Bladder cancer: Risk factors, diagnosis, and management
Bladder cancer: Risk factors, diagnosis, and management
Kristen Burns Farling, DNP, MS, CRNP, CUNP
The Nurse Practitioner
Bladder cancer is the most common genitourinary cancer in the United States. Symptoms of bladder cancer mimic those of a urinary tract infection, which can delay timely diagnosis. Because of the high rate of bladder cancer, it is likely advanced practice registered nurses will be responsible for the care of patients with bladder cancer. This article reviews the signs and symptoms of bladder cancer along with management options to safely care for this patient population.
According to the American Cancer Society, bladder cancer will be responsible for 5% of all cancer diagnosed in the United States in 2017, with 79,030 patients expected to be diagnosed with the disease and 16,870 expected patient deaths from bladder cancer.1,2 The majority of newly diagnosed patients with bladder cancer are male, which is thought to be related to an increased rate of smoking and occupational exposure.1 White Americans have a higher incidence of bladder cancer than Black Americans, and the average age of bladder cancer diagnosis is 73 years.1,2
The most common type of bladder cancer is urothelial cancer (also called transitional cell carcinoma), which is responsible for over 90% of bladder cancer tumors in the United States.3 Squamous and adenocarcinoma, though less common (5% and 2%, respectively), are associated with an advanced stage and a higher mortality than urothelial cancer.4 Patients at increased risk for developing squamous cell bladder cancer reside in areas known to house the schistosoma parasite, which includes Africa, the Middle East, South America, and the Caribbean.5
Bladder cancer can be categorized as nonmuscle- invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC), with the majority of newly diagnosed patients having NMIBC (70% to 85%).6 This is an important distinction, as NMIBC allows the patient bladder-sparing options for cancer management. To help clarify between the two categories of bladder cancer, it is important to review the three histologic layers of the bladder.
The fi rst layer of the bladder is the urothelium, the second layer is the lamina propria (suburethral loose connective tissue), and the third layer is the muscularis propria.7 Cancers affecting the urothelium or lamina propria are NMIBC, and those invading the muscularis propria are MIBC.
In addition to distinguishing between NMIBC and MIBC, it is important to understand the staging and grade of bladder cancer. Staging of bladder cancer is determined by the TNM system.8 The TNM identifi es the primary tumor (T), presence of lymph node involvement (N), and if metastasis is present (M).8
The aggressiveness of bladder cancer is determined by the grade of the disease, with high-grade (poorly differentiated) most likely to progress and spread compared with low-grade (well-differentiated) bladder cancer.9
Patients with NMIBC are treated with bladder-sparing strategies, such as transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy or chemotherapy; MIBC patients are treated with neoadjuvant chemotherapy and surgical removal of the bladder.7
Smoking. The most common risk factor for bladder cancer, smoking is responsible for approximately two-thirds of bladder cancers in men and one-third in women.10 Smokers have a fourfold increased risk of bladder cancer compared with nonsmokers.10 The number of cigarettes smoked, length of years smoked, and age when smoking began all increase an individual’s bladder cancer risk.10 Because the bladder’s function is to store urine, there is ample time for carcinogens in the urine to affect the bladder.11 The carcinogens associated with smoking remain in constant contact within the genitourinary system until eliminated, thus the high rate for urothelial cancers.5
Occupational exposure. The second most common risk factor for bladder cancer is occupational exposure to aniline dyes, aromatic amines, and polycyclic aromatic hydrocarbons. These chemicals are often used in the textile, paint, plastic, printing, and rubber industries, which places these individuals at an increased risk for bladder cancer.10
Inflammation. Although the mechanism of action is unknown, patients with chronic urinary tract infections (UTIs), chronic use of urinary catheters, and bladder stones are at an increased risk for bladder cancer.3 Patients infected with the parasite Schistosoma haematobium are at an increased risk for developing squamous cell cancer, a virulent and morbid form of bladder cancer.3
Radiation. Patients treated with pelvic radiation for genitourinary and gynecologic cancers, such as prostate and cervical cancer, have a higher rate of bladder cancer; however, with advancements in radiation therapy, this number is expected to decrease.10
Chemotherapy. Patients treated with cyclophosphamide for cancer and autoimmune diseases have a fourfold to ninefold increased risk of developing bladder cancer.10 The risk is further increased with cumulative doses and length of treatment.10
The most common symptom of bladder cancer is gross, painless hematuria, occurring in 80% of patients with bladder cancer.10 Hematuria can be either microscopic (blood visible under the microscope) or gross (blood visible in the urine). The degree of hematuria does not correlate to severity of disease.10 Although patients may present with either continuous or intermittent hematuria, all patients with hematuria should be referred to a urologist to rule out bladder cancer, especially if they have a past or current history of smoking.12
It is important to note hematuria is not always caused by bladder cancer. It can also be caused by other conditions, including renal cancer, prostate cancer, interstitial cystitis, renal calculi, benign prostatic hyperplasia, and trauma, and can be exerciseinduced, further warranting a referral to a urologist.13
Irritative urinary tract signs and symptoms, such as urinary frequency, urgency, hesitancy, and dysuria, are less common, affecting 30% of patients with bladder cancer.12 Because irritative urinary signs and symptoms mimic those of a UTI, patients may be initially diagnosed with a UTI, delaying a bladder cancer diagnosis. Late signs and symptoms related to invasive or metastatic bladder cancer include flank pain, pelvic fullness, urinary retention, lower extremity edema, weight loss, and bone pain.12
The advanced practice registered nurse (APRN) should perform a focused genitourinary exam to evaluate for kidney and bladder abnormalities, including fl ank tenderness and/or mass, abdominal mass, and suprapubic distension and/or mass.14 The penis, urethral meatus, scrotum, rectum, and prostate should also be examined in male patients with gross or microhematuria.
