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Objectives

The following module was designed to supplement the clinical experience of medical students. It covers the anatomy, epidemiology, screening, presentation, diagnosis, staging, prognosis, treatment, and follow up care of bladder cancer.

This module covers the objectives listed below:

  1. Review the gross anatomy of the bladder and its surrounding structures. Recognize that these structures may be at risk for complications during treatment.
  2. Describe the layers of the bladder wall and their importance in staging bladder cancer.
  3. Know the most common histologies of bladder cancer.
  4. Know the major risk factors for bladder cancer.
  5. Estimate the incidence of bladder cancer.
  6. Understand the role of screening for bladder cancer in asymptomatic adults.
  7. Recognize the typical presentation of bladder cancer, including symptoms associated with bladder cancer.
  8. Describe the components of a workup for suspected bladder cancer.
  9. List factors affecting the prognosis and treatment of bladder cancer.
  10. Understand that TURBT is the mainstay of treatment for non-muscle-invasive bladder cancer.
  11. Recognize that non-muscle-invasive bladder cancer treated by TURBT frequently recurs.
  12. Describe the role of intravesical therapy in the management of non-muscle-invasive bladder cancer.
  13. Appreciate the treatment modalities available for muscle-invasive bladder cancer.
  14. Know the routine follow up of bladder cancer post-treatment.
  15. Know common and serious complications arising from the treatment of bladder cancer, and how they can be managed.

Overview of Anatomy

The bladder is a hollow, distensible organ that rests in the lower pelvic cavity when empty and protrudes into the suprapubic abdomen as it fills. It acts as a reservoir for urine, fed by two ureters originating from the kidneys and drained through the urethra.

Female pelvis

The bladder has an apex or dome, a superior surface, a posterior surface or base, two lateral walls, an anterior wall, a trigone, and a neck. The apex, located anterosuperiorly, is the insertion site of the median umbilical ligament. This ligament is a remnant of the embryonic urachus and represents an uncommon site for bladder malignancies. The apex and superior surface of the bladder are covered by peritoneum and overlying bowel. In women, the uterus is usually anteverted above bladder as well. Posteriorly, the bladder borders the vas deferens, seminal vesicles, and rectum in men; and the uterus and vagina in women. The ureters enter the bladder posteroinferiorly. The two ureteric orifices and internal urethral orifice triangular mark the vertices of a triangular region known as the trigone. As the most distal portion of the bladder, the neck surrounds the internal urethral orifice and connects with the urethra.

The bladder wall can be divided into four layers. From inside to outside, these layers are:

  1. Epithelium and underlying basement membrane
  2. Lamina propria
  3. Muscularis propria
  4. Serosa (surfaces covered by peritoneum) or adventitia (other surfaces)

The bladder's specialized epithelium, termed urothelium or transitional epithelium, is a stratified epithelium characterized by its ability to stretch without losing impermeability. Urothelial carcinoma, synonymous with transition cell carcinoma, is responsible for 85-90% of bladder cancers in developed countries. Far less common histologies include squamous cell carcinoma (3%), adenocarcinoma (3%), and small cell carcinoma (<2%) [1].

Epidemiology

Bladder cancer is the fifth most commonly diagnosed cancer in Canada, totaling an estimated 8900 new diagnoses and 2400 deaths in 2017 [2]. Worldwide, there are approximately 550,000 new cases and 200,000 deaths annually due to bladder cancer [3].

Risk factors

Smoking

Smoking is by far the most important modifiable risk factor for bladder cancer, accounting for around half of bladder cancers in both men and women [5]. Earlier initiation, longer duration, and increased frequency of smoking have all been associated with bladder cancer [4]. While smoking cessation reduces the risk of developing bladder cancer, former smokers remain at elevated risk even 10 years after quitting [5].

Occupational and environmental exposures

The aromatic amines (including 2-naphthylamine, 4-aminobiphenyl, benzidine, o-toluidine, and MBOCA) used in textile dyes, hair dyes, paint pigments, and polyurethane production are well-known bladder carcinogens [6]. Other substances implicated in bladder cancer include polycyclic aromatic hydrocarbons, diesel fumes, and heavy metals (including arsenic, cadmium, chromium, nickel, and lead) [7, 8].

Chronic bladder irritation

Recurrent cystitis, bladder stones, and indwelling catheters have all been linked to bladder cancer, likely as a result of chronic inflammation [9-12].

