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Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019
| Contributor Information
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Image courtesy of Medscape.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Worldwide, urinary bladder cancer is the ninth most common cancer in both sexes (preceded by malignancies of the lung, breast, colon and rectum, prostate, stomach, liver, cervix, uterus, and esophagus).[1] In the United States, however, bladder cancer is the sixth most common cancer (after breast [female], lung and bronchus, prostate, colorectal cancer, and melanoma).[2]
For unknown reasons, men are affected by carcinoma of the bladder at three to four times the rate that women are, and they also have more than three times the mortality.[3,4]
The image in the slide is a cross-section of a gross pathology specimen demonstrating a large tumor mass in the bladder wall.
Cytoscopic photograph of bladder carcinoma in situ courtesy of Abbott and Vysis Inc.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Pathophysiology
In industrialized countries, including the United States, approximately 90% of bladder neoplasms are urothelial (formerly, transitional cell) carcinoma, occurring in the urothelial cells of the bladder lining.[4-6] These lesions can also affect other areas of the urinary tract, such as the renal pelvis, ureters, and urethra.[3,4]
Squamous cell carcinoma (SCC) is the next most common type (~4%); it can be associated with parasitic infection from Schistosoma haematobium and is particularly prevalent in developing nations, such as those in the Middle East and in Africa.[4-6]
Other types of bladder cancers include nonurothelial neoplasms such as adenocarcinoma (~1-2%), which affects glandular cells; small cell carcinoma (< 1%) which is poorly differentiated and malignant and has variable neuroendocrine expression; and sarcoma (rare).[4,6]
Adapted image courtesy of National Cancer Institute (NCI)/SEER Program.[2]
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Incidence and Mortality
The International Agency for Research on Cancer (IARC) has estimated that worldwide, approximately 429,793 new cases of bladder cancer occurred in 2012, with about 59% of cases in more developed countries. The highest incidence was in Northern America and Europe; the lowest was in Asia, Latin America, and the Caribbean.[1] The estimated number of deaths that year was 165,084.[1]
In the United States, the incidence of bladder cancer has decreased slightly over the past decade (by 0.9% annually), whereas mortality has remained relatively steady. The Surveillance, Epidemiology, and End Results (SEER) Program estimated that there would be approximately 81,190 new cases of bladder cancer in the United States in 2018—representing approximately 4.7% of all new cancer cases—with about 17,240 deaths (2.8% of all cancer deaths) from this disease.[2,4] Data from 2013 to 2015 indicate that about 2.3% of men and women will be diagnosed with bladder cancer in their lifetime.[2]
Image courtesy of Wikimedia Commons/Oxfordian Kissuth.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Risk Factors
In the Western Hemisphere, tobacco use is the single most important cause of bladder cancer (~40-70% of cases); in comparison with nonsmokers, smokers have up to a fourfold higher risk of bladder cancer.[3,4,7] A possible culprit is the presence of known carcinogens (polyaromatic hydrocarbons) in tobacco products. Advancing age is also a key risk factor.
Other factors implicated in bladder malignancies include, but are not limited to, the following[3,4,8]:
Family history of bladder cancer and genetic mutations (eg, HRAS, Rb1, PTEN/MMAC1, NAT2, GSTM1)
Occupational exposure to types of organic chemicals found in textile dyes, rubber and petroleum products, metals (eg, aluminum, iron, steel), processed leather, and paints (eg, polycyclic aromatic hydrocarbons, 2-napthylamine, beta-napthylamine, aromatic amines, benzidine and its derivatives); many of these industrial products are banned in the United States but remain available in other countries
Previous chemotherapy with cyclophosphamide or ifosfamide and/or pelvic radiotherapy for other cancers
Chronic bladder inflammation/infections and the presence of indwelling urinary catheters (common in the United States)
Low fluid intake
Long-term use of pioglitazone or use of herbal supplements containing aristolochic acid (eg, herbs from the genus Aristolochia)
Histopathologic images courtesy of Hansel DE, Zhang Z, Petillo D, Teh BT. BMC Med Genomics. 2013;6:42. [Open access.] PMID: 24134934,] PMCID: PMC4015777 (left); and Centers for Disease Control and Prevention (CDC)/Dr Edwin P Ewing, Jr (right).
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Chronic urinary tract infection (UTI) and infection with the parasite S haematobium have also been associated with an increased risk of bladder cancer (often SCC).[3,4] Chronic inflammation may play a key role in carcinogenesis in these settings.
