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Bladder Cancer

Author: Stephen W. Leslie Author: Taylor L. Soon-Sutton Editor: Narothama R. Aeddula Updated: 8/15/2024 9:53:00 PM

Introduction

Bladder cancer, a prevalent malignancy affecting the urinary system, arises from the tissues of the bladder, a hollow organ responsible for storing urine (see Image. Bladder Cancer, Magnetic Resonance Image). Urothelial carcinoma is the most frequent type of bladder cancer, constituting over 90% of cases in industrialized nations. This type of cancer is notably common among older adults, with risk factors including smoking, chemical exposure, and chronic bladder inflammation.

Presenting symptoms such as gross or microscopic hematuria, urinary frequency, and unexplained pelvic pain typically lead to its detection. Early diagnosis and treatment are crucial for improving outcomes, as bladder cancer can range from noninvasive forms that are confined to the inner layers of the bladder to invasive types that penetrate deeper and can spread to other parts of the body.

Treatment primarily involves transurethral resection and intravesical chemotherapy instillations but may also include laser ablation, Bacillus Calmette-Guerin bladder treatments, radiation therapy, chemotherapy, or surgical removal of part or all of the bladder.

This activity reviews the intricacies of bladder cancer, from its etiology to its therapeutic strategies. The latest advancements and comprehensive knowledge in diagnosing, treating, and managing this prevalent malignancy are discussed. Participants gain enhanced diagnostic acumen, learn evidence-based treatment protocols, and are updated on emerging research, fostering a deeper understanding of bladder cancer's evolving landscape and ultimately improving clinical practice. The role of the interprofessional team in improving care for patients with this common malignant condition.

Collaborating with an interprofessional team enhances patient outcomes by integrating diverse expertise, ensuring comprehensive treatment plans, and providing holistic care that addresses all aspects of the patient's health. This improves the overall management and prognosis of bladder cancer.

Etiology

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Etiology

Urothelial carcinoma develops via two distinct pathways. One relates primarily to papillary neoplasms, and the other to flat or sessile lesions.

Non-muscle-invasive bladder cancers (NMIBC) are typically low-grade papillary tumors that usually arise from simple hyperplasia and/or minimal dysplasia. This category also includes carcinoma in situ (CIS), a high-grade but superficial cancer.

NMIBCs are characterized by the following:

  • Activating mutations of fibroblast growth factor receptor 3                                                                                     
  • Inactivating mutations of STAG2                                                                                                                   
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform                                          
  • The loss of heterozygosity of chromosome 9                                                                                                            
  • Telomerase reverse transcriptase 

Low-grade papillary NMIBC can progress to a muscle-invading malignancy in about 10% of cases due to cyclin-dependent kinase inhibitor 2A loss.[1]

Muscle-invasive bladder cancer (MIBC) arises from flat dysplasia or carcinoma in situ  and is characterized by the following:

  • The lesions show TP53 mutations and loss of heterozygosity of chromosome 9.
  • Invasive carcinoma can then acquire metastatic potential by gaining RB1 and PTEN loss, together with other alterations.
  • Copy number alterations and genetic instability correlate with tumor progression and a poorer prognosis.
  • Overall, NMIBC usually shows diploid or near-diploid karyotypes as compared to muscle invading.
  • MIBC is usually aneuploid, with numerous chromosomal alterations.[2][3]

Results from recent studies have demonstrated 4 subtypes of NMIBC based on abnormal ribonucleic acid (RNA) expression analyses.[4] These abnormal prognostic molecular subtypes involve early cell cycle abnormalities, chromosomal instability, stem cell-like disorders, and immune depletion problems.[4] Of these, chromosomal instability, which involves p53 and deoxyribonucleic acid damage repair genes, as well as apolipoprotein messenger RNA-editing enzyme, catalytic polypeptide, appears to be the most significant, as it has the highest recurrence and progression rates.[4]

Risk Factors

There are multiple known risk factors for bladder cancer. Important risk factors include smoking, schistosomiasis infection, and occupational exposure to certain chemicals.[2][5][6]  Smoking is the most important known risk factor for bladder cancer as the average incidence in smokers is triple (2- to 6-fold) that of nonsmokers; the risk depends on smoking duration and intensity, with 10-pack-years generally considered the high-risk threshold.[7] At least 50% of bladder cancers will be found in current or former smokers.[8][9][10] Cigarette smokers also tend to develop more aggressive tumors and have a worse prognosis.[11] Smoking cessation lowers the bladder cancer risk, which eventually approaches that of nonsmokers.[8][10] Within the first 4 years after smoking cessation, the bladder cancer risk drops by 40% and is reduced by 60% after 25 years.[12]

In developing countries, schistosomiasis infection is an important cause of bladder cancer. Schistosoma haematobium ova becomes embedded in the bladder wall, leading to irritation, chronic inflammation, squamous metaplasia, and dysplasia, ultimately progressing to squamous cell carcinoma of the urinary bladder (see Image. Poorly Differentiated Urothelial Carcinoma with Metaplastic Squamous Appearance). Worldwide, about 600 million people are at risk in endemic areas of Africa, Asia, the Caribbean, and South America.[13]

Genetic and/or environmental factors also affect the development of bladder cancer but only account for about 7% of all such cases.[14][15][16][17][18] Chemicals associated with bladder cancer include arylamine and aniline dyes, formaldehyde, phenacetin, cyclophosphamide, and arsenic in the drinking water.[19][20][21][22]

Occupational exposure to paint, rubber, petroleum products, agricultural chemicals, and dyes correlates with an increased risk of bladder cancer. Occupations that typically have the most exposure to such chemicals include the following: 

  • Agricultural crop production workers
  • Barbers
  • Bartenders and waiters
  • Beauticians
  • Chemical plant employees
  • Dental office workers
  • Dry cleaners
  • Housecleaners
  • Metalworkers (welding)
  • Oil refinery workers
  • Painters
  • Paper production workers
  • Pesticide production or use by agricultural workers
  • Rope, string, and twine production workers [23]

Epidemiology

In the United States (US), bladder cancer is the fourth most common cancer in men, eighth in women, and fifth overall, with a man-to-woman ratio of 4:1.[24] While women have bladder cancer less often than men, they typically present with more advanced disease and have a poorer prognosis.[25][26][27][28][29] According to the National Cancer Institute, there were 82,290 new cases and 16,710 deaths from bladder cancer in the United States in 2023. Bladder cancer represents 4.2% of all new cancers detected and 2.7% of all cancer deaths, with an overall 5-year relative survival rate of 77.9%. The incidence of new cases and mortality rates are slowly declining in the US by about 1% a year.

Bladder cancer is twice as common in White populations (the ethnic group with the highest incidence) compared to those in the Black population, and the risk increases with age, particularly in those older than 70. However, disease-specific survival is lower for Black individuals.[30][31] In the US, almost all bladder cancer is urothelial, but worldwide, most (75% of cases) are squamous cell carcinomas, which correlates closely with the incidence of endemic schistosomiasis.[30][32][33] 

Worldwide, bladder cancer is the seventh most common malignancy overall. The reported incidence globally is 9.5/100,000 population/year for men and 2.4/100,000 for women.[13] In 2020, 213,000 individuals died from bladder cancer worldwide.[34] The incidence of bladder cancer is twice as high in developing nations compared to highly industrialized countries. According to the World Health Institute (WHO), Greece has the highest overall risk of bladder cancer, followed by the Netherlands, Italy, Denmark, Belgium, and Spain. The WHO reports the highest mortality rate in the world from bladder cancer is in Egypt, followed by Tunisia, Libya, Poland, and Mali.

Pathophysiology

The most critical characteristics related to bladder cancer's aggressiveness and prognosis are its degree of invasiveness (penetration) into the bladder wall and its tumor cellular grade. Therefore, bladder cancers are classified into MIBC and NMIBC based on tumor invasiveness and low and high grade based on cellular characteristics.

Non-muscle-invasive bladder cancer is urothelial carcinoma that is confined to the mucosa and submucosa as it does not penetrate through the lamina propria into the underlying muscle layer.[35][36][37] This type tends to be less aggressive and is usually treated with localized therapy such as transurethral resection.[1][36] NMIBC is the most commonly found type of bladder cancer and accounts for about 75% of the total cases. One exception is CIS, which is an aggressive and high-grade but relatively rare (1% to 3%) and superficial form of bladder cancer.[38] While technically non-muscle-invasive, it is typically discussed and treated differently.[38]

Muscle-invasive bladder cancer penetrates the lamina propria and enters the superficial or deep muscle layers of the bladder.[30][35][37] It may also extend to other tissues surrounding the bladder or elsewhere. MIBC accounts for about 25% of all bladder malignancies.[39] This type of cancer is far more likely to metastasize than NMIBC and is treated much more aggressively, often with radical surgery and chemotherapy.[30]

Histopathology

The urinary bladder wall is comprised of 4 layers: mucosa, submucosa, muscularis, and serosa. The mucosa has a normal urothelium layer consisting of a 3– to 6-cell thick layer of stratified, uniform, nonsquamous (transitional cell) epithelium (urothelium). Large umbrella cells form on top, with an additional superficial glycosaminoglycans layer, which acts as a protective barrier to irritating urinary chemicals. Basal cells are found below, and intermediate cells are in between. 

Bladder cancer originates from the basal cell layer (CIS, muscle-invasive urothelial cancer, and squamous cell carcinoma) or intermediate cells (noninvasive urothelial cancer).[40] The urothelium extends from the renal papilla to the urethra.[41] This is quite impermeable and chemically inert due to the protective glycosaminoglycans layer on the superficial mucosal surface, tight cellular junctions between the umbrella cells, and uroplakin proteins in the membrane of the umbrella cells, which block any mucosal penetration. Urothelial carcinoma stains positively for GATA-3, CK7, CK20, p63, thrombomodulin, and uroplakins II and III.

Bladder cancer is classified by stage (muscle-invading or not) and grade (low grade or high grade). Based on its morphology and pathway, it may also be subdivided into papillary (papilloma, low malignant potential, and papillary carcinoma) and flat (urothelial CIS and invasive) categories (see Image. Urothelial Carcinoma in Situ in the Setting of Cystitis Cystica and Glandularis).

The WHO classifies urothelial carcinoma based on histopathology as low-grade or high-grade, depending on the degree of nuclear anaplasia and architectural abnormalities. The histology of infiltrating urothelial cancer is variable (see Image. Urothelial Carcinoma, Prostatic Infiltration and Image. Urothelial Carcinoma, Perineural Invasion). Most T1 (non-muscle-invading) cancers are papillary, low, or high grade, whereas T2-T4 (muscle-invading) carcinomas tend to be non-papillary and high grade.

