Evolving Paradigms In Bladder Cancer: Introduction

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Though many bladder cancers are nonmuscle invasive and successfully treated with local resection and/or adjuvant intravesical therapy,³the number of deaths from bladder cancer in 2016 is projected to be over 16,000, a number that has remained relatively unchanged since the 1970s.^1,2These deaths are largely due to the high rate of disease relapse in bladder cancer patients, who require additional procedures in order to manage their disease. Between 50% and 70% of patients with superficial bladder cancer will experience recurrence, and 10% to 15% of those patients will progress to muscle-invasive disease.⁴The anatomical structure of the bladder is shown inFIGURE 1.

Following a period of stagnation in the development of new therapies for advanced bladder cancer, novel targeted and immunotherapeutic agents have demonstrated promising outcomes in clinical trials and their clinical investigation and the development of molecular profiling approaches is an area of active investigation and intense interest.⁵In this article, we provide a general overview of bladder cancer as a disease, highlighting current therapeutic strategies, as well as potential new avenues for advancing bladder cancer therapy.

Bladder cancer can arise from any part of the bladder wall (FIGURE 2). The most common type of bladder cancer is transitional cell carcinoma (TCC), which accounts for 90% of all bladder cancers. TCC arises from the transitional epithelium, comprised of cells in the inner lining of the bladder that expand and contract, and TCC is usually caused by exposure to environmental carcinogens that pass through the urinary tract. Other types of bladder cancer include squamous cell carcinoma (1%-2%), adenocarcinoma (1%), sarcoma (<1%), and small cell (<1%).⁶

Risk Factors and Symptoms

TABLE 1

The biggest risk factor for bladder cancer is smoking, which accounts for about half of TCC cases and triples the risk of developing bladder cancer.^7,8Exposure to other carcinogens in the workplace or ingestion of arsenic is also associated with a higher risk for bladder cancer, as is age >55 years, male sex, and white race. Chronic bladder infections and a family or personal history of bladder cancer predisposes individuals to the development of bladder cancer. Individuals with mutations in the genes encoding GNT, NAT, Rb1, and PTEN, or those who have Lynch syndrome are also at a higher risk for bladder cancer ().^9,10

Patients with bladder cancer typically present with symptoms such as gross/macroscopic hematuria or microscopic hematuria, a frequent urge to urinate (sometimes without needing to do so), painful urination, and/or lower back pain. Those patients with advanced disease may experience pelvic/bony pain, lower extremity edema, and/or flank pain. Rarely, a palpable mass may also be detected.¹¹Diagnostic tests are performed by a urologist before patient referral to a urological surgeon or a medical oncologist.FIGURE 3illustrates percent of deaths from bladder cancer by age.1 Survival differs between races and is lower in blacks than in whites, Hispanics, and Asian Pacific Islanders.¹²

Detection and Diagnosis

Guidelines for the diagnosis and staging of bladder cancer have been developed by the National Comprehensive Cancer Network (NCCN) and are well accepted (FIGURE 4).¹³The gold standard for detection of bladder cancer and suspicious lesions is biopsy by cystoscopy. In this procedure, the urologist inserts a camera-guided, flexible tube into the urethra of the patient and uses surgical instruments in the cystoscope to remove a section of suspicious tissue or tumor. This biopsy is then analyzed by a pathologist to determine staging.¹⁴Blue light (Hexvix/Cysview-guided fluorescence) cystoscopy may be used in addition to standard white light cystoscopy for a more thorough screen for bladder cancer detection.¹⁵

Imaging and urine testing are less invasive methods that are also used to diagnose bladder cancer. Imaging tests include computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasound, and CT urogram. Urine cytology is also commonly used for bladder cancer detection. A major limitation of urine cytology is insensitivity; a negative reading does not absolutely rule out thepresence of bladder cancer. However, its noninvasive approach and ease of processing has maintained its high level of use.¹⁴Several other noninvasive urine tests have been developed to detect bladder cancer biomarkers.