Schistosoma haematobium infection

Infection by S. haematobium is strongly associated with SCC of the bladder, elevating bladder cancer to one of the most common malignancies in areas of the Middle East and Africa where it is endemic [13].

Sex

Men are three to fourfold more likely to develop bladder cancer than women and account for ~6700 of the 8900 of the new diagnoses in Canada. This makes bladder cancer the fourth most often diagnosed cancer among men after prostate, lung, and colorectal cancer. In contrast, bladder cancer is the 12th most commonly diagnosed cancer in women [2].

Age

The incidence rate of bladder cancer increases with age. Of those newly diagnosed with bladder cancer, over 90% are over 55 years old [14].

Race

The incidence of bladder cancer is approximately twice as high in Caucasians as African Americans. The disease is less common in Asians, Hispanics, and American Indians [14].

Family history and genetics

Having a first-degree relative diagnosed with bladder cancer confers additional risk, but high penetrance genes account for few cases of bladder cancer [15, 16]. Lynch syndrome, RB mutations, and Costello syndrome are some hereditary conditions that increase the risk of bladder cancer [16].

Prior pelvic irradiation and cyclophosphamide

There is a significant dose-response relationship between cyclophosphamide use and risk of bladder cancer [17, 18].

Screening

Possible tests that can be used to screen for bladder cancer include urinalysis, urine cytology, and urine biomarkers; however, the US Preventive Services Task Force concluded that there was inadequate evidence to assess the balance of benefits and harms in screening asymptomatic adults for bladder cancer [19]. There are no major professional organizations that endorse screening for bladder cancer in average-risk patients at this time.

Presentation and Diagnosis

Painless visible hematuria is the most common and key presenting symptom of bladder cancer [20]. Approximately 10% of patients presenting to their general practitioner with visible hematuria had a urologic malignancy. This proportion increased to 22% among men over age 60 [21]. The predictive value of microscopic hematuria is markedly lower [22]. A minority present with irritative voiding, obstructive symptoms, abdominal and pelvic pain, constipation, or systemic manifestations [20]. Bladder cancers can pose a diagnostic challenge as hematuria is often transient and easily confounded by menstruation while its other symptoms are nonspecific.

At the time of diagnosis, ~70% of bladder cancers are not muscle invasive (Ta/Tis/T1) [23]. Approximately 4-5% present with metastatic disease, most commonly involving bones, lungs, or liver [24].

History Taking

The following are aspects to consider when bladder cancer is suspected:

  1. Personal information including age and sex
  2. Full history of presenting illness
  3. Any episodes of visible hematuria or passed clots (indicates lower urinary tract source)
  4. Any associated symptoms (consider differential diagnoses, symptoms suggestive of metastatic disease)
  5. Gynecologic history
  6. Trauma or surgery
  7. Smoking history
  8. History of UTIs
  9. Connection to endemic areas of S. haematobium (Middle East and Africa)
  10. Medications and substances -- in particular cyclophosphamide use, any mimics of hematuria (e.g. beet)
Physical Examination

Most patients presenting with non-muscle-invasive bladder cancer will not have physical exam findings. Consider including the following on physical examination of hematuria with suspicion for bladder cancer:

  1. Vitals, with particular attention to BP and temperature (rule out infection or nephropathy)
  2. Abdominal exam
  3. Assessment of flanks and CVA for obstructive uropathy or concerns of upper urinary tract (e.g. stones, tumor, infection)
  4. Genital examination, looking for evidence of bleeding or trauma near the urinary meatus
  5. Pelvic examination, including bimanual examination, in women to assess extent of disease and rule out other sources of bleeding
  6. Bimanual DRE, and palpate for prostatic involvement in men
  7. Other exams as indicated by history

If a tumor is felt, any fixation should be noted.

Investigations

The history and physical examination should guide investigations. If bladder cancer is suspected, cystoscopy is the best diagnostic test. The following can be completed at the same time:

  1. Urinalysis and cytology
  2. CBC, CMP
  3. Assessment of the upper urinary tract with CT or MR urography, IVP, renal US with retrograde ureteropyelography, or ureteroscopy (procedure of choice depends on site and patient considerations)
  4. Consider PSA

Staging

If a suspicious lesion is identified, the following should be completed:

  1. CT or MR abdomen if not already completed, ideally prior to any procedures
  2. Bimanual examination under anesthesia
  3. Transurethral resection of bladder tumor (TURBT), with biopsy specimens sent to pathology
  4. Chest x-ray or CT chest if there is muscle-invasive disease
  5. Bone scan if ALP is elevated or patient is symptomatic
  6. Consider PET/CT skull to mid thigh

These steps should provide the information required for grading, staging, and further treatment decisions.