Low-grade urothelial bladder tumors typically appear as thin papillary fronds with frequent branching.[42] Variation in nuclear polarity is common with enlarged irregular nuclei and frequent nucleoli.[42] Mitoses may be present, and most tumor cells are aneuploid.[42]

High-grade urothelial cancers show a more disordered arrangement with cytological atypia than low-grade neoplasms.[42] Papilla are often fused with more cytological and architectural abnormalities than in low-grade tumors.[42] Nuclei are pleomorphic, have prominent nucleoli, and have altered polarity with frequent mitoses present.[42] CIS is often seen in adjacent mucosal areas, and aneuploidy is common.[42]

Carcinoma in situ (CIS) of the urinary bladder describes a flat, superficial, high-grade urothelial malignancy with severe cytological atypia and nuclear anaplasia.[43] Other characteristics include loss of polarity, cellular crowding, and pleomorphism with markedly enlarged hyperchromatic nuclei and large nucleoli.[43] Loss of cellular adhesion results in denuded mucosal areas, common from shed cells, resulting in positive urinary cytological findings.[44] Urothelial CIS typically stains negatively with CD44 but strongly positively with CK20 and p53. CIS of the bladder has a 60% rate of disease recurrence and/or progression. CIS is relatively rare as a primary malignancy at no more than 3% of all bladder cancers, but it is frequently seen with invasive urothelial cancers and is considered a poor prognostic sign when detected.[43][45]

Divergent differentiation is the term used to describe urothelial carcinoma together with non-urothelial histology.[45] This is found in 15% to 25% of all invasive bladder cancers.[45] Possible associated morphologies with such "divergent differentiation" may occur single or in combination and include squamous, glandular, small-cell, micropapillary urothelial cancer, nested, microcytic, microtubular, sarcomatoid, high-grade neuroendocrine, and even trophoblastic lines.[46][47][48] All of these subtypes and variations are considered high-grade.[13][48] The percentage of such divergent differentiation should be reported when identified as it has prognostic significance.[46][47][49]

Pathology plays a crucial role in managing bladder cancer. Most patients (75%) present with NMIBC at initial diagnosis, which correlates with better overall survival and prognosis. The most critical factor in the pathological assessment of urothelial carcinoma is identifying the extent of invasion to set proper staging, followed by the tumor grade. Bladder cancers can be unifocal or multifocal. Most cases present as multifocal, which may be multiple and independent or arise from a common origin.

The pathology report should include the following:

  • Depth of tumor penetration or invasion into the bladder wall (Microinvasion is defined as a depth of invasion ≤2 mm.)          
  • Histological type and grade 
  • Location of the tumor: where in the bladder it was found 
  • Number of separate specimens or tumors                                                                                                                                    
  • Presence or absence of CIS                                                     
  • Presence or absence of detrusor muscle in the specimen 
  • Presence and percentage of any divergent differentiation                                                  
  • Size of the specimen

In complex or difficult cases, an additional review by an experienced genitourinary pathologist is recommended.[46][47]

Squamous cell malignancies constitute the majority of non-urothelial bladder cancer cases worldwide, although over 90% of bladder tumors in the US and industrialized countries are urothelial carcinomas.[50]

In the US, squamous cell carcinoma of the bladder is related to chronic inflammation from foreign bodies, catheters, human papillomavirus (HPV) infections, cyclophosphamide exposure resulting in hemorrhagic cystitis, or schistosomiasis in travelers or immigrants.[51][52] Squamous cell carcinoma is the second most common cancer type found in the bladder at about 5%.[53] Squamous cell carcinoma is followed by adenocarcinoma at 2% and neuroendocrine malignancies.[51]

Up to approximately 40% of high-grade or invasive bladder cancers will have some squamous cell characteristics (polygonal cell shape, abundant light eosinophilic cytoplasm, distinct cell borders, and peritumoral lymphocytic aggregates).[45] The diagnosis of primary squamous cell carcinoma is reserved for keratin-forming squamous neoplasms that lack any typical urothelial components.[45] Squamous cell carcinoma of the bladder stains positive for cytokeratin CK 5/6, desmoglein 3, p63, CD44, and p40.

Treatment is generally surgical, possibly with preoperative radiation therapy. Patients with disease not amenable to surgical resection may receive chemoradiation. Metastatic disease is uncommon but may be best treated with carboplatin, gemcitabine, and paclitaxel.[54] Enrollment of patients with advanced disease in a clinical trial is strongly encouraged.

Adenocarcinoma of the bladder is far more likely to metastasize than squamous cell cancer; this cancer is typically classified as urachal or non-urachal. Urachal adenocarcinoma develops from the urachal remnant and is typically located in the dome of the bladder, often extending into the prevesical space. These malignancies are mucin-producing (90%) tumors that typically present as locally advanced with hematuria and a palpable lower abdominal mass.[55][56][57] Treatment is surgical, with a substantial number of patients able to receive partial cystectomies. Five-year overall survival has been reported at about 50%.[58]

Non-urachal adenocarcinoma of the bladder tends to be associated with schistosomiasis or bladder exstrophy.[59][60] Cystoscopic appearance may be papillary or flat; these tumors are usually muscle-invasive neoplasms at presentation.[61] Extrinsic adenocarcinomas need to be excluded. Treatment is primarily surgical, but partial cystectomies are generally avoided due to poor outcomes.[62][63][64][65] The prognosis for non-urachal adenocarcinoma of the bladder is usually bleak, with a 5-year overall survival of 35%.[66]

History and Physical

Bladder cancer is primarily a tumor in adults who are 60 and older. Hematuria, either gross or microscopic, is the most common initial symptom in patients with bladder cancer. Over a third of patients with gross hematuria and slightly over 10% of those with microscopic hematuria will ultimately be diagnosed with bladder cancer. Other less common symptoms include painful micturition, increased urinary frequency, a pelvic mass, and constitutional symptoms such as fatigue and weight loss.

A complete history and physical examination are recommended for all patients presenting with unexplained hematuria to identify risk factors for urothelial malignancy as well as other sources of bleeding such as medical kidney disease, renal neoplasms, urolithiasis, gynecological disorders, benign prostatic hyperplasia, and other nonmalignant genitourinary disorders.[67] In women, a pelvic examination, as well as a careful inspection of the external genitalia, introitus, and periurethral area, should be performed. The evaluation is the same for patients taking anticoagulants.[68][69][70]

If a nonmalignant cause of the hematuria is discovered, repeat urinalyses should be performed following treatment and resolution of the disorder. If the hematuria remains, a risk-based evaluation should be performed.[67] For example, patients with microscopic hematuria due to a urinary tract infection should have a follow-up microscopic urinalysis after treatment to verify that the hematuria has also resolved.[67]

There are no screening tests for the early detection of bladder cancer other than the finding of unexplained, persistent, gross, or microscopic hematuria. Gross hematuria may correlate somewhat with a more advanced disease stage.[46] Smoking history is a strong predisposing factor. A history of 10 pack-years or more is sufficient to increase the patient's bladder cancer risk significantly. Medical renal disease as a source of hematuria should be suspected in patients with proteinuria, dysmorphic red blood cells, cellular casts on microscopic urinalysis, or kidney failure.[67]

High-Risk Factors for Bladder Cancer

  • A chronic indwelling catheter or foreign body
  • Chemotherapy (cyclophosphamide, ifosfamide)
  • Concurrent irritative voiding symptoms
  • History of pelvic radiation
  • Increasing age
  • Male sex
  • Positive family history of bladder cancer, Lynch syndrome, Peutz-Jeghers syndrome, or Cowden syndrome
  • Smoking history of 10 or more pack-years
  • Toxic chemical exposure
    • Aromatic amines and hydrocarbons
    • Arsenic
    • Benzene products
    • Formaldehyde
    • Nitrosamine
    • Petrochemicals
    • Rubber [67]

Schistosoma hematobium is a risk factor for squamous cell carcinoma in those parts of the world where the parasite is endemic.

Evaluation

Screening patients for bladder cancer is not recommended. Patients who are found to have hematuria on routine urinalysis should be considered for an evaluation of possible bladder cancer. Modalities used in diagnosing bladder cancer include imaging (eg, ultrasound, computed tomography, and magnetic resonance imaging), cystoscopy, cytology, transurethral resection, and biopsy. (see Image. Bladder Cancer) Intravenous pyelography is no longer used.

American Urological Association Patient Risk-Stratification [67]

Low-Risk Patients

Microhematuria and must have all of the following:

  • Women younger than 50, Men younger than 40 
  • Smoking: Never smoked or <10 pack-years
  • Urinalysis shows ≤10 red blood cells/high power field (RBC/HPF) with no prior hematuria 
  • No high-risk factors 

Patients with microscopic hematuria at low risk for urothelial cancer should proceed with an ultrasound and cystoscopy or have a repeat urinalysis in 6 months.

Intermediate-Risk Patients

Microhematuria and any of the following:

  • Women 50 to 59 years; men, 40 to 59 years
  • Smoking: 10 to 30 pack-years
  • Urinalysis shows 11 to 25 RBC/HPF
  • One or more high-risk factors 
  • Previously categorized as low risk without further evaluation

Patients with microscopic hematuria at moderate risk for urothelial cancer should proceed with ultrasound and cystoscopy.

High-Risk Patients

The patient does not qualify as low or intermediate risk OR microhematuria and any of the following:

  • Gross hematuria
  • Age 60 or older (women and men)
  • Smoking >30 pack-years
  • Urinalysis shows >25 RBC/HPF

Patients considered high risk or who fail to qualify as low or intermediate risk should be evaluated with a computed tomography (CT) urogram (ie, CT scan of the abdomen and pelvis without and with IV contrast) and a cystoscopy.

Imaging

Imaging is a critical diagnostic component for evaluating bladder cancer. Ultrasound may be used in patients considered low-risk (eg, microscopic hematuria, younger age, no significant smoking history, and no high-risk factors).[71] However, it is not as thorough or comprehensive as a CT urogram, and it will miss small tumors, cystic lesions, and CIS.[72]

A CT urogram is the gold-standard imaging modality for the upper urinary tract.[73] This imaging should be performed in all patients who are high-risk and those who do not otherwise qualify as low or intermediate risk.[67] A CT urogram is also indicated if a bladder tumor is confirmed on cystoscopy and the CT study has not already been performed. The incidence of finding a simultaneous urothelial malignancy at the same time as bladder cancer is quite low at 1.8%, except for trigonal neoplasms, where the reported incidence is 7.5%.[74] 

A CT urogram is optimally performed in 3 phases as follows:

  • The non-contrast phase optimizes the identification of calcifications and urinary calculi.                                          
  • An early arteriovenous phase study optimizes visualization of renal masses and neoplasms.                                    
  • Delayed imaging (about 15 minutes after contrast injection) opacifies the entire urinary collecting system and is optimized for identifying filling defects in the bladder and upper urinary tracts (possible urothelial tumors). Such upper urinary tract filling defects should be further evaluated with ureteroscopy.

CT urography has a reported diagnostic accuracy of 91.5%, sensitivity of 86.3%, and specificity of 92.4%.[73] Its positive predictive value was 63.6%, with a negative predictive value of 97.8%.[73] A magnetic resonance imaging (MRI) urogram should be performed if intravenous contrast cannot be administered due to inadequate renal function or an allergy. If this cannot be done, a non-contrast CT scan with bilateral retrograde pyelograms is recommended.[71] Filling defects in either the ureter or renal pelvis discovered on imaging should be further evaluated by ureteroscopy with biopsies, laser therapy, and/or selective cytology or washings for cytological examination.