Two assays have been developed for the detection of nuclear mitotic apparatus protein (NMP22), an enzyme-linked immunosorbent assay (ELISA) and the BladderChek immunochromatography method. NMP22 is overexpressed in bladder cancer cells and aids in cell division by facilitating proper chromosome segregation. One drawback of NMP22 for bladder cancer detection is its varying sensitivity and false-positive results.¹⁶

The bladder tumor antigen (BTA) TRAK ELISA and the BTA stat tests have been developed to detect complement factor H-related protein in the urine of bladder cancer patients.^17,18Complement factor Hrelated protein is expressed by bladder cancer cells and is supposed to promote degradation of other complement factors.¹⁹BTA TRAK and BTA stat are more sensitive than cytology; however, specificity of these assays is compromised by a history of urinary tract foreign body, bowel interposition segment, other genitourinary cancer, and benign genitourinary conditions. Patients with hematuria, proteinuria, infection, stones, and inflammation have also experienced false-positive results from these tests. Because of these characteristics, BTA TRAK and BTA stat have not been widely utilized.¹⁶

Two mucin-like proteins, as well as a high-molecular-weight form of carcinoembryonic antigen (CEA) have been reported as specific markers of bladder cancer that can be detected in the urine.²⁰ImmunoCyt utilizes fluorescently labeled monoclonal antibodies against these three proteins for adjunct bladder cancer detection.²⁰While ImmunoCyt has improved sensitivity compared with cytology, especially in lower-stage and lower-grade tumors,²¹it has not been used widely as an independent clinical marker of bladder cancer, due to varying sensitivity in detecting disease recurrence in patients receiving bacillus Calmette-Guérin (BCG) therapy. However, the combination of ImmunoCyt and cytology resulted in a sensitivity of 100% in patients receiving BCG therapy.²²Other drawbacks of ImmunoCyt include a high level of variability between observers and up to a 17% failure rate because of inadequate cellularity in the specimens.^23,24

Aneuploidy for chromosomes 3, 7, and 17 and loss of locus 9p21 are common in bladder cancer.²⁵The UroVysion fluorescence in situ hybridization (FISH) assay has been developed to detect these genetic aberrations. It has been used to detect new bladder cancer, as well as recurrent bladder cancer.¹⁶UroVysion has shown promising ability to predict future recurrences in the presence of a negative cystoscopy, especially for high-risk tumors, such as pT1 and carcinoma in situ (CIS).^26,27However, due to varying sensitivity based on tumor grade, it has not been used as an independent surveillance tool for nonmuscle-invasive disease. Due to its high cost, need for trained personnel, need for intact cells, and limited use in low-grade tumors, the use of UroVysion has been limited. Nevertheless, it seems to be useful as an adjunct to cytology and cystoscopy in bladder cancer follow-up.²

Importantly, rather than relying on one test for the detection of bladder cancer, urologists will usually combine multiple tests for the best probability of finding disease if it is present.²⁸For example, cystoscopy, though a frequently used and relied upon method for cancer detection, is not always able to detect carcinoma in situ or some small papillary tumors.²⁸In these cases, imaging and/or urine testing may be the most useful tests for bladder cancer diagnosis.

Tumor staging

In order to determine the best treatment strategy for each patient with bladder cancer, tumor stage is carefully considered. Following detection, a pathologist is consulted to provide tumor staging. Staging is performed using the TNM system, in which T indicates the growth and invasion of the tumor, N indicates lymph node status, and M indicates presence of metastases.FIGURE 5demonstrates, pictorially, the different stages of bladder cancer. Carcinoma in situ, a &ldquo;flat tumor,&rdquo; is the smallest and least invasive stage of bladder cancer. A tumor of stage Ta is a small tumor that affects only the bladder epithelium. T1 indicates tumor invasion into the lamina propria, subepithelial connective tissue. Carcinoma in situ, Ta, and T1 bladder cancers are described as nonmuscle-invasive bladder cancers because they have not grown into the layers of muscle in the bladder wall. Tumors in stages T2, T3, and T4 are muscle-invasive bladder cancers.²⁹

Stage T2 bladder cancers have invaded the superficial (T2a) or deep muscle (T2b) of the bladder wall. Cancers in stage T3 move beyond the muscle layers and into the perivesical tissue, either microscopically or macroscopically. Finally, stage T4 bladder cancers invade into neighboring organs, such as the prostate, uterus, vagina, abdominal wall, rectum, or pelvic wall.²⁹