelial connective tissue) |
| T2 | Tumor invades muscularis propria |
| pT2a | Tumor invades superficial muscularis propria (inner half) |
| pT2b | Tumor invades deep muscularis propria (outer half) |
| T3 | Tumor invades perivesical soft tissue |
| pT3a | Microscopically |
| pT3b | Macroscopically (extravesical mass) |
| T4 | Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall |
| T4a | Extravesical tumor invades directly into prostatic stroma, seminal vesicles, uterus, vagina |
| T4b | Extravesical tumor invades pelvic wall, abdominal wall |
| Definition of Regional Lymph Nodes (N) a | |
| N Category | N Criteria |
| NX | Lymph nodes cannot be assessed |
| N0 | No lymph node metastasis |
| N1 | Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node) |
| N2 | Multiple regional lymph node metastasis in the true pelvic (perivesical, obturator, internal and external iliac, or sacral lymph node metastasis) |
| N3 | Lymph node metastasis to the common iliac lymph nodes |
| Definition of Distant Metastasis (M) | |
| M Category | M Criteria |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| M1a | Distant metastasis limited to lymph nodes beyond the common iliacs |
| M1b | Non-lymph node distant metastases |
a Regional lymph nodes include both primary and secondary drainage regions. All other nodes above the aortic bifurcation are considered distant lymph nodes.
Histology
The majority of primary BlCa are urothelial carcinomas, representing more than 90% of all bladder tumors. Urothelial cancer has a propensity for divergent differentiation and include squamous, glandular, micropapillary, sarcomatoid, plasmacytoid, and nested variant histologies. Nonurothelial malignancy includes small cell carcinoma, pure squamous cell carcinoma, and adenocarcinoma. Small cell carcinoma should be treated as metastatic disease with chemotherapy (usually cisplatin and etoposide) followed by either radiation therapy or surgery for elimination of the local disease. Radical cystectomy is the mainstay treatment for squamous cell carcinoma and primary bladder adenocarcinoma. The standard treatment for urachal adenocarcinoma is en bloc resection of the bladder dome, urachal ligament, and umbilicus.
Management of nonmuscle invasive bladder cancer
Approximately 70%–80% of BlCa cases are nonmuscle-invasive bladder cancer (NMIBC) at presentation with 60%–70% as stage Ta, 20%–30% as T1, and approximately 10% as CIS. Risk of recurrence is typically approximately 40%–60% but can be influenced by multiple clinical factors. Risk of progression, however, is of key concern in patients with NMIBC given the heterogeneity of tumors with rates of progression as low as 6% in patients with low-grade Ta lesions to as high as 17% in high-grade T1 tumors. There are several tools such as European Organization for Research and Treatment of Cancer risk calculator that can be used to predict risk of recurrence and progression. Table 20.2 shows American Urological Association (AUA) risk stratification for NIMBC.
| LOW RISK | INTERMEDIATE RISK | HIGH RISK |
|---|---|---|
| LG solitary Ta ≤3 cm | Recurrence within 1 year, LG Ta | HG T1 |
| PUNLMP | Solitary LG Ta >3 cm | Any recurrent, HG Ta |
| LG Ta, multifocal | HG Ta, >3 cm (or multifocal) | |
| HG Ta, ≤3 cm | Any CIS | |
| LG T1 | Any BCG failure in HG patient | |
| Any variant histology | ||
| Any LVI | ||
| Any HG prostatic urethral involvement |
Endoscopic surgical management
Transurethral resection of bladder tumor.
TURBT is intended to be diagnostic and therapeutic by providing specimens to allow for pathological determination of stage and grade, while simultaneously removing and/or fulgurating all visible tumors. Traditionally, TURBT has been performed with monopolar loop using sterile water or glycine solution. The use of bipolar loop allows use of saline irrigation, which can decrease risk of transurethral resection (TUR) syndrome in cases of perforation and if the resection is prolonged.
The incidence of perforation can be reduced by avoiding overdistention of the bladder and using anesthetic paralysis during the resection of significant lateral wall lesions to lessen an obturator reflex response. Resection of diverticular tumors presents significant risk of bladder wall perforation, and accurate staging is difficult to achieve given the absence of underlying detrusor.
Complications of transurethral resection of bladder tumor and bladder biopsy.
Minor bleeding and irritative symptoms are common side effects in the immediate postoperative period. The major complications of uncontrolled hematuria and clinical bladder perforation occur in 1%–6.7% of cases. The majority of perforations are extraperitoneal; however, intraperitoneal rupture is possible when tumors are resected at the dome. Extraperitoneal bladder perforation during TURBT can typically be managed with prolonged urethral catheter drainage. Intraperitoneal perforation is less likely to close spontaneously and usually requires open or laparoscopic surgical repair. TUR syndrome from fluid absorption is uncommon, particularly with the use of bipolar energy, and managed in the same manner as during transurethral resection of the prostate.
Repeat transurethral resection of bladder tumor.
AUA guidelines recommend repeat TURBT of primary tumor site, to include muscularis propria, within 6 weeks of the initial TURBT in patients with incomplete initial resection, and patients with stage T1 disease. These guidelines also recommend consideration of repeat TURBT in patients with high-risk, high-grade Ta tumors.
Enhanced cystoscopic techniques: Fluorescence cystoscopy, narrow band imaging.