Magnetic resonance imaging (MRI) is superior to CT scanning for the staging of muscle-invasive disease, with a sensitivity and specificity reported at >90%.[75] MRI can also detect a significant tumor recurrence sooner by identifying early bladder wall neovascularization.[76][77] Newer modifications and improvements such as the Vesical Imaging-Reporting and Data System (VI-RADS), Synthetic Magnetic Resonance Imaging (SynMRI), multi-sequence MRI radiomics, and biparametric MRI techniques may be able to predict muscle invasion and histopathological tumor grade even better.[78][79][80] In general, pelvic lymph nodes >8 mm and abdominal nodes >10 mm in diameter should be considered pathological and consistent with metastasis.[81]

The 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) is a test for metastatic urothelial malignant disease and may be helpful for staging before a radical cystectomy in selected patients, preferably in a clinical trial, but it should not be used for anatomical details or diagnostic imaging of the urinary tract and is not beneficial in the initial diagnosis of bladder cancer as its exact role is still being determined.[82][83][84][85][86][87][88] FDG-PET is highly specific for metastatic bladder cancer and provides superior sensitivity compared to CT scans.[86][89][90]

Cystoscopy

Cystoscopy is considered the gold standard for the initial management of bladder cancer, with a reported 98% sensitivity.[67][91] However, this high sensitivity rate has been questioned, suggesting that there may be a role for repeat cystoscopies, photodynamic enhancement techniques, and/or urinary biomarkers, particularly in high-risk or equivocal cases.[92] Diagnostic cystoscopy is usually performed with minimal anesthetic in the office or clinic, but it may also be performed in the operating room simultaneously with a biopsy or transurethral resection.

Non-muscle-invasive bladder cancer typically appears as 1 or more papillary lesions. Cystoscopically, they are frond-like neoplasms with multiple, tiny vascularized projections that tend to bleed easily. The hematuria they produce ultimately results in their early discovery in most cases. They are the most common (75%) forms of bladder cancer, are typically noninvasive, and tend to be low-grade histologically.[1][36] However, if undetected and untreated, they can progress and penetrate the lamina propria, becoming dangerous and muscle-invading, with a risk of metastasizing.

Muscle-invasive bladder cancer may appear as a solid tumor that is flat, sessile, or nodular. These tumors may also have a papillary appearance. They tend to be more dangerous and aggressive than NMIBC as they are more likely to be high-grade.

Cystoscopy has been reported to demonstrate a sensitivity of 92% and specificity of 88% for MIBC, along with a positive predictive value of 72% to 78% and a negative predictive value of 92% to 96%, making it a reasonably reliable method of identifying MIBC.[39][93] However, this does not negate the need for an accurate histological diagnosis and staging of bladder cancers with appropriate biopsies and transurethral cancer resections.

Using this evaluation protocol (CT urogram and cystoscopy), the etiology of hematuria in approximately 57% of patients with asymptomatic microscopic hematuria and 92% of those with gross hematuria will be identified. A malignancy will be found in about 3% to 5% of patients presenting with microscopic hematuria and 23% with gross hematuria.

Carcinoma in situ (CIS) classically appears as a flat, irregular patch of erythematous mucosa with a velvety or granular surface, which looks very similar to routine inflammation, making cystoscopic diagnosis extremely difficult. Most of the patients with CIS (80%) will present with irritative voiding symptoms, which doubles the risk of finding CIS (from 5% to 10%) in patients with microscopic hematuria.[94][95] However, several other urological disorders can cause these same symptoms, such as urolithiasis, urinary tract infections, and benign prostatic hyperplasia.

Due to its similarity to inflammation, CIS can be easily overlooked on standard cystoscopy. For this reason, any inflammatory bladder lesions in patients with urothelial carcinomas should be considered for biopsy and/or cautery at the time of transurethral bladder tumor resection (TURBT).    

Carcinoma in situ (CIS) may be clinically classified as primary, secondary, concurrent, or recurrent as follows:

  • Primary: CIS with no prior or concurrent disease
  • Secondary: CIS diagnosed during surveillance of patients previously diagnosed with bladder cancer but not CIS
  • Concurrent: CIS identified simultaneously with any other bladder cancer
  • Recurrent: CIS identified in a patient with a previous diagnosis of CIS

Bladder biopsies should be performed on all papillary and solid bladder neoplasms, as well as any suspicious erythematous lesions. If a TURBT is being performed, all erythematous areas should be considered suspicious and biopsied, along with possible fulguration. Cauterization or fulguration should be done to the biopsy bed and the superficial mucosa around the biopsy or resection site for about a 1 cm radius due to field change disease.

All erythematous and suspicious mucosal lesions should also be biopsied. Random biopsies for mapping should be performed if the cytology is positive or the tumor appears solid or sessile rather than papillary. Biopsies may be performed with cold cup biopsy forceps (flexible or preferably rigid) or transurethral resection. Electrosurgical resection is not preferred for biopsies as it causes cautery artifacts. Every effort should be made to obtain a deep sample, including muscle tissue, for staging, but it is absolutely essential to avoid a bladder perforation, which could spread malignant cells outside the bladder.

Keeping the bladder relatively empty and using continuous flow instrumentation will keep the bladder wall relatively thick and immobile, minimizing the risk of accidental perforation. Tumor and biopsy locations should be carefully recorded as this is associated with progression and prognosis.[13] Bladder cancers at the trigone, bladder neck, or prostatic urethra have an increased risk of nodal involvement and decreased survival.[96][97][98][99]

Cytology, Fluorescence In Situ Hybridization, and Urinary Biomarkers

Cytology, fluorescence in-situ hybridization (FISH), and other urinary biomarkers are not currently recommended by the American Urological Association (AUA) or European Association of Urology (EAU) guidelines for the routine initial evaluation of patients with hematuria due to their high cost and relatively poor specificity.[36][47][67] While they can be useful for monitoring progression in patients with known disease and borderline or equivocal situations, they are not considered an adequate substitute for cystoscopy.[36] Urinary biomarkers may also be useful in patients with persistent microscopic hematuria after a negative workup, particularly if they also have high-risk factors for CIS and/or irritative voiding symptoms.[67] Urine-based biomarkers can potentially reduce unnecessary referrals and cystoscopic procedures, but none has yet reached a level of clinical reliability to replace cystoscopy.[100][101][102]

Urine cytology has been recommended for high-risk patients with gross hematuria. Some healthcare professionals will also order it routinely for high-risk microhematuria patients, particularly those with a history of 10 or more pack-years of smoking. Cytology may also be useful in detecting and following CIS, which may be easily missed during cystoscopy.[67][103] Cytology is quite reliable when positive, but it lacks sensitivity and will miss many malignancies, especially low-grade neoplasms. It is also highly dependent on the cytopathologist's skill and experience.[104]

Cytology is considered a valuable tool for the follow-up of patients with high-grade bladder cancer and, especially, CIS of the bladder.[30][46][105] A large review of 36 separate studies with over 14,000 patients showed the sensitivity of urinary cytology to be only 44% with a high specificity of 96%.[106] The first morning voided urine is unsuitable for cytological evaluations due to cytolysis.[47] Cytology diagnostic reports should indicate the specimen's adequacy and the presence of high-grade urothelial carcinoma, atypical cells, or "suspicious" findings for high-grade cancer.[13]

Bladder washing for cytology is typically obtained during cystoscopy using normal saline. With the bladder emptied by a catheter, 50 mL to 100 mL of normal saline is instilled and then immediately extracted using a catheter tip syringe. This procedure is repeated 3 to 6 times. Bladder washing provides larger numbers of well-preserved urothelial cells than standard voided urine cytology and detects more urothelial cancers.[107][108] Washing can be performed immediately after TURBT to identify any invisible high-grade tumor and is often preferred in the follow-up of high-risk cancer cases, particularly in patients with CIS.[109][110] Cytology and bladder washing may be performed together, with the voided cytology collected first. Labeling the specimens correctly to avoid any potential confusion for the cytopathologist is important.

Fluorescence in-situ hybridization (FISH) is a relatively sensitive genetic test marker for bladder cancer that detects aneuploidy of chromosomes 3, 7, and 17 and the loss of the 9p21 locus.[111] Results are reported as either positive or negative, which makes interpretation easy. If the FISH test is positive, an increased frequency of surveillance is recommended, and further evaluation of the ureters and upper tracts bilaterally should be considered.[36]

  • About 27% of patients with NMIBC on surveillance with negative cystoscopies will have a positive FISH test, and two-thirds of these will develop recurrent bladder cancers within the next 2 to 3 years.[112]                                   
  • A systematic review and meta-analysis reported the overall sensitivity and specificity of FISH testing as 68% and 64%, respectively.[113]                           
  • The FISH test is most useful for monitoring bladder cancer, especially after bacillus Calmette-Guerin (BCG) therapy, and in the initial diagnosis of high-risk
  • A positive FISH test following BCG therapy is suggestive of an impending bladder cancer recurrence, particularly within the following 6 months.[114][115][116][117] Close follow-up of such patients is therefore recommended.[114]     
  • The FISH test has a significant rate of false negatives for bladder cancer and is expensive, which limits its clinical utility.

Various other biomarkers for bladder cancer are available. They are primarily used to monitor the response to BCG therapy and where cystoscopy or cytology findings are equivocal or atypical, particularly in high-risk patients. Overall sensitivity ranges from 58% to 82%, and specificity from 78% to 88%.[36] 

Genetics-based urine testing, using urinary mRNA, is a promising urinary biomarker for recurrent bladder cancer.[118][119][120] Preliminary results from a 2-year trial of 313 bladder cancer patients suggest that surveillance cystoscopies can be safely reduced by 54% using a new genetics-based urine test. The new urine test identifies 5 separate genes and identified bladder cancer recurrences earlier than cystoscopy.[121] While preliminary, this data appears quite promising, but it will require publication of the final trial results, independent confirmation, and additional testing before it can become clinically accepted and available.