AJCC 8th edition (2017) T staging

TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
Ta: noninvasive papillary carcinoma
Tis:
urothelial carcinoma in situ ("flat tumor")
T1:
tumor invades lamina propria
T2a:
tumor invades inner half of muscularis propria
T2b:
tumor invades outer half of muscularis propria
T3a:
microscopic invasion of perivesical soft tissue
T3b:
macroscopic invasion of perivesical soft tissue
T4a:
tumor invades directly into prostatic stroma, seminal vesicles, uterus, or vagina
T4b:
tumor directly invades pelvic or abdominal wall

AJCC 8th edition (2017) N staging

NX: lymph nodes cannot be assessed
N0:
no regional* or common iliac lymph node metastases
N1:
single regional* lymph node metastasis
N2:
multiple regional* lymph node metastases
N3:
lymph node metastases to the common iliac nodes

*regional lymph nodes refer to the true pelvis lymph nodes (i.e. perivesical, obturator, internal and external iliac, or sacral nodes)

AJCC 8th edition (2017) M staging

M0: no distant metastases
M1a:
distant metastases limited to lymph nodes beyond the common iliacs
M1b:
non-lymph node distant metastases present

AJCC 8th edition (2017) prognostic stage groups

Stage 0a: Ta N0 M0
Stage 0is:
Tis N0 M0
Stage I:
T1 N0 M0
Stage II:
T2 N0 M0
Stage IIIA:
T3-4a N0 M0 or T1-4a N1 M0
Stage IIIB:
T1-4a N2-3 M0
Stage IVA:
T4b M0 or M1a disease
Stage IVB:
M1b disease

Prognosis

Overall survival

SEER [13] reports that the 5-year survival rates for bladder cancer (based on patients diagnosed between 2009 and 2015) are 95.8% for in situ, 69.5% for localized, 36.3% for regional, and 4.6% for distant metastatic disease.

Aside from stage, it appears that the main determinants of survival are grade on pathology, age, and to some extent, social class [4].

Recurrence and progression risk

Depending on patient characteristics, past studies have found that 15 to 70% of patients with non-muscle-invasive bladder cancer will experience recurrence after TURBT, and 7 to 40% will progress to muscle-invasive disease within five years. The risks of recurrence and progression are affected by the number of tumors, tumor size, T stage, pathologic grade, presence of concomitant in situ disease, and past recurrence rate [37]. 

A calculator estimating recurrence and progression risk by the EORTC is available online for download.

Treatment

Non-muscle-invasive disease (cTa, Tis, T1)

Transurethral resection of bladder tumor (TURBT) is the mainstay of non-muscle-invasive bladder cancer (NMIBC) treatment. At the time of biopsy, an attempt should be made to excise the entire lesion together with adequate muscle sampling to rule out any muscle involvement. A second re-excision is indicated for high-grade cTa with uncertain pathology, or T1 disease where the rates of residual tumors may be as high as 53% [4, 25].

Maintaining remission after TURBT is a challenge, with up to 70% of patients developing recurrent disease under surveillance. Further, up to 40% of these patients will progress to muscle-invasive cancer [4]. This risk can be mitigated by intravesical chemotherapy, with a meta-analysis finding a 39% relative reduction in recurrence risk [26]; however, the impact on disease progression and survival is less clear [4]. There is evidence supporting the superiority of maintenance intravesical BCG over chemotherapy in preventing recurrence and progression, albeit with higher toxicity [26-29].

AUA and EAU risk stratification [30, 31]

After TURBT, NMIBCs can be stratified by risk categories to guide treatment and follow up. There are two systems, by AUA and EAU, that stratify risk into the same low, intermediate, and high risk groups [30, 31]. Low-risk tumors can be selected for observation, although offering intravesical therapy is also reasonable. Intermediate and high-risk tumors warrant stronger consideration for intravesical therapy. Typically, intravesical chemotherapy (e.g. mitomycin C or gemcitabine) is offered for lower-risk tumors while intravesical immunotherapy with BCG is preferred for higher-risk tumors [23, 25]. Aggressive treatment with radical cystectomy may improve long-term cancer-specific survival in high risk disease, but no randomized control trials have been completed to date [40].