If the penis is uncircumcised, a phimotic foreskin can be irritated and bleed, contributing to a false diagnosis of hematuria. Inspecting the urethral meatus for mass, meatal narrowing, or blood can help identify external sources of hematuria. Additionally, performing a digital rectal and prostate exam is done to assess for an enlarged prostate or prostate mass, both of which may contribute to hematuria.14
A genitourinary exam on a female patient should include inspecting the urethra for a mass, blood, or urethral caruncle, and inspecting the vagina for signs of genitourinary syndrome of menopause (vaginal stenosis or atrophic vaginal changes) as possible external causes for hematuria.13 It is important to inspect the vagina for bloody discharge or mass, as this can help distinguish if hematuria is related to a gynecologic source. A catheterized urinalysis can be performed if any question remains as to a genitourinary or gynecologic source of bleeding.14
Because bladder cancer signs and symptoms mimic those of a UTI, it is vital to rule this diagnosis out in any patient complaining of gross or microhematuria and/or irritative voiding symptoms. A urine specimen should be sent for both a urinalysis (dipstick and microscopic) and urine culture to rule out an infection. If the urine culture rules out a UTI, it is important to review the microscopic (not dipstick) urinalysis for microhematuria.15
According to the American Urological Association’s (AUA) Guideline for the Diagnosis, Evaluation, and Follow-up of Asymptomatic Microhematuia in Adults, a urinalysis with three or more red blood cells present per high-powered field (and without signs of a UTI, such as pyuria and bacteriuria) is defined as mircrohematuria and warrants further evaluation to rule out urothelial cancer.15 The AUA further specifi es a urologic evaluation is recommended once to rule out benign causes of microhematuria, such as menstruation, vigorous exercise, viral illness, and trauma.15 In addition to submitting a urinalysis and urine culture, a urine specimen should also be sent for cytology. Urine cytology evaluates for the presence of abnormal cells, which may indicate urothelial cancer.7 Urine cytology can aid in the initial diagnosis of bladder cancer and can also be used during routine surveillance monitoring of patients with bladder cancer.