Similarly, molecular markers for MIBC are still in the investigational stage and are not appropriate for use outside of a clinical trial.[13]

Enhanced cystoscopic diagnostic techniques use either drug-induced cystoscopic tumor cellular fluorescence or special image-processing techniques to help identify pathological urothelial tissue during cystoscopy.[122][123][124] These are very sensitive techniques for detecting CIS of the bladder and otherwise invisible superficial urothelial malignancies, reducing recurrences through better identification and elimination of affected urothelium, but their precise role is not yet clearly defined.[123][125][126] Overall, enhanced cystoscopic diagnostic techniques are significantly underutilized.[127]

The AUA and EAU guidelines now recommend photodynamic cystoscopic enhancement, where available, at the time of initial therapy for NMIBC, at the first 3-month surveillance cystoscopy and thereafter for the first 2 years, prior to intravesical chemotherapy, and in cases where there is a new finding of positive cytology or abnormal/equivocal cystoscopic findings.[36][47]

  • Photodynamic cystoscopic diagnostic enhancement, also called "blue light" cystoscopy, uses 5-aminolevulinic acid (5-ALA) or hexylaminolevulinate (HAL) to help identify and visualize malignant tissue changes in the bladder mucosa.[124] This greatly enhances the diagnosis and localization of CIS of the bladder.[128][129][130][131] These medications cause the preferential accumulation of photoreactive porphyrins in malignant bladder mucosal urothelial cells. These become visible under blue cystoscopic light as the porphyrins fluoresce red, while normal tissue appears blue.[124]                                                             
    • 5-ALA or HAL is instilled into the bladder 2 hours before the cystoscopy.[131]                                               
    • Blue light (380 to 440 nm) is used during the cystoscopy, and any malignant areas will fluoresce red.[132][133][134][135] These highlighted areas can then be selectively biopsied, cauterized, or resected.
    • In 1 study, 5-year cancer-specific survival was improved over white light cystoscopy from 74% (with white light) to 91% using HAL and blue light.[136] 
    • False positives from photodynamic-enhanced diagnostic cystoscopy may be seen when 5-ALA or HAL is taken up by mucosal cells due to localized inflammation, recent transurethral surgery, or intravesical therapy.[137][138][139]    
    • Photodynamic cystoscopic enhancement is now available and FDA-approved for flexible cystoscopy in the office or clinic.   
    • Bladder urine can cause a green discoloration, and visualization in recorded images may be "foggy" due to hardware or irrigation fluid issues. Advanced image processing techniques can correct these.[140]
  • Narrow-band imaging is a technique to enhance the cystoscopic visualization of malignant bladder urothelium through enhanced digital image processing. Narrow-band imaging does not require fluorescent drugs but instead uses special image processing of bandwidths 415 and 540 nm (blue and green). This improves the identification and visualization of abnormal urothelial tissue but requires special equipment.[141][142][143] Overall results are similar to photodynamic cystoscopic enhancement with fluorescing drugs.

Treatment / Management

The treatment strategy for urothelial cancer depends on whether there is histological evidence of muscle invasion (eg, therefore, it is either NMIBC or MIBC). This initial staging is determined after an initial biopsy and/or TURBT.

Transurethral resection of a bladder tumor is both diagnostic and therapeutic. Smaller tumors may be removed with cold cup biopsy forceps, which is preferred due to the preservation of the histology without any cautery artifact. Transurethral resection is reserved for larger tumors. Attaining hemostasis is important as active bleeding will interfere with endoscopic visualization. However, unnecessary cautery should be avoided to minimize coagulation artifacts in the tissue specimens.

A complete cystoscopic inspection of the bladder and urethra should be performed, with all lesions, masses, and erythematous patches carefully noted. While the patient is under full anesthesia, a bimanual examination should be performed to determine if there is any indication of a palpable mass or any evidence of possible tumor fixation to the pelvic sidewall or other structures.[144][145] A standard TURBT should contain at least 3 separate specimens: the main tumor, a deep biopsy from the tumor base if any muscle invasion might be present, and a random biopsy sample from "normal" bladder mucosa.[1][13][36][47] In addition, any abnormal mucosal areas should be biopsied with their location carefully documented and sent to pathology separately.[1][13][36](B3)

Possible involvement of the prostatic urethra has been reported in up to one-third of men with bladder cancer.[146][147][148][149][150] This risk is increased for patients who have a tumor located at the bladder neck, in the trigone, or if the patient has multifocal disease or CIS.[151][152][153]

TURBT tips include the following:

  • The bladder should not be overstretched or overfilled, as this will attenuate the bladder wall thickness;  should be filled enough so all major bladder folds are flattened to avoid overly deep unintended trauma and possible perforation.
  • Continuous-flow instrumentation is recommended to minimize the motion of the bladder wall during resection. Adjust the flow rate to the minimum necessary to maintain a constant level of filling.
  • The resection motion should generally be straight, towards the operator, and without actively angling the scope laterally.
  • One helpful technique is to place the end of the resectoscope loop under the far edge of the tumor and gently lift it away from the bladder wall before electrifying the cutting loop to perform the resection. This will help minimize unintentional bladder wall damage.
  • If there are multiple or large tumors, start resecting at the edge, where there will be complete visualization.
  • The goal is to complete the resection in 1 area or 1 tumor at a time until it is flush with the rest of the bladder wall. At that point, consider using a cold cup biopsy for tissue samples and try to avoid an inadvertent perforation.
  • Do not resect in a bladder diverticulum, as these areas do not have a muscle layer, and perforation may easily occur; careful fulguration may be used instead. A partial cystectomy may be appropriate in some situations.
  • Regardless of the technique, a deeper biopsy, including muscle tissue, is recommended for staging. This deeper biopsy is usually sent as a separate specimen for identification.                                                                          
  • TURBT will fail to identify muscle invasion in about 30% of cases, usually due to inadequate tissue sampling or problems with postsurgical processing, handling, or analysis.[39][154][155]                                                                    
  • A separate biopsy of the edge of the tumor should also be sent for a separate pathological examination if muscle invasion is suspected.
  • There is evidence that laser ablation and bipolar resection are superior to monopolar transurethral resection for primary NMIBC. (Laser ablation does not yield any tissue for pathology.)
  • Larger tumors may be resected in stages, starting with the endoluminal portion. The tumor should be resected until it is flush with the neighboring bladder wall. Deeper resection should be performed cautiously, and the specimen should be sent separately to help pathology with staging.
  • Superficial cauterization should be done to the bladder mucosa for about a 1 cm margin around the base of any resected tumor. 
  • If available, enhanced cystoscopic techniques ("blue light" cystoscopy or narrow-band imaging) should be performed during the TURBT to enhance disease detection and allow for optimal therapy of all involved bladder mucosa.
  • A biopsy should be taken from any abnormal urothelium at the time of the TURBT.
  • Random mapping biopsies should be performed even from normal-appearing mucosa if the cytology is positive or the neoplasm is non-papillary.
  • Any erythematous or suspicious areas should be biopsied and superficial cauterized, especially if highlighted by "blue light" fluorescence or narrow-band imaging.                                                             
  • At the end of the procedure, the bladder should be thoroughly examined for any signs of a possible perforation, remaining tumor, or tumor fragments. Use the extra time to continue irrigation to facilitate the removal of as many floating malignant cells as possible.

An en-bloc resection may also be done endoscopically and is preferred when technically feasible. This technique removes the entire tumor, along with surrounding stromal tissue and some underlying detrusor muscle, as a single specimen. A systemic meta-analysis has shown that en-bloc resection facilitates the pathological examination, decreases the incidence of inadvertent perforation, reduces the incidence of finding residual tumor on repeat resections, and lowers the risk of perforation.[156][157](A1)

The obturator reflex is a sudden, violent spasm of the adductor thigh muscles from unintended obturator nerve stimulation during TURBT. This stimulation causes the patient to experience a sudden and severe jerk of the hips and thighs without warning. This unexpected violent motion can easily result in an inadvertent bladder perforation during TURBT.[158] 

The obturator nerve passes close to the inferolateral wall of the bladder and bladder neck. During transurethral bladder surgery, electrosurgical resection or cautery (both monopolar and bipolar) can cause unintended stimulation of the nearby obturator nerve, resulting in an unintended reflex.[158] Minimizing electrosurgical current levels and avoiding bladder overdistension will also help reduce the risk of an inadvertent obturator reflex.[159] Using bipolar resection is thought to help as well, but studies have failed to show a consistent benefit.[159][160] 

Effective elimination of the obturator reflex can be done by neuromuscular blockade during general anesthesia or using an obturator nerve block.[158][161] Spinal anesthesia alone will not block the obturator reflex.[159] Performing an obturator nerve block when using spinal anesthesia for a TURBT will reduce the incidence of obturator reflex reactions and bladder perforations.[162][163](A1)

Intravesical instillation of a chemotherapy agent (usually mitomycin C [40 mg/20 mL sterile water], gemcitabine [2000 mg/50 mL normal saline], or epirubicin [50 mg/50 mL normal saline]) immediately after a TURBT (within 24 hours) has been shown to reduce the incidence of urothelial cancer recurrence and progression significantly.[164][165][166][167][168][169][170][171] TURBT surgery releases tumor cells, which can be implanted elsewhere in the bladder.[174][175][176] This process can be impeded by a single intravesical chemotherapy bladder instillation within 24 hours of the resection.(A1)

Intravesical instillation should not be performed if there is a known or suspected bladder perforation, active bleeding, continuous irrigation, or if the resection is particularly extensive.[36] Gemcitabine is typically the preferred agent as it is equally effective but has been associated with fewer adverse events than other agents.[36]

Techniques for enhancing the effectiveness and pharmacodynamics of this intravesical chemotherapy include the following: 

  • The pH should be lowered. This can be accomplished by oral sodium bicarbonate starting the night before surgery, preoperatively, and intravenously during the TURBT procedure.                                                                                 
  • The duration of the intravesical therapy should be at least 1 hour. If possible, a longer dwell time of 2 hours is suggested.                                                 
  • Urine production during the instillation period should be minimized. Intraoperative and postoperative IV fluids should be minimized to limit urine production for the first 2 hours after surgery and avoid dilution of the intravesical chemotherapeutic agent.  
  • A high concentration of the intravesical chemotherapeutic agent should be used.[172][173][174]
    • (A1)

A single intravesical chemotherapy instillation after TURBT has been shown to reduce the recurrence rate from 10% to 15% when compared to TURBT alone in a number of studies, including 3 separate meta-analyses.[175][176][177][178][179][180][181] Results from a single trial of combination intravescial chemotherapy with mitomycin C and epirubicin showed a relative risk reduction of 31%.[182] While promising, this result requires further testing for confirmation.[180](A1)

The rationale for this treatment is that during TURBT surgery, numerous malignant cells are released into the bladder and may implant on the bladder wall. They become quickly covered by extracellular matrix but are initially susceptible to intravesical agents.[183] Preparing a bladder diagram of tumor locations is also recommended.[165](B2)

Operative reports of TURBTs should optimally contain all of the elements as follows: 

  • Describe the number, location, and estimated size of the bladder tumors (single largest diameter and aggregate size). 
  • Describe the American Joint Commission on Cancer clinical stage (cTa, cT1, cTis, cT2, cT3, cT4). 
  • Describe tumor morphology (nodular, solid, papillary, flat, sessile) . 
  • Indicate if this was a primary or recurrent tumor.                                                                                                        
  • Indicate if there was any evidence or suspicion of CIS.                                                                                          
  • Indicate if any immediate postoperative intravesical chemotherapy was used, the drug used, the indwelling duration, and the dose.                                 
  • Indicate if the resection was visually complete and if a deeper biopsy was performed.                                                      
  • Report any random biopsies taken and from where.                                                                                            
  • Report findings from the bimanual examination.                                                                                                   
  • Report if there was any evidence of perforation or if no such perforation was performed.                                                               
  • Report the results of a complete cystoscopic evaluation of the bladder and urethra.                                                  
  • Report whether any muscle was visually resected.[184][185]
    • (B2)