The left image demonstrates SCC of the bladder, which is characterized by desmosomes (intercellular bridges) and keratin pearls (bottom arrow) (with central keratin [top arrow]). The right image shows S haematobium eggs surrounded by intense eosinophil infiltrates.
Image courtesy of Blausen Medical Communications, Inc, via Wikimedia Commons.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Presentation
Initial signs and symptoms of bladder cancer may include the following[3,4]:
Painless gross or microscopic hematuria – The most common presenting sign
Irritative bladder signs/symptoms (eg, dysuria, urgency, frequency, nocturia) – More often seen in patients with carcinoma in situ (CIS)
Pelvic/bony pain, lower-extremity edema, or flank pain (uncommon) – Usually caused by tumor obstruction and indicative of advanced disease
Palpable mass on physical examination – Rare
Image of FISH centromere staining identifying aneuploidy of chromosome 3 from patient with suspected bladder cancer courtesy of Abbott and Vysis Inc.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Workup
A detailed history and a thorough physical examination are recommended for any patient suspected of having bladder cancer.[4,8] Laboratory urine studies include urinalysis (to detect hematuria or infection), cytology (to detect precursor or malignant cells), culture (to exclude infection), and tumor markers (to detect bladder cancer indicators).[4,9] If muscle-invasive disease is suspected, a complete blood count (CBC), comprehensive chemistry panel, and hepatorenal function studies should be obtained.[8]
Urinary cytology is not sensitive for low-grade and early-stage cancers; however, fluorescence in situ hybridization (FISH) may improve its accuracy.[9] If urinary cytology findings are positive, urothelial malignancy may be present anywhere in the urinary tract.[8]
Images courtesy of Cancer Research UK via Wikimedia Commons.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Cystoscopy
Cystoscopy is considered the primary diagnostic modality for evaluating patients with suspected bladder cancer,[3-5,8,9] and it can even be performed in an outpatient setting. This study allows direct visualization of the bladder lining, precise localization of the lesion(s), tissue sampling, and resection of small papillary tumors.[9] The images in the slide illustrate cystoscopic technique in men (left) and women (right).
If a tumor is found on cystoscopy, bimanual examination should be performed under general anesthesia, with a repeat cystoscopy and a transurethral resection of the bladder tumor (TURBT) to confirm the diagnosis.[3,8] Evaluate for the following[3]:
Size and mobility of palpable masses
Degree of induration of the bladder wall
Presence of extravesical extension or invasion of the adjacent organs
If the cystoscopy findings are normal but the urinary cytology results are positive, evaluate the upper urinary tract (and, in men, the prostate), and consider performing a ureteroscopic examination.[8]
Image courtesy of Gaughan EM, Dezube BJ, Bower M, et al. BMC Urol. 2009;9:10. [Open access.] PMID: 19719844, PMCID: PMC2746230.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Imaging studies
In general, radiologic studies such as computed tomography (CT) or ultrasonography (US) are insufficiently sensitive for detecting bladder malignancies,[3] and they also lack the ability to accurately assess the depth of invasion.[8] However, in the presence of a solid tumor, a high-grade lesion, or invasive cancer, CT or magnetic resonance imaging (MRI) of the abdomen and pelvis is recommended.[3,4,8] The CT scan in the slide reveals a large, lobulated, enhancing soft-tissue mass on the left side of the bladder.
The National Comprehensive Cancer Network (NCCN) suggests obtaining these imaging studies before performing TURBT, on the grounds that findings generally do not affect treatment decisions for tumors that appear to be purely papillary or are suggestive of CIS.[8]
Images courtesy of Yoshino T, Ohara S, Moriyama H. BMC Res Notes. 2014;7:779. [Open access.] PMID: 25367311, PMCID: PMC4233068.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
The left image shows a thumbtip-sized, solid, broad-based bladder tumor at the trigone under cystoscopy. The asterisk indicates the flexible cystoscope; the arrow points to the neck of the bladder. The right image is a sagittal contrast-enhanced MRI from the same patient that reveals a bladder tumor (arrow) at the trigone with muscle invasion.
The malignancy was later found to be lymphoepitheliomalike carcinoma of the urinary bladder.