Although urine cytology is easy to obtain and highly sensitive and specifi c for high-grade lesions, it has a low sensitivity for low-grade lesions and a high rate of equivocal results.16 Because of the low sensitivity for low-grade lesions, urine cytology should be used as an adjunct test to aid in the diagnosis of bladder cancer.16
Another urine test used to aid in the diagnosis and surveillance of bladder cancer is the fl uorescence in situ hybridization (FISH) test.17 FISH has the capabilities of detecting common chromosomal defects associated with urothelial cancer with a sensitivity and specifi city of 72% and 83%.17 FISH results, like cytology, are higher for highgrade than low-grade disease, but FISH has the capacity to foresee recurrent disease, unlike cytology.17 This ability to “anticipate” recurrent bladder cancer is due to the FISH test’s ability to recognize microscopic disease prior to being identifi ed by cystoscopy.18 Serum blood work, including a basic metabolic panel, should also be ordered to assess kidney function (serum creatinine) and if applicable, a prostatespecifi c antigen.14
In addition to the above-mentioned lab tests, radiologic imaging with computed tomography (CT) scan or magnetic resonance imaging (MRI) is used to assess the kidneys, ureters, and bladder for evidence of a mass or tumor.19 A multiphasic CT urogram with precontrast, nephrographic, and excretory images is the radiologic test of choice for its high sensitivity and specifi city for identifying upper tract lesions.14
Prior to obtaining a CT urogram, blood work, including a basic metabolic panel, is obtained to assess the patient’s creatinine level before pursuing an I.V. contrast CT urogram. An abdominal pelvic MRI is an alternative in patients with a contraindication to a CT urogram, such as those with an elevated creatinine level or iodine contrast allergy.14 Conversely, in patients who cannot tolerate an MRI due to the risk of nephrogenic systemic fi brosis (such as those with a glomerular filtration rate less than 30 mL/min/1.73 m2 ), noncontrast CT scan or kidney ultrasound with retrograde pyelogram is a viable option.14
Nephrogenic systemic fibrosis is a severe systemic fibrosing condition that occurs primarily when patients with advanced kidney disease are exposed to gadolinium-based contrast. Avoiding gadolinium-based contrast in this patient population has dramatically reduced the incidence of nephrogenic systemic fibrosis, thus the importance of appropriately screening patients prior to MRI.20
The urologist will perform an in-office cystoscopy to directly visualize the bladder for presence of a tumor. During a cystoscopy, the urologist inserts a fl exible scope into the urethra with the assistance of topical anesthesia to inspect the urethra and bladder for bladder stones, tumors, or lesions.19 (See Cystoscopy.) If a bladder tumor is identifi ed, the patient is scheduled for either a bladder biopsy or a TURBT in the OR to remove the tumor and submit it for pathologic diagnosis.19
When obtaining tissue samples for biopsy, it is imperative that the biopsy or TURBT specimen include detrusor muscle, as this differentiates between NMIBC and MIBC.19 Once the pathology results are available, the APRN can properly stage and grade the bladder cancer.
Treatment and management of bladder cancer
NMIBC. Previously referred to as superfi cial bladder cancer, urothelial tumors that have not invaded the bladder muscle (detrusor) are now called NMIBC.13 NMIBC accounts for approximately 75% of bladder cancers, including those diagnosed with stage Ta, carcinoma in situ (CIS), or T1 invasive urothelial cancer involving the subepithelial lining/ lamina propria.9,12
Although the treatment options for patients with NMIBC allow them to keep the bladder, they are at risk for recurrence and progression to MIBC.6 The risk of recurrence is increased by the number of NMIBC tumors identifi ed during cystoscopy, tumor size, concurrent CIS, tumor grade, and prior recurrence.19 Based on the above-mentioned risk factors, the 5-year rate of recurrence can be as high as 78% and the rate of progression as high as 45%.19
Recurrence of NMIBC can be managed successfully with transurethral surgery and intravesical therapy.7 Instilling a single dose of intravesical chemotherapy (mitomycin C) immediately after TURBT can decrease the tumor recurrence rate from 48% to 37%.5 Though not FDA approved for bladder cancer, mitomycin C is the most common perioperative intravesical chemotherapeutic agent recommended by the National Comprehensive Cancer Network (NCCN) guidelines.21
Because of the high rate of recurrence, patients with NMIBC require vigilant monitoring with cystoscopic exams and intravesical immunotherapy with bacillus CalmetteGuerin (BCG) or chemotherapy with mitomycin C to prevent or delay tumor recurrence and progression.13 Although the mechanism of action is unknown, BCG is thought to stimulate an immune response against further tumor cell growth, and BCG immunotherapy is the most effective treatment for managing NMIBC.22
Pending the stage and grade of NMIBC, patients may be candidates for intravesical BCG therapy induction and/ or maintenance. Although various guidelines exist, the AUA and the NCCN recommend the following:
For multifocal and/or large low-grade Ta tumors: BCG induction once per week for 6 weeks, followed by maintenance (3 weeks of BCG at 3 and 6 months, then every 6 months for 12 months)
For high-grade Ta, T1, and/or CIS tumors: BCG induction followed by maintenance for 36 months.6,21-23
BCG induction begins approximately 4 to 6 weeks after TURBT when the patient returns to the urology offi ce; a urethral catheter is used to instill BCG into the bladder. The patient is asked to hold his or her urine for 1 to 2 hours, allowing the BCG to remain in constant contact with the bladder epithelium prior to voiding.5
BCG adverse reactions
BCG is known to cause local adverse reactions, with 80% of patients reporting cystitis-like symptoms.19 Because BCG has a cumulative effect, patients may notice an increase in adverse reactions further in the maintenance schedule.19 Other common adverse reactions include dysuria, frequency of urination, and hematuria.19 Systemic adverse reactions such as sepsis are less common, occurring in less than 5% of patients.22 Systemic adverse reactions are minimized by not administering BCG in patients with acute UTI, gross hematuria, or after a traumatic catheterization.22
Muscle-invasive bladder cancer
Although the majority of patients with MIBC are diagnosed at the time of their fi rst urology offi ce visit, some patients with NMIBC will ultimately progress to MIBC.24 MIBC has a high mortality rate, with 85% of patients dying within 2 years if left untreated.24
The gold standard treatment for MIBC is surgical removal of the bladder and pelvic lymph nodes with or without neoadjuvant chemotherapy.24 In males, a radical cystectomy consists of removing the bladder, prostate, and seminal vesicles; in women, radical cystectomy consists of removing the bladder, ovaries, uterus with cervix, and the anterior vagina.24 Following a radical cystectomy, a urinary diversion is required for elimination of urine.