Repeat or "Second Look" TURBT is often recommended within 6 weeks of the original resection, as indicated below. Care should be taken to avoid bladder perforations, but underlying muscle tissue needs to be present in the specimen. Repeat or "second look" TURBTs have been shown to increase recurrence-free survival, improve outcomes from BCG therapy, and provide important prognostic information if performed within 6 weeks of the original surgery.[186][187][188][189][190][191](A1)

Indications for a "second look" TURBT include the following: 

  • High-grade superficial papillary (high-grade Ta) or any invasive carcinoma into the submucosa or lamina propria (any T1), even if bladder muscle was found in the original specimen                                                          
  • Highly multifocal tumor                                                                                                                                     
  • Incomplete initial resection of the bladder tumor and/or visible tumor left behind                                                            
  • Large bladder tumor (defined as >3 cm) [36] 

Such second-look TURBTs have found residual cancer in half of all Ta cancers, resulting in upstaging in 15% of cases. These procedures also found persistent tumor in about half of the T1 lesions (48%), and 30% were upstaged to include muscle invasion.[36]  (Cancer risk staging for low-, intermediate-, and high-risk NMIBC malignancies can be found below in the "Postoperative and Rehabilitation Care" section)

Non-muscle-invasive bladder cancer is managed primarily with transurethral (endoscopic) resection, which includes all Ta and T1 lesions. This procedure may be followed by risk-based intravesical therapy, like Bacillus Calmette-Guérin (BCG). CIS is usually treated with BCG as first-line therapy.

Low-risk bladder NMIBC malignancies will do well with a single intravesical chemotherapy instillation and routine surveillance cystoscopy.[36] (See surveillance protocol below in "Postoperative and Rehabilitation Care.") Additional intravesical chemotherapy installations have not shown any additional benefit beyond the first, single, initial treatment for low-risk malignancies.[192][193][194][195] Low-risk, noninvasive malignancies rarely metastasize, so a cystectomy is rarely indicated. Intravesical chemotherapy or BCG can be considered in selected cases.(A1)

Intermediate-risk NMIBC urothelial cancers should be considered for a 6-week induction course of Bacillus Calmette–Guérin (BCG) immunotherapy or intravesical chemotherapy with mitomycin C, doxorubicin, or epirubicin.[36] All meta-analyses have shown reduced recurrences using such therapies, with BCG and mitomycin showing the best overall results.[36] Given the difficulty in obtaining BCG due to shortages, its increased adverse effects, and complications, intravesical mitomycin is usually preferred for intermediate-risk disease.[36]  

Mitomycin C intravesical treatment efficacy can be enhanced by the following: 

  • No oral fluids for 8 hours prior to the instillation                                                                                                                       
  • Urinary alkalinization therapy (1.3 g sodium bicarbonate by mouth taken the evening prior to, the following, and one-half hour before the instillation   
  • Complete evacuation of the bladder just prior to the instillation. (Checked by a bladder scanner or a quick urethral catheterization)                                     
  • High concentration of mitomycin C (40 mg in 20 mL sterile water)[172]
    • (A1)

Intermediate-risk patients who have a complete response to an initial induction course of intravesical chemotherapy may be considered for maintenance BCG therapy for 1 year.[36]

High-risk NMIBC malignancies, including CIS, are best treated after TURBT, with a 6-week course of BCG induction (1 dose weekly for 6 weeks), which has been shown to provide superior results to all other immuno- or chemotherapies.[196][197][198][199] Transurethral resection and/or fulguration is of limited value in CIS of the bladder due to the extent of the disease, so BCG is considered first-line therapy.[38][200] Treatment of squamous cell carcinoma of the bladder is primarily surgical, as radiation, chemotherapy, and combined chemoradiation therapy do not appear to provide an overall survival benefit.[53](A1)

Bacillus Calmette–Guérin is a weakened form of Mycobacterium bovis (cowpox). Initially designed as a vaccine for tuberculosis, it is now also used as an immunotherapy for high-grade urothelial cancer.[117] Compared to chemotherapy, BCG has been shown to decrease disease recurrences and reduce progression (up to 37% compared to no BCG therapy) of high-grade urothelial carcinoma. The mechanism of action of BCG against tumor cells is incompletely understood. Originally, it was thought that the immune response to BCG was cross-reacting with bladder tumor cell antigens, but this simplistic mechanism has been largely disproven. Now it appears that BCG has a direct toxic effect on high-grade bladder cancer cells and a local immune-stimulating effect, which allows easier identification of BCG-affected tumor cells by the body's natural anti-tumor cellular defenses (macrophages, natural killer cells, neutrophils, and T lymphocytes.)[201][202](B3)

BCG initially attaches to malignant urothelial cells due to a unique cellular fibronectin protein interaction with the bacteria, after which the BCG becomes internalized. Once inside the tumor cell, the BCG causes an increase in intracellular cytokine production (granulocyte-macrophage colony-simulating factor, interferon-γ, interleukins 1, 2, 6, and 8, and tumor necrosis factor).[38][203] Nitric oxide production may also be increased, which further slows tumor growth.[204][205](A1)

For optimal efficacy from BCG bladder instillations, the following conditions are required:

  • The patient is not immunocompromised.
  • There is a relatively small tumor burden.
  • Direct contact of the BCG with the tumor is possible (superficial disease).
  • The dose used is sufficient to generate an immunological reaction.
  • There is sufficient BCG available to complete the course of therapy.

BCG is particularly useful in CIS, where it is relatively easy to meet the above criteria as the tumor is completely superficial. In such cases, complete eradication of CIS is possible in 70% or more of these patients.[206]  Standard treatment is 6 weekly installations, followed by 3 weekly installations at 3 months and 6 months, then every 6 months afterward for maintenance therapy, which should be continued for 3 years.[207][208][209] Recently, an alternate protocol utilizing 12 weekly induction BCG installations with no maintenance therapy has shown good efficacy; it utilizes fewer treatment vials per patient, making this treatment modality more efficient when BCG is in short supply.[210](A1)

There does not appear to be any significant difference between different BCG strains or dosage amounts, except that adjustments should be made as needed to maintain efficacy and tolerability.[211] Reduced dosages (ie, one-half, one-third) still appear to maintain efficacy, but there is no evidence that combination therapy with other chemotherapy agents improves the results.[36] If recurrent or persistent disease is found after completing the initial 6-week course of BCG, a second induction course may be given.[36]

Recurrent or persistent disease and/or positive cytologies after full intravesical BCG therapy suggests undetected disease. The upper urinary tracts should evaluated with contrast-enhanced imaging along with upper tract cytologies, and a prostatic urethral biopsy should be considered before administering further intravesical therapy.[36]

  • Recurrent high-grade Ta disease should be managed by TURBT and intravesical therapy. A radical cystectomy should not be considered until such therapies have been tried and failed.[36]
  • For recurrent high-grade T1 disease after an initial 6-week course of BCG, a radical cystectomy should be considered in eligible patients.[36]
  • Recurrent high-grade urothelial cancer (CIS or NMIBC) within 6 months of starting BCG therapy constitutes a BCG failure, and additional immunotherapy should not be given.[36] The patient is then a candidate for radical cystectomy or alternative intravesical chemotherapy.[36]
  • Recurrent high-grade urothelial cancer (CIS or NMIBC) within 1 year of completion of appropriate and adequate BCG therapy is an indication for a radical cystectomy. If the patient does not want such surgery or is otherwise unfit, alternative intravesical chemotherapy protocols may be used, but a clinical trial is recommended if possible.[36] 

Expected symptoms from BCG therapy include dysuria, urinary frequency, hematuria, urgency, general malaise, and fever.[212] Such symptoms typically develop within 48 hours of BCG instillation and are often dose-related.[213][214] The dose of BCG may be reduced in patients who do not tolerate it well. The morbidity and severity of the adverse events can often be minimized by reducing the BCG dosage. Still, about 8% of patients will not be able to tolerate BCG treatment due to adverse effects.[212](B3)

BCG-osis, also known as disseminated BCG, occurs in less than 1% of patients receiving BCG therapy. This condition may present with mild flu-like symptoms or as a major systemic septic infection, ultimately proving fatal in some cases.[213][215] BCG-osis may occur years after the last BCG instillation, so clinicians should maintain a level of suspicion even long after BCG therapy has ceased.(B3)

Severe cases are quite rare at only a fraction of 1% and are thought to be due to disseminated BCG-related sepsis and/or hypersensitivity to Mycobacterium bovis.[216] These cases may present with mental status changes, chills, high-grade fevers, granulomatous prostatitis, arthritis, pneumonitis, granulomatous epididymo-orchitis, respiratory failure, hypotension, liver failure, jaundice, hepatitis, and various coagulopathies.[217] Negative blood cultures do not exclude the diagnosis, as BCG-osis is still found in about 40% of such cases.[217] Treatment involves antituberculosis medications (ethambutol, isoniazid, and rifampicin) and oral steroids.[213] Antituberculosis treatment is typically continued for at least 3 to 6 months.(B3)

Therapy for BCG failures

Radical cystectomy should be the primary option for consideration in patients who are surgical candidates with tumors refractory to conservative management such as BCG therapy.[36] 

Nonsurgical alternatives include the following:

  • Pembrolizumab, an alternative IV immunotherapy, may be considered for patients with recurrent CIS that returns within a year of completing BCG therapy.[36]   
  • Valrubicin has been US Food and Drug Administration (FDA)-approved for intravesical therapy in CIS patients who fail BCG therapy and cannot or will not undergo a cystectomy. However, the complete response rate is only 18%.[218]  
  • Nadofaragene is another FDA-approved intravesical therapy for patients with CIS who are not responding to BCG therapy.[219] Early data from phase III trials indicates an initial complete response of just over 50% at 3 months, and about 45% of these patients maintained their response for 1 year.[219]   
  • Nogapendekin alfa inbakicept plus BCG was recently FDA-approved as intravesical therapy for treating high-risk BCG-unresponsive CIS of the bladder. This approval was based on a study of 160 patients with BCG-unresponsive CIS in which the complete response rate was 71% with a median response duration of over 2 years and cancer-specific overall survival of almost 100%.[220] Cystectomy was avoided for over 90% of patients in this very high-risk group during the 2-year follow-up period.[220] 
  • Experimental treatments under investigation include intravesical gemcitabine, gemcitabine alternating with mitomycin or docetaxel, and intravesical paclitaxel.[36][221][222]                                                                             
  • Other investigational therapies include immune checkpoint inhibitors, oncolytic virus regimens, recombinant fusion proteins, immune modulation therapies, cytotoxic agents (cabazitaxel, cisplatinum, and gemcitabine,) and targeted small molecule kinase inhibitors.[36][223]
    • (A1)

A systematic review of the currently available treatment modalities available for patients who fail BCG who are not candidates for cystectomy suggested the following protocol as follows: 

  • For CIS only, intravesical nadofaragene, CG0070 adenovirus, or mitomycin C hyperthermic intravesical chemotherapy                                                   
  • For CIS with Ta or T1 disease, intravesical nogapendekin alfa inbakicept plus BCG, intravesical radiofrequency-induced chemohyperthermia, or electromotive mitomycin C administration       
  • For Ta or T1 disease, intravesical nogapendekin alfa inbakicept plus BCG, intravesical hyperthermic chemotherapy with epirubicin, or electromotive mitomycin C followed by mitomycin C chemohyperthermia                      
  • If the above treatment fails, then combination chemotherapy with cabazitaxel, cisplatin, and gemcitabine is suggested.[219][220][224]
    • (A1)

Due to BCG shortage issues, the National Comprehensive Cancer Network has recommended adjustments as follows:

  • BCG should be prioritized for CIS and high-grade T1 cancers, particularly at 3 and 6 months after induction.                                                             
  • Induction and maintenance dosages may be reduced (one-half or one-third) to allow for more treatments from a single vial.                                           
  • Alternative intravesical agents may be used (mitomycin C, gemcitabine, etc).                                                           
  • Consider early radical cystectomy in patients at high risk for recurrence or progression.

