Carli Calderone and Jennifer Marie Taylor

INTRODUCTION

Urothelial cancer can arise in the renal pelvis, ureter, bladder, or urethra. This chapter focuses on urothelial cancer of the bladder.

HISTOLOGIC TYPES

Urothelial Carcinoma

By far, the most common histologic type of bladder cancer arises from the urothelium, accounting for greater than 90% of bladder tumors (1). This will be the type predominately discussed in this chapter. Urothelial carcinoma (UC) was formerly known as transitional cell carcinoma (TCC) and is sometimes still referred to as such.

Variants of UC

Up to 25% of UC can demonstrate mixed histological features, many of which portend a worse prognosis (2). These variants include micropapillary, plasmacytoid, nested, sarcomatoid, microcystic, squamous, and adenocarcinoma. In addition to their association with more invasive disease, they also may predict poor response to certain treatments and are an important consideration in treatment decisions.

158Non-urothelial Cancers of the Bladder

Squamous cell carcinoma (SCC) accounts for 1% to 2% of bladder tumors and is often invasive at the time of diagnosis. It is associated with chronic inflammation, such as that from long-term indwelling catheters or schistosomiasis infection. In areas where schistosomiasis is endemic, squamous cell cancer is the most common bladder malignancy (3), although rates of UC are a rising proportion given increasing tobacco use in those regions. Likewise, adenocarcinoma contributes to 1% of bladder tumors and is often located at the urachus, where there may be a remnant of nonurothelial epithelium. Small cell carcinoma can also occur in the bladder less than 1% of the time. These tumors tend to grow quickly, metastasize early, and are treated primarily with chemotherapy. Sarcoma arising from bladder muscle is very rare, but may also present as a bladder tumor.

CLASSIFICATION OF BLADDER NEOPLASMS

Grade

The current classification according to the 2004 World Health Organization (WHO) system designates four categories. Urothelial papillomas are completely benign lesions. The term papillary urothelial neoplasm of low malignant potential (PUNLMP) is used to describe premalignant lesions, which exhibit much less aggressive behavior than even the most low-risk UC (4). UC, which will be discussed here, are classified as low grade or high grade.

While no longer in use, occasionally one may come across the terminology used in the 1973 guidelines, especially in prognostic tools. In this former 3-tier system, which assigned from grade 1 to 3, all G1 (well-differentiated) and most G2 (moderately-differentiated) tumors correlate to a 2004 WHO low-grade tumor, while some G2 and all G3 (poorly-differentiated) tumors are considered high grade.

Stage

Bladder tumors are broadly categorized according to depth of bladder wall invasion into nonmuscle-invasive bladder cancer 159(NMIBC) and muscle-invasive bladder cancer (MIBC). These two groups generally differentiate bladder cancer based on aggressiveness, risk of metastasis, and treatment options.

The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system (Table 24.1) is the most widely used system, and can be assigned for both clinical and pathologic stage. Clinical stage is obtained from 160information gathered from transurethral resection of bladder tumor (TURBT), physical exam, and imaging. Pathologic stage is based on operative findings at time of cystectomy. It is generally agreed that a biopsy specimen from TURBT is not substantial enough to constitute pathologic staging, and therefore most NMIBC are classified by their clinical stage (4). Under this system, NMIBC includes stages Ta, T1, and Tis.

161Ta: Papillary tumors which are limited to the mucosa are classified as Ta, and describe 70% to 75% of NMIBC at time of diagnosis. Furthermore, the majority of Ta lesions are low grade, with an average of only 6.9% of Ta tumors being high grade (6). The recurrence rates are high, as much as 60% within 5 years; however, the rate of progression to MIBC is rare.

T1: Papillary tumors, which invade the lamina propria, comprise 25% of NMIBC at time of diagnosis (1). Resection by TURBT must include muscle in the specimen for accurate determination of muscle involvement. T1 tumors carry a higher risk of progression to MIBC. However, the overall prognosis is still very good. The presence of lymphovascular invasion has been demonstrated to be a poor prognostic indicator for T1 tumors.

CIS: Carcinoma in situ tumors are flat and confined to the mucosa. They are by definition always high grade, and left untreated, an average of 54% of patients with CIS will progress to MIBC (7). Treatment of CIS can be more challenging to treat and varies considerably from papillary disease, and therefore is often discussed separately.

CIS is further classified into primary, secondary, or concurrent, based on whether the CIS tumor was detected by itself, as a recurrence after prior papillary NMIBC, or concomitantly with papillary disease. Most are concurrent with other high-grade lesions, with only 3% to 5% occurring as isolated CIS.