PET/CT scan of bladder tumor courtesy of Wikimedia Commons/Hg6996.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Upper urinary tract imaging is necessary when hematuria is present and when cytology results are positive. This evaluation may be obtained by means of CT without contrast with retrograde pyelography, CT or MRI urography, and ureteroscopy, alone or in combination.[3,4,8]
If a CT scan has not been performed, a routine chest radiograph can be obtained to help rule out pulmonary or other metastases.[3,4,8] Bone scanning is indicated for patients with a nonhepatic elevation of alkaline phosphatase (ALP) levels or symptoms that suggest bone metastases.
Occasionally, positron emission tomography (PET), alone or in conjunction with CT (shown), may be useful for evaluating the extent of the disease.[5] MIP = maximum-intensity projection.
Images courtesy of Xu C, Zhang Z, Wang H. PLoS One. 2014;9(4):e92385. [Open access.] PMID: 24704988, PMCID: PMC3976253.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
US is also commonly performed to assess bladder malignancies, but this modality may miss urothelial tumors of the upper urinary tract, as well as small renal calculi.[9] The left sonogram demonstrates the normal muscle layer of the bladder wall. The right sonogram reveals a non-muscle-invasive bladder tumor (red arrow) near the bladder neck, with the black arrows depicting a continuous muscle layer.
Once the lesion has been identified via cystoscopy and the diagnosis has been confirmed via biopsy, imaging, or both, grading and staging follow.
Image of solid (sessile) lesion, which usually invades muscle, courtesy of Abbott and Vysis Inc.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Grading
Histopathologically, urothelial bladder carcinoma may be categorized as low grade or high grade, as well as on the basis of whether invasion of the muscularis propria, or detrusor muscle, has occurred (ie, muscle-invasive or non-muscle-invasive disease).[3,8] There are also two subtypes, papillary and flat,[4,8] with or without squamous or glandular differentiation or with both.[8]
Low-grade (differentiated) bladder cancer is rarely fatal.[3,5] Posttreatment recurrence is common, but invasion of the bladder wall or metastasis is unusual. High-grade (poorly differentiated) disease is aggressive and more likely to be fatal; recurrence, muscle-invasive disease, and metastasis are common.[3,5]
Non-muscle-invasive (superficial) disease affects the urothelium (transitional epithelium) of the bladder wall but has not invaded the deeper layers.[3-5] Muscle-invasive disease may invade the lamina propria and deeper muscular or fatty layers of the bladder wall; these cancers are more likely to metastasize and to be more difficult to treat.[3-5]
Papillary urothelial carcinomas (or noninvasive papillary cancers) have a fingerlike appearance.[4] These tumors protrude from the inner bladder surface in the direction of the bladder center but do not invade the deeper layers of the bladder wall. Very low-grade noninvasive papillary cancer is also known as papillary urothelial neoplasm of low malignant potential (PUNLMP); although this tumor may recur, the risk of it progressing to advanced disease is low.[5]
Unlike papillary tumors, flat urothelial carcinomas do not grow toward the hollow center of the bladder.[4] When these tumors remain in the urothelial layer, they are known as flat CIS or noninvasive flat carcinoma.[4]
Image courtesy of Cancer Research UK via Wikimedia Commons.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Staging
The American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) classification is the most commonly used system for staging bladder cancer.[4]
Clinical staging is determined by extent of the disease and is made on the basis of clinical findings from the patient's history and physical examination, cystoscopic examination under anesthesia, and cytology, as well as other laboratory and imaging studies.[3,4,8]
Pathologic staging has prognostic significance and is made on the basis of cellular atypia, nuclear abnormalities, and the number of mitotic figures.[3]
Image courtesy of Hansel DE, Zhang Z, Petillo D, Teh BT. BMC Med Genomics. 2013;6:42. [Open access.] PMID: 24134934, PMCID: PMC4015777.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
The image in the slide shows urothelial carcinoma with variably sized invasive nests of carcinoma cells.
Images courtesy of Wikimedia Commons/Saltanat ebli (left) and the CDC/Dr Edwin P Ewing, Jr (right).
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
In the United States, as noted earlier, the development of SCC of the bladder is commonly associated with persistent inflammation from long-term indwelling urinary catheters (left), bladder stones, and possibly infection.[3,4,8] In developing nations, SCC is often associated with parasitic S haematobium bladder infection (right).
Image courtesy of Wikimedia Commons/Nephron.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
The image in the slide is a very-high-magnification view of small cell carcinoma of the bladder. Note the poorly differentiated cells.