Intravesical gemcitabine for an hour, followed by docetaxel for 2 hours, has been successfully used as an alternative to BCG therapy and for BCG failures.[221][225][226] It is associated with reduced adverse effects, fewer treatment discontinuations, better tolerability, and equal or greater efficacy (as defined by progression-free, cancer-specific, and overall survival) than BCG treatments.[221][225][226] 

Long-term analysis has demonstrated that intravesical gemcitabine followed by docetaxel for high-risk NMIBC patients who failed BCG therapy provided a 5-year cancer-specific survival of 91%, and 75% of patients were able to avoid cystectomy.[222] These results indicate that intravesical gemcitabine combined with docetaxel therapy may be reasonably considered an alternative to BCG treatment for suitable high-risk bladder cancer patients.[225]

Chemohyperthermia (heated intravesical chemotherapy, HIVEC), electromotive drug administration (EMDA), and radiofrequency-induced thermo-chemotherapy (RITE) are promising technologies designed to improve bladder wall penetration of intravesical chemotherapeutic agents. Still, they are not yet recommended by guidelines due to insufficient clinical data and evidence.[227][228][229][230] However, they are not unreasonable to use where available during BCG shortages.[230](A1)

An abstract from the 2023 European Society of Medical Oncology (ESMO) by Necchi and associates described their early results with a unique investigational implantable drug delivery device (TAR-200) allowing for the sustained delivery of intravesical chemotherapy to the bladder for patients with high-risk BCG-unresponsive CIS. This intravesical device using gemcitabine has shown a complete response rate of 77%, of which over 90% have been maintained over a median of 48 weeks. It is now being tested in combination with cetrelimab, an investigational programmed cell death receptor-1 (PD-1) monoclonal antibody. Further studies are needed to determine and verify the duration and optimal usage of such therapies.

Cretostimogene is a unique investigational oncolytic immunotherapy that has produced durable complete response rates of more than 75% lasting over a year in patients with BCG-unresponsive CIS. These preliminary results are quite encouraging.

MUSCLE-INVASIVE BLADDER CANCER 

MIBC accounts for approximately 25% of all primary bladder cancer cases.[13][30] Once a malignant bladder tumor invades the detrusor muscle, even superficially, there is a markedly increased rate of metastases and reduced life expectancy as the overall 5-year recurrence-free survival rate is only about 50%.[30][31][231]

Staging is done with CT or MRI urogram imaging plus a chest x-ray or CT.[30] Despite advances in imaging technology, upstaging after surgery due to unanticipated extravesical disease is found in as many as 40% of cases.[232][233][234] Preoperative imaging that demonstrates hydronephrosis has been found to be a strong predictor of extravesical disease and a more guarded prognosis.[233][234](A1)

Involvement of the prostatic urethra may be found in as many as one-third of all patients with MIBC.[146][148][149] The risk is highest with tumors located in the trigone or bladder neck as well as in patients with CIS, positive cytologies without visible lesions, and in multifocal disease.[151][152][153] A prostatic urethral biopsy involves a limited transurethral prostate resection from the bladder neck to the verumontanum between 5 and 7 o'clock.[13] Any abnormal appearing urethral tissue should also be biopsied.[13]

The initial management of MIBC is transurethral (endoscopic) resection, but it will require further therapy once it has been staged as a T2 or higher lesion. Higher-stage lesions are managed with local palliative therapy and as metastatic cancers (see "Medical Oncology" section)

Treating MIBC without metastases is generally neoadjuvant cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy with bilateral pelvic lymphadenectomy.[13][235]  In men, removal of the prostate and seminal vesicles is usually included, especially if urethral or prostatic involvement is demonstrated or suspected. In women, the uterus, cervix, ovaries, and anterior vaginal wall are usually removed.[235] Perioperative pharmacologic thromboembolic prophylaxis is recommended for patients undergoing radical cystectomy surgery.[30] There does not appear to be any difference in overall complications, progression-free survival, or overall survival between robotic and open surgical cystectomies.[236][237][238][239][240](A1)

Indications for a radical cystectomy include the following: [13][235]

  • MIBC with no known nodes or metastases                                                                                                                                                                 
  • Very high-risk NMIBC (Lymphovascular invasion, variant or divergent histology, extensive lamina propria involvement, large (>5 cm) high-grade T1 tumors, persistent or unresectable malignant tissue after repeat TURBT, and prostatic urethral involvement)
  • CIS not responding to BCG                                                                                                                               
  • Extensive papillary tumors are not controllable with TURBT and intravesical therapy 

Salvage cystectomy should be considered in the following: [13][30]

  • Recurrence after bladder-sparing procedures                                                                                                     
  • Palliation for intractable pain, unmanageable hematuria, or extensive fistula formation 

The limits of dissection for the lymphadenectomy are as follows: 

  • Distal: Node of Cloquet (The uppermost of the deep inguinal nodes, the node of Cloquet, is located under the inguinal ligament and is the lowest of the external iliac lymph nodes.)[241][242][243][244]                                                   
  • Inferior: Internal iliac lymph nodes and the pelvic floor                                                                                                                                      
  • Lateral: Genitofemoral nerve                                                                                                                              
  • Posterior: Sacrum                                                                                                                                         
  • Proximal: Up to the bifurcation of the iliac arteries is standard, but the dissection may be extended to the aortic bifurcation. Further extension up to the inferior mesenteric artery (superextended dissection) does not appear to offer any additional survival benefit and is not recommended.
    • (A1)

An extended dissection may also include the presacral lymph nodes and the triangle of Marcille (medial edge of the psoas major, lateral border of the vertebra, and the iliolumbar ligament below. The obturator nerve passes through this area.)[245] Currently, most surgeries use the standard template, and the benefits of extended dissections are unclear.[246][247][248](A1)

Neoadjuvant therapy for MIBC has been proven beneficial as demonstrated in results of several large randomized clinical trials and systematic meta-analyses.[249][250][251][252][253][254][255] Neoadjuvant chemotherapy for bladder cancer typically consists of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).[30] These medicines are usually given now in a dose-dense (ddMVAC) manner where the chemotherapy is combined with growth factors.[13][30] This technique is better tolerated, is less likely to be interrupted by adverse effects, requires a shorter course of therapy, and may provide a slight improvement in cancer control compared to standard MVAC treatment.[256][257] (A1)

The combination of gemcitabine and cisplatin appears to be an acceptable, safer, and more tolerable substitute for MVAC, but additional studies are needed for definitive confirmation.[258][259][260] Patients who responded well to neoadjuvant chemotherapy tend to have better outcomes and improved overall survival, especially if they are complete responders.[261][262](A1)

Adjuvant chemotherapy is given after surgery and reserved for patients with a high recurrence risk. This would include patients with extravesical disease and those with positive lymph nodes at the time of surgery who did not receive preoperative chemotherapy. Nivolumab, an immune checkpoint inhibitor, is also FDA-approved for adjuvant therapy in patients with urothelial bladder cancer at high risk for a recurrence who refused, could not tolerate, or were ineligible for prior chemotherapy.[263][264] Unlike neoadjuvant chemotherapy, there is no definitive evidence of any significant benefit to adjuvant chemotherapy. However, adjuvant radiation therapy may help with local control and disease-specific survival but has not demonstrated any overall survival benefit when used alone. Fiduciary markers can help target radiation therapy.(B3)

Urinary reconstruction after radical cystectomy is typically a choice between an ileal conduit, continent cutaneous reservoir, or an orthotopic neobladder. The advantages and disadvantages of each of these should be discussed with patients prior to surgery.[13][30] Patients and their families should be thoroughly taught how to manage their chosen urinary diversion drainage system.[30]

  • The ileal conduit remains the most popular urinary diversion after a cystectomy, most likely due to its relative simplicity. A short section of the distal ileum is used to passively pass urine from the anastomosed ureters at the proximal end through a distal stoma on the abdominal skin surface. While technically easier to perform, its associated complications are frequently underappreciated. These include hyperchloremic, hypokalemic metabolic acidosis as well as long-term deterioration of the renal units over time, ureteral strictures, stenosis of the stomal opening, frequent urinary tract infections, stomal hernias, skin irritation and ulceration, and urostomy bag leakage problems. Leaving the terminal 15 cm of the distal ileum can minimize problems of impaired absorption of bile salts and fat-soluble vitamins, particularly vitamin B12.[30][265]
  • Continent cutaneous (Indiana pouch, Miami, and similar) urinary diversions create a continence reservoir, usually from the right colon, and the ileocecal valve is used as a continence mechanism. The ileal segment may need to be tapered, and the ileocecal valve may require plication or reconstruction to maintain continence. The ileal stomas open onto the abdominal skin surface and are drained periodically by self-catheterization. Variations include using ileal segments to form the reservoir and the appendix as a ready-made continence mechanism and catheterizable access point. Continence rates are reported as high as 90%.[266][267] The Kock reservoir has been largely abandoned due to its technical complexity and unacceptably high complication/reoperation rate.
  • Continent orthotopic neobladder diversions require a clear margin at the urethral margin. If this is positive on a frozen section, a neobladder is absolutely contraindicated. Neobladders are constructed from a tabularized intestinal segment, usually the ileum, which is folded back on itself to minimize any contractions. The ileum is usually selected because of its reduced complication rate and superior mobility, which means it can easily reach the urethra without tension. The Studor, Hartmann, and Y-pouch ileal orthotopic neobladder techniques are frequently utilized.[268][269][270] Daytime continence rates of 85% have been reported.[271]

All of these urinary reconstruction methods are associated with many possible complications, such as hyperchloremic, hypokalemic metabolic acidosis, as well as kidney failure, decreased bone density, chronic diarrhea, vitamin B12 deficiency, calcium oxalate nephrolithiasis (from enteric hyperoxaluria), and hyperammonemia. Overall, patient satisfaction and quality of life scores are similar between the various urinary reconstructive surgical options, although a few studies indicated marginally higher quality of life scores with neobladders.[272][273][274][275][276](A1)