RISK STRATIFICATION

NMIBC represents a widely heterogeneous group of cancers with highly variable natural histories. Risk stratification is essential to guide management of these patients. In 2016, the American Urological Association (AUA) updated the risk categories for NMIBC, as summarized in Table 24.2 (7). Patients can evolve from one risk group to another as the disease recurs or progresses. This AUA risk stratification is very similar to the system adopted by the European Association of Urology, which has been utilized in research and prediction models. These risk strata correlate with risk of recurrence and progression and align with different choices in the treatment algorithm.

CLINICAL PRESENTATION

Risk Factors

Tobacco exposure, both first-hand and second-hand, carries the greatest exposure-related risk for development of bladder cancer. Other occupational and environmental exposures which have been linked to bladder cancer include aromatic amines (e.g., benzenes), aniline dyes, trichloroethylene pesticides, and arsenic. Treatments used for other malignancies, including cyclophosphamide and ionizing pelvic radiation, also may predispose to secondary bladder malignancy. Familial or inherited bladder cancers are rare, but Lynch syndrome is the most common genetic syndrome associated with both upper urinary tract and bladder malignancy.

Despite similar exposure-related risks, UC of the bladder is significantly more prevalent than UC in the upper urothelial tract, due to the cumulative duration of exposure of the urothelium to carcinogens in the urine. This also explains in part the higher incidence of bladder cancer in men relative 163to women, despite equal rates of tobacco use, due to chronic incomplete bladder emptying associated with age-related prostate enlargement.

Signs and Symptoms

The most common presenting sign of NMIBC is hematuria, either grossly visible to the patient or found incidentally as microscopic hematuria on urinalysis. Gross hematuria is more ominous, with up to 20% of patients demonstrating a urologic malignancy (8). However, even a single episode of unexplained microhematuria necessitates a full work up, including cystoscopy and upper tract imaging, as around 3.3% of these unselected patients may be found to have a urologic malignancy (9).

CIS in particular can cause irritative voiding symptoms, such as frequency, urgency, and dysuria (7). Physical exam is usually normal. Very rarely, NMIBC can lead to obstruction and hydronephrosis, which may present with flank pain or a palpable mass. If hydronephrosis is present from obstruction at the uretero-vesical junction, it is likely to be a more invasive stage.

DIAGNOSTIC WORKUP

Urine Studies

Urine cytology is commonly used as an adjunct to cystoscopy as part of a complete bladder cancer work up. It is more helpful in detecting high grade (HG) tumor cells, where sensitivity has been shown to be 84%, compared to 16% for low grade (LG) tumors (10). Urine cytology is an essential part of diagnosis of CIS and is very specific, although sensitivity varies from 28% to 100%.

Efforts continue to identify urine markers to use as a noninvasive alternative for bladder cancer screening or follow up. At the present time, no marker has demonstrated a high enough sensitivity to replace office cystoscopy. However, when used as adjuncts, some markers have shown promise in providing useful diagnostic information. Once a diagnosis 164is made, genetic markers have been shown to assist in giving prognostic information, such as recurrence, progression, and even response to therapy.

Cystoscopy

An office-based procedure is typically done for evaluation. Surgical resection by TURBT is necessary for complete diagnostic information and is therapeutic for most cases. Adjuncts to white light cystoscopy, such as narrow band imaging (NBI) and blue light cystoscopy, can improve detection of tumors or lesions and reduce rates of recurrence.

Papillary tumors will be easily visualized and appear grossly as clusters of papillary stalks with a fibrovascular core (see Figure 24.2). Note should be taken endoscopically of tumor appearance (e.g., papillary, nodular, sessile, flat, necrotic), size, location, and number. CIS is more difficult to detect and may appear erythematous or inflamed. A positive urine cytology with a normal-appearing bladder mucosa should raise suspicion for presence of CIS or disease arising in nonbladder urothelium.

Imaging

A CT urogram (CTU), which includes a delayed phase allowing contrast to opacify the urinary tract, provides the most diagnostic information about the upper urothelial tracts. This is especially important in patients that are at high risk for upper tract urinary carcinoma, including patients with multiple tumors or tumors of the trigone (11). Papillary tumors usually appear as filling defects (see Figure 24.3), and obstructing tumors may cause hydroureter and hydronephrosis. CTU also images the regional and retroperitoneal lymph nodes, as well as surrounding structures, and can give information about local and distant extent of disease. Ultrasound, although not used routinely in the assessment of bladder tumors, can be a useful tool when upper tract obstruction is suspected and can be utilized when CT is not feasible or for surveillance of lower-risk patients after initial diagnosis.