Images courtesy of Xu C, Zhang Z, Wang H. PLoS One. 2014;9(4):e92385. [Open access.] PMID: 24704988, PMCID: PMC3976253.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Treatment
The choice of treatment for bladder cancer depends on whether the tumor is muscle-invasive, as well as on the disease stage at diagnosis.[3,4] Treatment may comprise one or more of the following[3,4]:
Surgery
Intravesical therapy
Chemotherapy
Radiation therapy
Palliative therapy
The top left image is a cystoscopic view of a non-muscle-invasive bladder tumor (thin arrow) near the bladder neck; the thick arrow indicates the bladder wall. The top right image shows the associated radical cystectomy specimen, with the arrow indicating the tumor near the bladder neck. The bottom left image is a cystoscopic view of a muscle-invasive bladder tumor (thick arrow); the thin arrow indicates the bladder wall. The bottom right image shows the associated radical cystectomy specimen, with the left arrow indicating the bladder neck and the right arrow the tumor.
Image of bipolar TURBT of lateral bladder wall lesion courtesy of Geavlete B, Stănescu F, Moldoveanu C, et al. J Med Life. 2013;6(2):140-5. [Open access.] PMID: 23904872, PMCID: PMC3725437.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Non-muscle-invasive bladder cancer
Guidelines recommend stratifying the risk of recurrence and progression to determine appropriate treatment for non-muscle-invasive bladder cancers (Ta, T1, Tis).[3,8,10] The initial treatment is TURBT.[3] On the basis of the depth of tumor invasion and grade, as well as the likelihood of recurrent or progressive disease, immediate intravesical instillation chemotherapy (mitomycin C [most common], thiotepa, valrubicin, doxorubicin, gemcitabine) or immunotherapy (bacillus Calmette-Guérin [BCG]) following TURBT may be indicated.[3,8,10]
Thereafter, treatment is based on risk and usually involves one of the following[3,8]:
Surveillance for relapse or recurrence (tumors with low risk of recurrence or progression)
Intravesical therapy for 1 year or longer with BCG in addition to surveillance for relapse (lesions at intermediate or high risk of progression to muscle-invasive disease)
Additional intravesical chemotherapy (neoplasms with a high risk of recurrence but a low risk of progression to muscle-invasive disease)
Image courtesy of NCI/Bill Branson.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Muscle-invasive bladder cancer
In patients with muscle-invasive bladder cancers with a curative goal, the National Cancer Institute (NCI) has indicated that standard therapy consists of neoadjuvant multiagent cisplatin-based chemotherapy followed by radical cystectomy and urinary diversion or radiation therapy with chemotherapy.[3] The NCCN has advocated TURBT as the initial treatment for these malignancies.[3]
Other treatment options for muscle-invasive bladder malignancies include the following[3,4,8]:
Radical cystectomy, with or without extended lymphadenectomy, followed by multiagent cisplatin-based chemotherapy
Radical cystectomy or radiation therapy, without perioperative chemotherapy
Partial cystectomy, with or without perioperative chemotherapy
Images courtesy of Pastore AL, Palleschi G, Silvestri L, et al. BMC Urol. 2014;14:89. [Open access.] PMID: 25403723, PMCID: PMC4239397.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Post–radical cystectomy reconstruction
Following radical cystectomy, one of the following may be performed to provide a route for urinary flow[3,4,8,11]:
Incontinent urinary diversion - An ileal conduit is created between the kidneys and a stoma, through which urine drains into an exterior pouch
Continent urinary diversion - A portion of intestine is used to create an interior pouch that connects to the ureters proximally and to a valve distally; urine is removed by inserting a catheter through the valve via the stoma
Orthotopic urinary diversion (neobladder) - A portion of intestine is used to create a new bladder
Contraindications for performing continent urinary diversions are as follows[9]:
Multiple comorbid conditions
Chronic renal insufficiency
Hepatic dysfunction
Advanced disease stage
The surgical images in the slide depict key steps of cystectomy and ileal neobladder reconstruction in a male patient: (A, top left) seminal vesicles and vas deferens (VD) dissected and maintained en bloc with the bladder; (B, top right) "U-shaped" neobladder configuration with a stapler; (C, bottom left) neobladder-urethral anastomosis completed; (D, bottom right) neobladder-ureteral anastomosis.
Image courtesy of Medscape.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Treatment Complications
The table in the slide shows the most common complications of radical cystectomy, in descending order.