Blue light cystoscopy with cysview uses the photosensitizing agent hexaminolevulanic acid with preferential accumulation of photoactive porphyrins in malignant cells. Under blue light, cancer cells emit red fluorescence resulting in better tumor visualization ( Fig. 20.1 ). When blue light cystoscopy with cysview is used, small papillary tumors and almost one-third more cases of CIS overlooked on white light cystoscopy are identified.
NBI is an optical image enhancement technology intended to improve the visibility of blood vessels inherent to neoplastic processes. NBI light is composed of two specific wavelengths that are absorbed by hemoglobin; 415-nm light penetrates only the superficial mucosal layers, whereas 540-nm light penetrates more deeply. The combination allows improved visualization of tumors and enables distinguishing blood vessels on and below the surface from tumors.
Intravesical therapy
Perioperative intravesical therapy.
AUA guidelines recommend that in a patient with suspected or known low- or intermediate-risk BlCa, a clinician should consider administration of a single postoperative instillation of intravesical chemotherapy (e.g., gemcitabine, mitomycin C) within 24 hours of TURBT. A meta-analysis of 18 randomized controlled trials showed that a single dose of intravesical chemotherapy within 24 hours after TUR of NMIBC resulted in a 13% absolute reduction in tumor recurrence from 50%–37%, yielding a number needed to treat of 7.2. Although local irritative symptoms are the most common complications of postoperative instillation, serious sequelae and rare deaths have also occurred, especially in patients with perforation during resection. Chemotherapy should be withheld in patients with extensive resection or when there is concern about perforation.
Intravesical immunotherapy.
Bacille Calmette-Guérin (BCG): Intravesical BCG treatment leads to cytokine induction with preferential upregulation of IFN-γ, IL-2, and IL-12 reflects induction of a T-helper type-1 (Th1) response. This immunologic response activates cell-mediated cytotoxic mechanisms believed to underlie the efficacy of BCG. Intravesical BCG decreases both tumor recurrence and progression.
Treatments are typically started 2–4 weeks after tumor resection, allowing time for reepithelialization of the bladder after TURBT, thereby minimizing the potential for intravasation of live bacteria. Patients receive a 6-week induction course followed by three weekly instillations at 3 and 6 months and every 6 months thereafter for 3 years. Recent data suggest that 1-year course of maintenance BCG can be considered for intermediate risk disease instead of 3 years. Contraindications to BCG therapy and management of infectious complications of BCG is shown in Boxes 20.1 and 20.2 .
Absolute contraindications
Immunosuppressed and immunocompromised patients a
Immediately after transurethral resection on the basis of the risk of intravasation and septic death
Personal history of BCG sepsis
Gross hematuria (intravasation risk)
Traumatic catheterization (intravasation risk)
Total incontinence (patient will not retain agent)
Relative contraindications
Urinary tract infection (intravasation risk)
Liver disease (precludes treatment with isoniazid if sepsis occurs)
Personal history of tuberculosis (risk theorized but unknown)
Poor overall performance status
Advanced age
No or insufficient data on potential contraindications
Patients with prosthetic materials have not been shown to have increased risk of infectious or other complications in limited literature (Rosevear et al., 2010)
Ureteral reflux
Antitumor necrosis factor medications (theoretically predispose to BCG sepsis)
a Recent small series suggest this may not be an absolute contraindication (Herr, 2012).
Grade 1: Moderate symptoms <48 hours
Mild or moderate irritative voiding symptoms, mild hematuria, fever <38.5°C
Assessment
Possible urine culture to rule out bacterial urinary tract infection
Symptom management
Anticholinergics, topical antispasmodics (phenazopyridine), analgesics, nonsteroidal antiinflammatory drugs
(Asymptomatic prostatic granulomas that occur after BCG therapy can occasionally mimic prostate cancer clinically and/or radiographically. There is no evidence to support treatment in this setting [Suzuki et al., 2013].)
Grade 2: Severe symptoms and/or >48 hours
Severe irritative voiding symptoms, hematuria, or symptoms lasting >48 hours
All maneuvers for grade 1, plus the following:
Assessment
Urine culture, chest radiograph, liver function tests
Management
Consider dose reduction to one-half to one-third of dose when instillations resume.
Treat culture results as appropriate.
Can also consider pretreating with a single dose of isoniazid before each subsequent instillation
Antimicrobial agents
Administer isoniazid and rifampin orally until symptom resolution.
Also use vitamin B6 or pyridoxine.
Do not use monotherapy.
Observe for rifampin drug-drug interactions (e.g., warfarin).
Monitor liver function tests.
Grade 3: Serious complications (hemodynamic changes, persistent high-grade fever)
Allergic reactions (joint pain, rash)
Perform all maneuvers described for grades 1 and 2, plus the following:
Isoniazid and rifampin, depending on response.
Also use vitamin B6 or pyridoxine.
Solid organ involvement (liver, lung, kidney)
Stop BCG instillations. Initiate antimycobacterial therapy with isoniazid, rifampin. If symptoms persist, consult with infectious disease specialist with expertise in antituberculous therapy. Can add ethambutol.
Cycloserine often causes severe psychiatric symptoms and is to be strongly discouraged.
BCG is almost uniformly resistant to pyrazinamide, so this drug has no role.
Consider prednisone when response is inadequate or for septic shock (never given without effective antibacterial therapy).
Intravesical chemotherapy.
The agents are summarized in Table 20.3 . Optimization of mitomycin delivery can be achieved by eliminating residual urine volume, fasting overnight, using sodium bicarbonate to reduce drug degradation, and increasing concentration to 40 mg in 20 mL.
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