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To address the limitations of white light cystoscopy with occult papillary tumors and CIS, improved methods of visualization have been developed. Photodynamic diagnosis (PDD) takes advantage of the fact that photoactive porphyrins accumulate preferentially in neoplastic tissue, which fluoresce pink with exposure to blue light (see Figure 24.4). Multiple studies have demonstrated that PDD increases the detection of tumors and leads to more complete resection (12,13). An optical imaging agent (Hexaminolevulinate HCl, Cysview®, in United States) is instilled in the bladder at least one hour prior to surgery and the cystoscopy camera and image processing unit can alternate between white and blue light.

Similarly, Narrow Band Imaging (NBI) enhances visualization through the use of a light emitted at two specific wavelengths, which are strongly absorbed by hemoglobin and enhance the visualization of capillaries (see Figure 24.5) (14). This technology can be visualized with an NBI camera and processing unit and does not require instillation of an imaging agent. NBI use in conjunction with standard white light has been shown to improve tumor detection and resection, but has yet to demonstrate an improvement in recurrence or progression.

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TURBT is the mainstay of the diagnosis of NMIBC. TURBT is best performed in an operating room, where an exam under general anesthesia can be performed to determine clinical stage. All visible tumors should be resected at first TURBT, which is both diagnostic and therapeutic. A good resection specimen should include detrusor muscle to achieve the most accurate staging as well as to minimize the chance of local recurrence (15).

Random or targeted bladder biopsies are sometimes necessary in order to diagnose CIS. Biopsy of prostatic urethra may also be indicated. Tumors at high risk for urethral involvement include CIS, multiple tumors, and tumors located in the trigone or bladder neck.

169Repeat Resection

Understaging on initial resection is relatively common and does not necessarily reflect a poor quality resection. Repeat or restaging TURBT has been shown to upstage the initial tumor pathology in 21% of specimens (16). Therefore, the AUA 2016 guidelines recommend a repeat TUR in all patients with T1 tumors and most patients with Ta tumors to assess for muscle invasion, regardless of status of muscle in the initial resection (7). Furthermore, repeat resection has been associated with lower recurrence rates after Bacillus Calmette-Guérin (BCG) (17). Persistent T1 disease on repeat resection carries a higher risk prognosis and may prompt discussion of early cystectomy in select patients.

Intravesical Therapies

Perioperative Instillation

A single, immediate postoperative instillation of intravesical chemotherapy has been found to decrease recurrence of low-risk tumors compared to TURBT alone. One meta-analysis of over 2,000 patients with low- and moderate-risk tumors found that the recurrence rate in those who received intravesical chemotherapy was reduced by 14% when compared to patients who received TURBT alone (18). There was no benefit to patients with high-risk tumors.

Mitomycin C (MMC), epirubicin, and pirarubicin are all effective, with none being shown to be superior to the others. Although none is Food and Drug Administration (FDA) approved, MMC is most commonly used in the United States.

Adjuvant Therapies

Additional adjuvant intravesicular instillations may be indicated for patients with AUA risk groups of intermediate-risk and high-risk tumors. These are broadly grouped into cytotoxic agents and one immunomodulatory agent.

MMC is an alkylating agent, which has been shown to decrease tumor recurrence risk by 38% (7). It is given in weekly instillations for 6 to 8 weeks followed by monthly instillations for up to a year, at a dose of 20 to 60 mg per instillation. Efficacy can be optimized by placing patients NPO for 8 hours prior to instillation, assuring an empty bladder, alkalinizing urine with 170oral sodium bicarbonate, and concentrating the dose of MMC (19). As a full course agent, it is inferior to BCG in preventing tumor progression and is not considered first line for high-grade disease.

Several other agents including thiotepa, doxorubicin, and epirubicin, which are not used commonly in current practice, continue to be studied in clinical trials.

Valrubicin was approved by the FDA in 2009 for treatment of BCG-unresponsive CIS. Gemcitabine has also been shown to have modest effect in the BCG-unresponsive NMIBC patient population. Both of these agents are considered salvage therapy in patients who cannot undergo or refuse cystectomy.