Urinary diversions can be classifi ed as either incontinent or continent. The most frequently used incontinent urinary diversion is the ileal conduit, and the most frequently used continent diversion is the orthotopic neobladder.25
Used since 1950, the ileal conduit remains the most common choice for urinary diversion due to the relative ease to perform, rapid recovery, and ease to maintain.26 The ureters are implanted into a section of the small bowel (ileum), which is then attached to abdominal wall as a stoma. 5 Urine travels through the ileal conduit and is collected in an external storage pouch attached to the abdominal skin surrounding the stoma.5
For patients who do not want a stoma or external storage pouch, the continent orthotopic neobladder is another option. A section of bowel is used to create a reservoir that resembles the bladder and can attach to the urethra. The ureters are implanted in the neobladder, allowing urine to travel into the neobladder and out of the body via the urethra.5 The neobladder does not have the same sensation as a native bladder and requires bladder retraining such as timed voiding and abdominal straining to empty the neobladder.27
Additionally, because the neobladder is constructed from the ileum, it is possible for the urine to contain mucus. Pending how much mucus the ileum produces, urinary retention may develop. In order to combat potential mucus production and urinary retention, patients are instructed on clean intermittent catheterization.28
For patients who want to avoid an external urinary storage pouch, another option is a continent catheterizable stoma or continent cutaneous diversion.24 Commonly referred to as the Kock pouch, the Mainz pouch, or the Indiana pouch, a urinary reservoir is created using a section of ileum that patients catheterize throughout the day.25,29 The location of the stoma is usually located near the umbilicus (see Types of continent urinary diversions).
Implications for advanced practice nursing
Patients with potential bladder cancer red fl ags, including gross or microhematuria, irritative voiding symptoms unresponsive to conservative medicinal therapy, and a history of smoking, should always be referred to urology. If the APRN identifi es a patient as a current smoker, this opportunity can be used to educate the patient on the many adverse reactions of smoking, including bladder cancer.
Many patients are not aware of the association between smoking and bladder cancer, making this an important lifestyle modifi cation recommendation.30 Providing patients with smoking cessation support tools (such as the smoking cessation quitline 1-800-QUIT-NOW) can augment the teaching provided during the APRN offi ce visit.
Patients with bladder cancer are under the care of not only their primary care APRN but their urologist; wound, ostomy, and continence nurse; and if applicable, a pelvic fl oor physical therapist. The urologist routinely monitors patients with bladder cancer during surveillance urology offi ce appointments and cystoscopies.
In addition to surveillance urology appointments, many MIBC patients have to learn to coexist with an ileal conduit or learn to void with a neobladder. Collaborating or referring MIBC patients who have an ileal conduit to a wound, ostomy, and continence nurse can help facilitate the patient’s ostomy care along with providing an opportunity for the patient to experiment with various ostomy appliances. Conversely, patients with a neobladder may have a diffi culty using their new bladder, and a pelvic fl oor physical therapist is instrumental to help educate patients.
As both patients with NMIBC or MIBC require longterm follow-up, the APRN is in a position to forge meaningful connections with patients with bladder cancer and family members along with members of the patients’ interprofessional team. Connecting patients with bladder cancer to their local Bladder Cancer Advocacy Network (www.bcan.org) can help foster a sense of community in those affected by bladder cancer.
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3. Wood D. Tumors of the bladder. In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology. 11th ed. Philadelphia, PA: Elsevier; 2016.