Non-metastatic muscle-invasive disease

The management of muscle-invasive bladder cancer (MIBC) is usually multimodal, with a full spectrum of treatment options encompassing surgery, chemotherapy, and radiation therapy. Patients may benefit from discussion and review by all of these specialties. Broadly, the two treatment pathways are cystectomy or bladder preservation therapy. There are no randomized studies comparing their efficacy, and existing evidence does not clearly favor one approach [32]. The reality is likely more nuanced, with patient and disease factors affecting the most suitable treatment choice. Those with poor bladder function, extensive in situ disease, multifocality, and incomplete TURBTs are more likely to benefit from radical cystectomy. In contrast, bladder preservation therapy may be preferable for poor surgical candidates such as the elderly, obese, and diabetics [4].

For patients proceeding with cystectomy, neoadjuvant platinum-based combination chemotherapy has been found to improve survival in stage II/IIIA disease and resection rate in more locally advanced disease [33]. Gemcitabine and cisplatin (GC) and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) with G-CSF are the preferred regimens in this setting [25], with recent retrospective evidence finding potential improvements in complete pathologic response rates and overall survival among patients receiving ddMVAC [41]. Postoperative radiotherapy could be considered for high-risk pathology (pT3+ tumors, positive margins, positive nodes), where the local failure rate is high despite chemotherapy [42]. There is some evidence indicating that radiotherapy improves local control [42], but the largest retrospective analysis to date only found an overall survival benefit among patients with positive margins post-cystectomy [43].

Concurrent chemoradiotherapy is the treatment of choice in bladder preservation therapy, providing superior locoregional control over radiotherapy alone [34]. It is reasonable to omit chemotherapy in select patients with poor performance status or limited life expectancy. Treatment is offered in either a continuous course, where the entire course of treatment is given before assessing response; or a split course, where a ~3-week break is planned between induction and consolidation phases. Split course treatment furnishes an opportunity to evaluate progress and permits early salvage radical cystectomy if there is an inadequate response. Continuous course is preferable for medically inoperable patients [24].

Metastatic disease

Metastatic bladder cancer patients can be assessed for systemic therapy. Cisplatin-based chemotherapy is the gold standard for patients who are able to tolerate it. Gemcitabine and cisplatin (GC) and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) with G-CSF are the preferred first-line regimens. There is some retrospective data supporting surgical excision of oligometastases following systemic therapy in select patients [25]. Targeted therapies have shown promise in reducing toxicity and improving survival as subsequent treatment. Pembrolizumab, atezolizumab, durvalumab, and avelumab have been approved by Health Canada and the FDA for disease refractory to platinum-based chemotherapy. 

Treatment for non-urothelial bladder cancer

Research on the treatment of non-urothelial bladder cancer is sparse, and it is essential to note that these rare cancers were generally excluded from trials used to develop existing guidelines [4].

Treatment summary

Below, we outline recommendations on the treatment of bladder cancer [25]. This is meant to summarize the information covered in this section and is not comprehensive. 

‍Toxicity

Intravesical BCG and chemotherapy toxicity

Despite its greater efficacy in preventing recurrence and progression compared to intravesical chemotherapy, intravesical BCG is usually reserved for high-risk patients due to increased toxicity. In one large study, treatment was discontinued in 7.8% of patients as a result of toxicity [36]. Common and important side effects associated with intravesical BCG and intravesical chemotherapy (IVC), along with suggested management strategies, are summarized below.



Radiation toxicity

Overall, patients tolerate definitive radiation therapy for bladder cancer reasonably well. Treatment completion rates exceed 95% with approximately 75-80% of patients reporting no late toxicity [4]. Among those that reported grade 3 or higher RTOG bladder or GI toxicity, only a minority experienced prolonged or recurrent high-grade toxicity. Importantly, concurrent chemotherapy does not appear to exacerbate the late complications of radiation significantly [36]. Some side effects are described below, along with some suggestions for management adapted from AAFP [39].