Immunotherapy

BCG is the original immunotherapy developed for bladder cancer, approved in 1998, and is the first-line treatment for adjuvant intravesical treatment of high grade NMIBC and CIS (7). Standard induction therapy is given weekly for 6 weeks, starting 2 to 4 weeks after a primary tumor resection. Maintenance therapy has been shown to further reduce recurrence and progression (20) over induction therapy alone, and is given in 3-week courses at intervals every 3 to 6 months consistent with the original Southwest Oncology Group study. According to 2016 AUA guidelines risk groups, maintenance is recommended up to 1 year in intermediate-risk and up to 3 years in high-risk patients. In patients who have poor tolerance of full-dose BCG, reduced-dose therapy is an alternative to the cessation of therapy.

In the treatment of CIS, BCG has been demonstrated to produce a complete response in up to 84% of patients (6), with approximately 50% of patients remaining disease-free for a median of 4 years. After 10 years, up to 30% remain disease-free. Of those who recur, the vast majority will do so within 5 years. Multiple meta-analyses have been performed comparing BCG to chemotherapy for CIS and papillary NMIBC, and all but one have demonstrated that BCG reduces recurrence and progression. However, a survival benefit has not been demonstrated.

Serious complications occur in less than 5% of patients and most are easily managed (21). Systemic BCG infection is quite rare but may require systemic antituberculous therapy. 171There is a relative contraindication to the use of BCG in immunocompromised patients; however, retrospective studies have shown no increased toxicity in these patients, with similar efficacy (22). Furthermore, maintenance therapy is not associated with a higher toxicity than induction therapy alone.

BCG-Unresponsive Disease

The term BCG failure is ambiguous and a 2015 consensus statement (23) highlighted the confusion in the multiple terms for failure or intolerance of BCG treatment. The term “BCG-unresponsive” has been established to create a consistent definition, particularly for eligibility in clinical trials. A patient with BCG-unresponsive disease has recurrent or progressive disease after induction BCG plus at least one course of repeat induction or maintenance therapy. This entity is defined as recurrent or progressive disease after induction BCG plus at least one course of repeat induction or maintenance therapy. Determining persistent CIS can take up to 6 months after therapy, as tumoricidal activity persists after the cessation of therapy.

How to Treat Failure/Intolerance of BCG

Patients who are resistant to their first induction course of BCG or who recur after an initial complete response of at least 12 months should consider a second induction course, as there is a 30% to 50% response with re-treatment (24). However, there is an increased risk of progression. Therefore, high-risk patients who experience early recurrence, multiple recurrences, or disease progression should consider immediate cystectomy. Further courses of BCG beyond two are not recommended, as they portend an 80% failure rate, causing an avoidable delay in treatment.

In those patients who cannot tolerate surgery or refuse cystectomy, salvage intravesical therapies are options and remain active spaces for therapeutic investigation. Valrubicin is the only FDA approved intravesicular therapy to treat such patients with CIS only, and a delay in cystectomy of 3 months to assess efficacy of valrubicin does not appear to increase the risk of progression (25). Gemcitabine has been used for salvage cases, with a moderate response rate (26).

172There are no combinations that have been studied to date which have been able to demonstrate a clear benefit over monotherapy with BCG. Interferon when combined as a mixture with BCG was not found to have any additional efficacy in preventing recurrence over BCG alone (27). It demonstrated similar toxicity as well and therefore is not advantageous over BCG monotherapy.

Additional ongoing studies are testing the efficacy of treatment with oncolytic viral therapy, checkpoint inhibitors, IL-2 derivatives, and other agents in this challenging disease setting.

CYSTECTOMY

There is a role for radical cystectomy (RC) in some high-risk patients with NMIBC. Clinical understaging is a real occurrence, with up to 50% of patients with HG NMIBC (<cT1) clinically actually found to have MIBC (>pT2) at cystectomy. One study found that in patients with cT1 + CIS disease who underwent RC, clinical staging was only accurate in 66% of patients, with 27% being upstaged by cystectomy pathology and 12% with positive nodal disease (28). To this end, the AUA guidelines list cystectomy as the first option for refractory disease after initial intravesical therapy.

In addition to tumors which are high-risk, tumors which cannot be reasonably controlled via TURBT should also be considered for cystectomy or partial cystectomy. This may include LG or HG tumors that are bulky or otherwise inaccessible endoscopically, for example due to urethral stricture or bladder diverticulum. Partial cystectomy can allow for more accurate pathologic staging with excision of the specimen and lymph node dissection. The majority of patients can have durable disease-specific survival with an intact, functioning bladder (29).

In conclusion, NMIBC is a complex entity which is not “one-size-fits-all.” The majority of cases carry higher risk of recurrence than of progression or metastasis. It carries a high burden of cost and potential morbidity from long-term and multiple interventions, and outcomes can be affected by patient adherence.

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