Bladder preservation techniques may be considered in selected patients with MIBC who are not candidates for cystectomy or who refuse such treatment.[30]

  • A partial cystectomy may be considered in carefully selected patients with a solitary tumor without CIS or a malignancy in a bladder diverticulum that TURBT cannot completely or safely remove. A lymph node dissection is recommended in patients undergoing a partial cystectomy. Patients with isolated tumors of the bladder dome would be the best candidates for this treatment option. Overall, 5-year survival is reported to be about 70%.[277]
  • Maximal or radical transurethral resection has been recommended as a treatment for selected patients with MIBC who are not candidates for a radical cystectomy. Essentially, a repeat TURBT is performed until no residual tumor is left. Enhanced cystoscopic detection techniques are suggested to maximize the results. Mandatory regular upper tract imaging with surveillance cystoscopies is required due to the high rate of local recurrence. Understaging is common with this treatment modality. Five-year survival rates have been reported as only 30% in an older series.[278]
  • Maximal transurethral resection of the bladder tumor with chemoradiation ("trimodal therapy") has been reported to achieve a 5-year survival of 60% to 76%. This therapy appears to be the best alternative to radical cystectomy in selected patients based on the limited available data.[279] This data makes it comparable to the 5-year overall survival (73%) in patients who underwent radical cystectomy surgery.[280] Good long-term studies are not available. The AUA and EAU guidelines, therefore, recommend trimodal and multimodal bladder-preserving therapy for selected patients unable or unwilling to undergo radical cystectomy and who clearly understand the risks and the mandatory need for careful follow-up.[13][30]

About 30% of patients who undergo bladder-preserving therapy will develop a recurrence of their muscle-invasive disease.[281] These patients should be offered radical cystectomy surgery.[30] They will experience a higher recurrence rate if treated with local therapy (TURBT, etc) and not treated with cystectomy.[282]

Trimodal therapy (maximum transurethral tumor resection followed by radiochemotherapy and/or systemic immunotherapy together with close cystoscopic follow-up) studies have reports of equivalent oncological outcomes, suggesting that optimized bladder preservation techniques may approach equivalence with standard radical cystectomy-based surgery in selected patients.[283][284] Future developments to improve patient selection by using optimized genetic and other biomarkers may lead to improved outcomes without the need for cystectomy, at least in some carefully selected patients.[283][284](B2)

Differential Diagnosis

Accurate diagnosis is crucial for ensuring appropriate treatment and management. When evaluating a patient for bladder cancer, it is essential to consider a range of differential diagnoses due to the overlap of symptoms with other urological and systemic conditions. The differential diagnosis for bladder cancer includes the following:

  • Amyloidosis
  • Benign prostatic hyperplasia
  • Bladder wall thickening from obstruction or infection
  • Cystitis cystica and glandularis
  • Diverticulitis
  • Enterovesical fistula
  • Gynecologic and other pelvic malignancies
  • Hemangioma
  • Hematuria unrelated to urothelial carcinoma
  • Hemorrhagic cystitis
  • Inverted papilloma
  • Interstitial cystitis
  • Leiomyoma
  • Malakoplakia
  • Median lobe of the prostate with intravesical extension
  • Nephrogenic adenoma
  • Nephrolithiasis
  • Overactive bladder 
  • Paraganglioma
  • Prostatitis
  • Radiation cystitis
  • Renal masses and neoplasms
  • Urinary tract infection

Medical Oncology

Metastatic Urothelial Disease

The National Comprehensive Cancer Network has indicated that FDG-PET/CT scanning may be useful in identifying metastases in selected patients with muscle-invasive disease and may change treatment in patients with stage T3 or higher disease. The initial spread of urothelial bladder cancer is by direct extension into adjacent organs and/or the pelvic side wall, through the lymph nodes, or hematogenously. The most likely locations for distant metastases are bone, liver, and lung.

An extensive review of chemotherapy for metastatic bladder cancer is beyond the scope of this review. Metastatic urothelial cancer generally has a good response rate to chemotherapy (about 70%), but the overall prognosis is still poor as the duration of the benefit is short. MVAC given in a dose-dense manner has been the most studied, but cisplatin and gemcitabine offer similar results with greater safety and less morbidity.[258]

Paclitaxel binds to tubulin and halts intracellular microtubule production, which blocks cell mitosis.[285][286] This therapy has demonstrated a very good response rate, with 27% of patients exhibiting a complete response.[285][287] Immune checkpoint inhibitors have shown activity in metastatic urothelial malignancies. These drugs reduce natural T-cell inhibition from their programmed death protein-1 (PD-1) cell surface protein, essentially releasing the T-cell's full immune potential. Examples include pembrolizumab, atezolizumab, avelumab, and nivolumab, which have all been approved for use in bladder cancer patients. Avelumab and pembrolizumab have shown improved overall survival in clinical trials.[288][289][290][291]

Erdafitinib is a tyrosine kinase inhibitor, which acts as a fibroblast growth factor blocker that is indicated for metastatic urothelial cancer patients who progressed on cisplatin-based chemotherapy. Hyperphosphatemia is common, and up to 25% of patients will need to stop therapy due to significant retinal eye issues.[292][293][294][295] Enfortumab vedotin is an antibody-drug conjugate, where a monoclonal antibody is attached to an anticancer drug.[296][297] Pembrolizumab is an immune checkpoint (PD-1) inhibitor. Results from a large, multinational trial involving 185 centers in 25 different countries recently demonstrated that combination therapy with enfortumab vedotin and pembrolizumab (EF+P) in advanced urothelial cancer patients nearly doubled their progression-free and overall survival.[298][299]

The latest recommendation from the FDA and the European Society of Medical Oncology is to use a combination of enfortumab vedotin and pembrolizumab (EV+P) as first-line chemotherapy for advanced or metastatic urothelial (bladder) cancer.[288][297]

Staging

TNM system: The American Joint Committee on Cancer 

Tumor T Stage

  • Ta lesions: Ta tumors are papillary (exophytic) lesions that tend to recur
  • Tis lesions: High-grade intraepithelial neoplasm without invasion into subepithelial connective tissue
  • T1 lesions: T1 tumors invade the submucosa or lamina propria
  • T2 lesions: Invasion into muscle is present in T2 lesions
    • T2a: Invasion into superficial muscle
    • T2b: Invasion into deep muscle
    • T3 lesions: T3 tumors extend beyond muscle into the perivesical fat
      • T3a: Microscopic invasion only
      • T3b: Macroscopic extension or invasion, extravesical mass
  • T4 lesions: Tumor invading surrounding structures
    • T4a: Invasion of the prostate, vagina, uterus, or bowel
    • T4b: Invasion of the abdominal or pelvic wall structures or other organs

Lymph Node N Stage

  • NX: Lymph nodes cannot be assessed
  • N0: No lymph node metastasis
  • N1: Single regional lymph node metastasis within the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node)
  • N2: Multiple regional lymph node metastases within the true pelvis
  • N3: Lymph node metastasis spread to the common iliac lymph nodes

Distant Metastasis M Stage

  • M0: No distant metastasis
  • M1: Distant metastasis
    • M1a: Distant metastasis limited to lymph nodes beyond the common iliac arteries
    • M1b: Non-lymph node distant metastases

Clinical Staging

  • Stage I: T1, N0, M0
  • Stage II: T2, N0, M0
  • Stage III:
    • Stage IIIA: T3a, T3b, or T4a; N0; M0 or T1 to T4a, N1, M0
    • Stage IIIB: T1 to T4a, N2 or N3, M0
  • Stage IV:
    • Stage IVA: T4b, any N, M0 or any T, any N, M1a
    • Stage IVB: any T, any N, M1b

Prognosis

The prognosis of urothelial bladder cancer depends on multiple factors. TNM stage is the single most important prognostic factor of urinary bladder carcinoma. The 5-year overall survival for pT1 is 75%, pT2 is 50%, and pT3 is 20%. Invasion of the muscularis propria determines whether the patient's staging is pT1 (NMIBC) or pT2 (MIBC).

Histological variants of urothelial carcinomas tend to have a poorer prognosis than typical bladder cancer. These variants include urothelial carcinoma with rhabdoid features, urothelial micropapillary carcinoma, plasmacytoid carcinoma, sarcomatoid carcinoma, small cell carcinoma, and undifferentiated carcinoma. Other poor prognostic factors of urothelial carcinoma include high histological cancer grade, lymphovascular invasion, the presence of CIS, recurrence, large tumor size, sessile nature, incomplete tumor removal, positive margins, and multicentricity.[46]

The National Cancer Institute reports that the 5-year relative bladder cancer survival rates are as follows: [300][301][302][303]

  • CIS: 97%. About 50% will become invasive within 5 years, and just over half will demonstrate tumor progression unless treated with BCG, in which case the risk of progression is less than 10%.                              
  • Localized bladder cancer: 71%.                                                                                                                       
  • Regional bladder cancer (spread to adjacent organs or nearby lymph nodes): 39%.                                              
  • Metastatic bladder cancer: 8%.

Complications

Complications of urothelial cancer of the bladder include symptoms related to the tumor and adverse effects of treatment. Complications related to the tumor include weight loss, fatigue, urinary tract infection, metastasis, and urinary obstruction leading to chronic kidney failure.[304] The adverse effects of surgical management include urinary tract infections, urinary leak, pouch stones, urinary tract obstruction, erectile dysfunction, and vaginal narrowing. Almost two-thirds of patients who receive a radical cystectomy will develop at least 1 postoperative problem within the first 3 months after surgery, and 13% will have a severe (grade 3 or more) complication.[305]

Complications of a neobladder include voiding dysfunction, ureteroenteric strictures, urinary infections, bladder stones, metabolic abnormalities, urinary retention, and rupture.[306] Of these, rupture or leakage of a neobladder is potentially the most dangerous and should be suspected in all patients after cystectomy with neobladders who develop abdominal pain.[306][307][308] A CT cystogram is diagnostic.[306]  Standard treatment of a ruptured neobladder is laparotomy with surgical repair, but selected cases (diagnosed early, hemodynamically stable, no significant comorbidities, neobladders are well drained and empty well) may be treated conservatively.[306][309] Failure of the patient to clinically improve or persistence of leakage from the neobladder should be treated surgically.[310]

The list of potential complications is exceptionally long. In addition to all of the standard complications associated with general anesthesia and surgical procedures, the possibilities include the following: 