Acute toxicities
  1. Irritative bladder including frequency, urgency, and dysuria
  2. Hematuria
  3. Bladder spasms
  4. RT dermatitis
  5. Fatigue

These are usually self-limiting and managed supportively.

Common late toxicities
  1. Chronic urinary frequency, urgency, or hematuria (consider hyperbaric oxygen)
  2. Erectile dysfunction (PDE5 inhibitors are often effective)
  3. Vaginal dryness or stenosis (lubrication, dilation as needed)
  4. Diarrhea (try dietary changes such as decreasing fiber intake or loperamide)
Uncommon late toxicities
  1. Urethral stricture
  2. Bowel complications including stenosis, obstruction, fistulas, perforation
  3. Pelvic insufficiency fractures
  4. Neuropathy
  5. Secondary malignancy

Follow up

Bladder cancers are usually followed closely due to their propensity to recur. A possible follow-up schedule, depending on the extent of disease and selected treatment, is below [25]. Characteristics unique to each patient should be considered when developing the surveillance plan.

Non-muscle-invasive disease

The surveillance of non-muscle-invasive bladder cancer should consider the risk of recurrence and progression. Both the AUA and EUA provide guidelines for risk stratification into low, intermediate, and high risk groups (see treatment of urothelial carcinoma, non-metastatic non-muscle-invasive disease). The guidelines shown here are based on AUA risk stratification.

Low risk
  1. Cystoscopy at 3 and 12 months, then annually until 5 years post-treatment. As clinically indicated afterward.
  2. Baseline upper urinary tract and abdomen/pelvis imaging, then as clinically indicated.
Intermediate risk
  1. Cystoscopy and urine cytology at 3, 6,12, 18, and 24 months. Then annually until 5 years after treatment. As clinically indicated afterward.
  2. Baseline upper urinary tract and abdomen/pelvis imaging, then as clinically indicated.
High risk
  1. Cystoscopy and urine cytology every 3 months for 2 years, then every 6 months for 3 more years. Finally, annually until 10 years after treatment. As clinically indicated afterward.
  2. Baseline upper urinary tract and abdomen/pelvis imaging. Then, starting at 12 months, every 1-2 years until 10 years post-treatment. As clinically indicated afterward.
  3. Consider following urinary urothelial tumor markers.
Cystectomy patients
  1. Urine cytology (consider with urethral wash cytology) every 6-12 months for 2 years post-cystectomy.
  2. CT or MR urography at 3 and 12 months, then annually until 5 years post-cystectomy. Then renal ultrasound annually until 10 years after cystectomy. Additional imaging as clinically indicated.
  3. Electrolytes, Cr, and LFTs every 3-6 months for 1 year. Add CBC and CMP if chemotherapy was given. Then electrolytes, Cr, and LFTs until 5 years post-cystectomy.
  4. Follow B12 annually indefinitely.
Muscle-invasive disease
Cystectomy patients, no suspicion for metastases
  1. Urine cytology (consider with urethral wash cytology) every 6-12 months for 2 years post-cystectomy.
  2. CT/MR urography and chest x-ray or CT chest every 3-6 months for 2 years, then annually until 5 years post-cystectomy.* Then renal ultrasound annually until 10 years post-treatment. Additional imaging as clinically indicated.
  3. Electrolytes, Cr, and LFTs every 3-6 months for 1 year. Add CBC and CMP if chemotherapy was given. Then electrolytes, Cr, and LFTs until 5 years post-cystectomy.
  4. Follow B12 annually indefinitely.
Bladder preservation treatment patients, no suspicion for metastases
  1. Cystoscopy every 3 months for 2 years, then every 6 months until 4-years post-treatment, then annually until 10 years post-treatment. As clinically indicated afterward.
  2. Urine cytology every 6-12 months for 2 years post-treatment.
  3. CT/MR urography and chest x-ray or CT chest every 3-6 months for 2 years, then annually until 5 years post-cystectomy.* Additional imaging as clinically indicated.
  4. Electrolytes, Cr, and LFTs every 3-6 months for 1 year. Add CBC and CMP if chemotherapy was given. Follow further if clinically indicated.
Concerns for metastatic disease
  1. If there are concerns for metastases, consider imaging with PET/CT imaging from head to mid-thigh on the same schedule as marked by *. Other follow up is unchanged from non-metastatic disease.

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Other

Bellmunt J, De wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11):1015-1026.

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