The perioperative mortality associated with radical cystectomy has reportedly ranged from 0.8% to 8.3%.[11] In general, increasing age is associated with higher complication rates.[11]
Image courtesy of Qin X, Zhang H, Wan F, et al. World J Surg Oncol. 2015;13:132. [Open access.] PMID: 25886313, PMCID: PMC4382937.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Complications of urinary diversion include the following[9]:
Hyperchloremic metabolic acidosis (if the ileum or colon is used)
UTIs
Stomal-peristomal inflammation, hernia, or stenosis
Urinary calculi
Vitamin B12 deficiency (with diversions affecting the terminal ileum)
Ureterointestinal stenosis leading to hydronephrosis
The surgical image in the slide shows extraperitoneal cutaneous ureterostomy, preparation of the ileal loop, neobladder or ileal conduit reconstruction, and urinary reconstruction.
Adapted image courtesy of NCI/SEER Program.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
The image in the slide is based on data from SEER 18 for the period from 2008 to 2014. Gray figures represent those who have died from bladder cancer; green figures represent those who have survived 5 years or more.
Prognostic Factors
Approximately 77% of patients with bladder cancer are alive 5 years after diagnosis. Major prognostic factors are depth of tumor invasion into the bladder wall, pathologic grade of the tumor, and presence or absence of CIS.[3]
The following factors are also prognostic for non-muscle-invasive cancers[3]:
Total number of lesions
Tumor size (eg >3 cm or < 3 cm)
Invasion of the lamina propria (Ta vs T1)
Primary or recurrent malignancy
Factors that affect recurrence of superficial tumors, thereby increasing the risk of malignancy over the entire urothelial surface, include the following[3]:
Less differentiation
Large or multiple lesions
Association with CIS (Tis) in other areas of the bladder mucosa
Adapted image courtesy of NCI/SEER Program.
Urinary Bladder Cancer: What You Need to Know
Ali Ahmad, MD, FACS | March 11, 2019 | Contributor Information
Survival
The majority of deaths from bladder cancer are in patients with high-grade disease, which has a much greater potential to invade deeply into the bladder's muscular wall and metastasize.[3] Mortality risk is significant even when the bladder malignancy is not muscle-invasive.[3]
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Metastatic breast cancer, or stage IV or advanced breast cancer, is incurable, with a low 5-year survival. Review the symptoms/signs of metastatic spread and 3 patient cases, as well as guidelines for, barriers to, and opportunities for improvement in palliative care.Slideshows, February 2019
Bladder cancer is a common urologic cancer that has the highest recurrence rate of any malignancy. In North America, South America, Europe, and Asia, the most common type is transitional cell carcinoma. Other types include squamous cell carcinoma and adenocarcinomas.Diseases/Conditions, January 2019
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Contributor Information
Author
Ali Ahmad, MD, FACS
Clinical Assistant Professor of Surgery
University of Kansas School of Medicine
Wichita, KS
Disclosure: Ali Ahmad, MD, FACS, has disclosed no relevant financial relationships.
Contributor
Vera Ruvinskaya, MS
Disclosure: Vera Ruvinskaya, MS, has disclosed no relevant financial relationships.
Editors
Olivia Wong, DO
Section Editor
Medscape Drugs & Diseases
New York, NY
Disclosure: Olivia Wong, DO, has disclosed no relevant financial relationships.
John Heinegg, RN
Section Editor
Medscape Drugs & Diseases
New York, NY
Disclosure: John Heinegg, RN, has disclosed no relevant financial relationships.
Cancer stat facts: bladder cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results (SEER) Program. Available at: http://seer.cancer.gov/statfacts/html/urinb.html. Accessed February 23, 2019.
Reuter VE, Al-Ahmadie H, Lin O. Cytology and pathology of carcinomas of the urinary tract. Scardino PT, Linehan WM, Zelefsky MJ, Vogelzang NJ, eds. Comprehensive Textbook of Genitourinary Oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2011: Chap 16.
Tobacco Free Initiative (TFI). World Health Organization. Available at: http://www.who.int/tobacco/en/. 2019; Accessed: February 23, 2019.
NCCN clinical practice guidelines in oncology (NCCN Guidelines®): Bladder cancer, Version 1.2019. National Comprehensive Cancer Network (NCCN). Available at: http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. December 20, 2018; Accessed: February 23, 2019.
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