  • Bleeding and vascular: Anemia, coagulopathy, deep vein thrombosis, hematoma formation, phlebitis, prolonged hematuria, pulmonary embolism, and the need for transfusions
  • Gastrointestinal: Anastomotic bowel leak, ascites, diarrhea, emesis, enterocutaneous fistulas, gastrointestinal hemorrhage, ileus, peptic ulcers, pseudomembranous colitis, and small bowel obstruction
  • Genitourinary: Bladder dysfunction or perforation, bladder neck stricture, erectile dysfunction, fistula formation, hydronephrosis, parastomal hernias, renal failure, stomal issues, ureteral or urethral strictures, voiding issues including urinary retention and incontinence
  • Infections: Abscesses, cellulitis, cholecystitis, diverticulitis, incisional and wound infections, peritonitis, pyelonephritis, sepsis, and unexplained fevers
  • Surgical: Bladder perforation, cellulitis, failure to identify CIS, fistula formation, iatrogenic obturator nerve injury, incomplete tumor resection, incisional hernia, intestinal injury (unrecognized), parastomal hernia, rectal trauma, retained drain, seromas, stomal ischemia, vascular injury, and wound dehiscence/infections.[235]

Postoperative and Rehabilitation Care

Patients with a history of NMIBC who have a negative cystoscopy but a positive cytology should be considered suspicious for a recurrence or of hidden disease. Upper tract imaging, ureteroscopy, random bladder biopsies, prostatic urethral biopsies, and photodynamic enhanced cystoscopy (blue light or narrow band imaging) should be considered.[36]

AUA NMIBC Cancer Risk StratificationLow risk:

  • Solitary Ta tumor ≤3 cm

Intermediate risk: 

  • Solitary Ta tumor >3 cm
  • Low-grade Ta tumor, which has recurred within 1 year
  • Low-grade Ta multifocal tumors (at least 2 separate locations)
  • Low-grade T1 tumor
  • High-grade Ta tumor ≤3 cm

High risk:

  • High-grade Ta tumor that is recurrent, >3 cm, or multifocal
  • High-grade T1 tumor
  • Any CIS
  • Any BCG failure in a patient with a history of high-grade tumor histology
  • Prostatic urethral involvement with high-grade histology
  • Lymphovascular invasion [311]
  • Any variant histology (extensive squamous or glandular differentiation, micropapillary, neuroendocrine, nested, plasmacytoid, or sarcomatoid changes) [312]

Follow-up Cystoscopic Surveillance after TURBT Surgery for NMIBC - AUA Guidelines 

The first surveillance cystoscopy should be 3 to 4 months after surgery. If negative, follow-up depends on the risk stratification.[36] 

Low-risk cancers

  • The next surveillance cystoscopy can be postponed for an additional 6 to 9 months and then performed annually for at least 5 years.                           
  • Continued annual surveillance cystoscopies after 5 years without a recurrence is optional and should be decided on a shared decision-making basis with the patient.                                                                                 
  • Cytologies and urinary biomarkers with negative cystoscopies are not recommended for surveillance in low-risk cancers.                                                 
  • Routine surveillance imaging of the upper tracts is unnecessary.                                                                         
  • Overall, the 5-year recurrence rate is 30% to 40%.[313]

Intermediate-risk cancers

  • Surveillance cystoscopy with cytology should be performed every 3 to 6 months for 2 years.                                           
  • After 2 years, surveillance cystoscopy with cytology should be repeated every 6 to 12 months for an additional 2 years, and then annually.               
  • Upper tract imaging should be considered every 1 to 2 years.                                                                                 
  • The reported recurrence rate for intermediate-risk bladder cancers is 45%.[36][314]

High-risk cancers

  • Surveillance cystoscopy with cytology should be performed every 3 to 4 months for 2 years.                                
  • After 2 years, surveillance cystoscopy with cytology should be performed every 6 months for an additional 2 years, and then annually.                               
  • Some practitioners will add a bladder washing for cytology at every cystoscopy in patients with a history of high-grade cancer or CIS.                               
  • Upper tract imaging should be considered every 1 to 2 years.                                                                                     
  • One-fifth (20%) of patients with high-grade NMIBC will develop metastases.                                                                                  
  • Consider early cystectomy in patients with variant histology due to the high rate of tumor upstaging in such cases.                                                         
  • Overall, the 5-year recurrence rate is 60% to 70%, with a 10% to 45% risk of progression to muscle-invasive or metastatic disease.[36][313]

Follow-up MIBC Post-Cystectomy: AUA Guidelines 

  • Imaging of the chest together with an MRI or CT of the abdomen and pelvis should be obtained at 6- to 12-month intervals for 2 to 3 years.                       
  • After the first 2 to 3 years, this may be continued annually.                                                                                                                                    
  • If the urethra was not removed, it should be evaluated regularly for possible recurrences.                                            
    • Cytology examinations of urethral washings can accomplish this evaluation.[315][316][317]                                           
    • The risk of a urethral recurrence can be as high as 17%.[30][318][319]

Follow-up after MIBC Bladder Preservation Therapy: AUA Guidelines 

  • Surveillance cystoscopy with cytology should be performed every 3 months for the first year.                        
  • After the first year, surveillance cystoscopy with cytology should be done every 4 to 6 months for another year, then every 6 to 12 months.[320][321]     
  • Imaging of the chest together with an MRI or CT of the abdomen and pelvis should be obtained at 6-month intervals for 2 years.[30]

Deterrence and Patient Education

Deterrence and patient education are pivotal in managing and preventing bladder cancer. Educating patients about reducing risk factors, such as smoking cessation and minimizing exposure to industrial chemicals, can significantly reduce their overall risk. Help for smoking cessation may be found at the American Cancer Society and SmokeFree.gov. Healthcare professionals should emphasize the importance of early symptom recognition, such as noticing blood in the urine and seeking prompt medical attention. Patients should know that painless gross or microscopic hematuria, urinary tract infection symptoms unrelated to infections and unresponsive to antibiotics, or irritative bladder symptoms may be early symptoms of urothelial bladder cancer.

Regular follow-up and monitoring are crucial for those with a history of bladder cancer due to the high recurrence rate. Patients who have been diagnosed with NMIBC should be given a clear schedule for their surveillance cystoscopies and strongly encouraged to stop smoking if they haven't already. The National Comprehensive Cancer Network offers a free guideline for patients with bladder cancer at NCCN.org/patientguidelines. Additionally, discussing lifestyle modifications, including maintaining a healthy diet and staying hydrated, can support overall urinary tract health. Empowering patients with knowledge fosters proactive health behaviors, ultimately improving outcomes and quality of life.

Pearls and Other Issues

Essential clinical pearls for bladder cancer management can enhance clinical practice. These insights aim to provide practical tips and key considerations for diagnosing, treating, and monitoring this prevalent malignancy effectively and include the following:

  • A persistently positive FISH test after BCG induction therapy is a poor prognostic indicator.[36]                                                                                
  • FISH and similar urinary biomarkers for borderline or equivocal cases should be considered.                                                                                               
  • Cytology is not recommended for the routine initial evaluation of patients with microscopic hematuria, but it may be used selectively, such as in patients with a significant smoking history. 
  • Enfortumab vedotin and pembrolizumab (EV+P) have replaced cisplatin-based treatments as first-line chemotherapy for advanced or metastatic urothelial (bladder) cancer.[297][298][299]
  • High-volume centers (>20 cases annually) have demonstrated substantially reduced perioperative mortality rates for radical cystectomy surgery.[322]
  • Inflammatory areas on cystoscopic examination of the bladder in patients with known urothelial cancers should be considered suspicious for CIS and biopsied.
  • Intravesical nogapendekin alfa inbakicept plus BCG therapy is now approved for high-risk BCG-unresponsive patients with CIS with or without Ta or T1 disease.[220]                                            
  • Most bladder cancer cases are low-grade and superficial, with minimal health risks if treated promptly and monitored appropriately according to guidelines.
  • Photodynamic-enhanced cystoscopic diagnostic technology ("blue light") and narrow-band imaging are probably underutilized with TURBT and could substantially improve outcomes.[127]                                                                                           
  • Screening patients who are at high risk for bladder cancer is not recommended, but a routine urinalysis would not be unreasonable, especially in patients who express concern. 
  • Trimodal therapy utilizing maximal TURBT with chemoradiation has shown equivalent survival to radical cystectomy in carefully selected patients.[283][284]
  • When performing a TURBT, the bladder should be filled enough so there are no significant mucosal folds and the surface is relatively flat, but the walls should not be thinned or attenuated. 
  • When there is doubt about the risk stratification for determining the workup, it is never wrong to go with a CT urogram and cystoscopy. The consequences of a missed bladder cancer far outweigh the negatives of an unnecessary but more comprehensive evaluation. 

Enhancing Healthcare Team Outcomes

Bladder cancer is a prevalent disease in the United States and around the world, with substantial morbidity and mortality that requires interprofessional medical and surgical management. Patients with high-risk factors such as a family history of urothelial cancer, prolonged chemical exposure, and smoking >10-pack-years should be routinely screened with periodic urinalyses to identify any unexplained microhematuria that might be an early warning sign of bladder cancer.

The interprofessional team includes primary care clinicians, urologists, radiologists, radiation oncologists, medical oncologists, intensive care unit specialists, hospitalists, anesthesiologists, pharmacologists, physical therapists, laboratory technicians, a cancer coordinator, specialty-trained nurses, such as stomal therapists and other healthcare professionals. Nurses assist in patient and family education, patient monitoring, and reporting significant clinical issues to the healthcare team. Nurses also arrange close follow-ups when needed.

Effective interprofessional communication fosters a collaborative environment where information is shared, questions are encouraged, and concerns are addressed promptly. Care coordination is critical to ensuring seamless and efficient patient care and optimizing outcomes. The interprofessional team must work together to streamline the patient's journey, from diagnosis through treatment and follow-up. This coordination minimizes errors, reduces delays, and enhances patient safety, ultimately leading to improved outcomes and patient-centered care that prioritizes the well-being and satisfaction of those affected by bladder cancer and their families.

Media


(Click Image to Enlarge)
<p>Bladder Cancer, Magnetic Resonance Image. The arrow points to cancer cells growing on the lateral side of the bladder.</p>

Bladder Cancer, Magnetic Resonance Image. The arrow points to cancer cells growing on the lateral side of the bladder.

Contributed by S Bhimji, MD

(Click Image to Enlarge)
<p>Urothelial Carcinoma In Situ. Urothelial carcinoma in situ in the setting of cystitis cystica glandularis.</p>

Urothelial Carcinoma In Situ. Urothelial carcinoma in situ in the setting of cystitis cystica glandularis.

CoRus13, Public Domain, via Wikimedia Commons

 

 

(Click Image to Enlarge)
<p>Poorly Differentiated Urothelial Carcinoma With Metaplastic Squamous Appearance. 10&times; H/E.</p>

Poorly Differentiated Urothelial Carcinoma With Metaplastic Squamous Appearance. 10× H/E.

Contributed by F Farci, MD

(Click Image to Enlarge)
<p>Urothelial Carcinoma, Perineural Invasion. 10&times; H/E.</p>

Urothelial Carcinoma, Perineural Invasion. 10× H/E.

Contributed by F Farci, MD

(Click Image to Enlarge)
<p>Urothelial Carcinoma, Prostatic Infiltration. 10&times; H/E.</p>

Urothelial Carcinoma, Prostatic Infiltration. 10× H/E.

Contributed by F Farci, MD

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