4. Willis D, Kamat AM. Nonurothelial bladder cancer and rare variant histologies. Hematol Oncol Clin North Am. 2015;29(2):237-252.
5. Turner B, Drudge-Coates L. Bladder cancer: risk factors, diagnosis and treatment. Cancer Nurs Practice. 2012;11(7):30-36.
6. Gregg JR, Dahm P, Chang SS. Guideline-based management of non-muscle invasive bladder cancer. Indian J Urol. 2015;31(4):320-326.
7. Jones J. Non-muscle-invasive bladder cancer (Ta, T1 and CIS). In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology. 11th ed. Philadelphia, PA: Elsevier; 2016.
8. Amin MB, Edge S, Greene F, et al. AJCC Cancer Staging Manual. 8th edition. New York, NY: Springer; 2016.
9. American Cancer Society. Bladder cancer stages. 2015. www.cancer.org/ cancer/bladdercancer/detailedguide/bladder-cancer-staging.
10. Griffi ths TR. Current perspectives in bladder cancer management. Int J Clin Pract. 2013;67(5):435-448.
11. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306(7):737-745.
12. Smith A, Balar A, Milowsky M, Chen R. Bladder cancer. In: Niederhuber JE, Armitage JO, Doroshow JH, et al., eds. Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA: Saunders Elsevier; 2013.
13. Sharp VJ, Barnes KT, Erickson BA. Assessment of asymptomatic microscopic hematuria in adults. Am Fam Physician. 2013;88(11):747-754.
14. Boorjian S, Raman J, Barocas D. Evaluation and management of hematuria. In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology. 11th ed. Philadelphia, PA: Elsevier; 2016.
15. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA Guideline. 2016. www.auanet.org/education/guide lines/asymptomatic-microhematuria.cfm.
16. Owens CL, VandenBussche CJ, Burroughs FH, Rosenthal DL. A review of reporting systems and terminology for urine cytology. Cancer Cytopathol. 2013;121(1):9-14.
17. Denice Smith G, Sangle NA, Wilson A, et al. A retrospective review of UroVysion FISH interpretations over 8.6 years: a major shift in the patient test population. Diagn Cytopathol. 2013;41(5):437-447.
18. Seideman C, Canter D, Kim P, et al. Multicenter evaluation of the role of UroVysion FISH assay in surveillance of patients with bladder cancer: does FISH positivity anticipate recurrence? World J Urol. 2015;33(9):1309-1313.
19. Harshman LC, Preston MA, Bellmunt J, Beard C. Diagnosis of bladder carcinoma: a clinician’s perspective. Surg Pathol Clin. 2015;8(4):677-685.
20. Todd DJ, Kay J. Gadolinium-induced fi brosis. Annu Rev Med. 2016;67: 273-291.
21. NCCN Clinical Practice Guidelines in Oncology - Bladder Cancer. National Comprehensive Cancer Network. 2016. www.nccn.org/professionals/physician _gls/pdf/bladder.pdf.
22. Alcorn J, Burton R, Topping A. BCG treatment for bladder cancer, from past to present use. Int J Urol Nurs. 2015;9(3):177-186.
24. Guzzo T, Vaughan D. Management of metastatic and invasive bladder cancer. In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology. 11th ed. Philadelphia, PA: Elsevier; 2016.
25. Daneshmand S, Bartsch G. Improving selection of appropriate urinary diversion following radical cystectomy for bladder cancer. Expert Rev Anticancer Ther. 2011;11(6):941-948.
26. Scherr D, Barocas D. Ileal conduit. In: Smith JA Jr, Howards SS, Preminger GM, eds. Hinman’s Atlas of Urologic Surgery. 3rd ed. Philadelphia, PA: Elsevier; 2012.
27. Minervini A, Serni S, Vittori G. Current indications and results of orthotopic ileal neobladder for bladder cancer. Expert Rev Anticancer Ther. 2014;14(4):419-430.
28. Herdiman O, Ong K, Johnson L, Lawrentschuk N. Orthotopic bladder substitution (neobladder): part II: postoperative complications, management, and long-term follow-up. J Wound Ostomy Continence Nurs. 2013;40(2):171-180.
29. Moon A, Vasdev N, Thorpe AC. Continent urinary diversion. Indian J Urol. 2013;29(4):303-309.
30. Meeks JJ, Herr HW. Offi ce-based management of nonmuscle invasive bladder cancer. Urol Clin North Am. 2013;40(4):473-479.
Kristen Burns Farling is a urology NP at Johns Hopkins Hospital, the Brady Urological Institute, Baltimore, Md.
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