eMedicine Specialties > Urology > Cancer, Bladder, Penis, and Urethra

Bladder Cancer: Differential Diagnoses & Workup

Author: Gary David Steinberg, MD, FACS, Professor and Vice Chairman of Urology, Director of Urologic Oncology, Section of Urology, Department of Surgery, The University of Chicago Cancer Research Center
Coauthor(s): Mark H Katz, MD, Fellow in Urologic Oncology and Minimally Invasive Surgery, University of Chicago Medical Center; Kush Sachdeva, MD, Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner; Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Cancer Center; Bagi RP Jana, MD, Assistant Professor, University of Central Florida College of Medicine; Attending Physician, Department of Medicine, Florida Hospital Cancer Institute, Orlando
Contributor Information and Disclosures

Updated: Jul 27, 2009

Differential Diagnoses

Hemorrhagic Cystitis: Noninfectious
Urinary Tract Infection, Females
Nephrolithiasis
Urinary Tract Infection, Males
Renal Cell Carcinoma
Transitional Cell Carcinoma, Renal
Ureteral Trauma

Workup

Laboratory Studies

  • Any patient with gross or microscopic hematuria should be urologically evaluated. Microscopic hematuria from bladder cancer may be intermittent; therefore, a repeat negative result on urinalysis does not exclude the diagnosis. Infection may cause hematuria and is usually associated with irritative voiding symptoms (eg, dysuria, frequency, urgency). Irritative voiding symptoms may also be caused by CIS or muscle-invasive bladder cancer. Further evaluate irritative voiding symptoms caused by a urinary tract infection that do not resolve with treatment.
    • Urinalysis with microscopy
    • Urine culture to rule out infection, if suspected
    • Voided urinary cytology (This may be helpful if results are positive, but a negative cytology result cannot be considered definitive. Urinary cytology for routine screening is controversial.)
  • Newer molecular and genetic markers may help in the early detection and prediction of urothelial carcinoma.
    • Newer, voided urine assays (ie, bladder tumor antigen [BTA-Stat, BTA-TRAK], nuclear matrix protein [NMP-22], fibrin/fibrinogen degradation products [FDP]) are being used for the detection and surveillance of urothelial carcinoma. These tests have high false-positive and false-negative rates. In the future, other newer assays based on telomerase and microsatellite analysis may prove to be a better detection method than urinary cytology.
    • Chromosomal alterations have been associated with urothelial carcinoma. One encouraging test is a multitarget interphase fluorescence in situ hybridization (FISH) assay called UroVysion that consists of probes to the centromeres of chromosomes 3, 7, 17, and the 9p21 region. Aneuploidy of chromosomes 3, 7, and 17 and deletion of chromosome 9 has been associated with high sensitivity and specificity to detect bladder cancer. Often, this is an anticipatory positive result with a positive finding preceding visual evidence of bladder tumor.
    • However, at this time, no urinary assay has been shown to effectively replace cystoscopy for the detection of bladder tumors.

Imaging Studies

  • Upper-tract imaging is necessary for the hematuria workup and should be able to visualize both the kidneys and the urothelium.
  • The American Urologic Association Best Practice Policy recommends CT scanning of the abdomen and pelvis with preinfusion and postinfusion phases. This is ideally performed with a CT urography or followed by radiography of the kidneys, ureters, and bladder (KUB) to obtain images similar to those produced with intravenous pyelography (IVP).
  • Two commonly used alternative studies are IVP and renal ultrasonography.
    • The IVP is the traditional standard for upper-tract urothelium imaging; however, it is poor for evaluating the renal parenchyma.
    • Ultrasonography is also commonly used; however, urothelial tumors of the upper tract and small stones are easily missed.
  • Conduct retrograde pyelography in patients in whom contrast CT scanning cannot be performed because of azotemia or a severe allergy to intravenous contrast.

Procedures

  • Cystoscopy
    • Obtain biopsy samples of suspicious lesions during cystoscopy. Attempt to include the bladder muscle in the biopsy specimen. This allows the pathologist to determine whether the tumor is muscle invasive.
    • Transitional cell tumors are typically papillary or sessile, and CIS may appear as an erythematous, velvety lesion. Unless the lesion is in a bladder diverticulum (pseudodiverticulum), attempt to resect the primary tumor completely.
    • A bladder diverticulum lacks a surrounding muscle layer, and a deep biopsy of a lesion within a diverticulum risks perforating the bladder and extravesical extravasation of cancer cells.
    • Because no muscle layer surrounds the bladder diverticulum, the next step in the progression of a superficial tumor is extravesical spread, requiring more aggressive surgical therapy (eg, partial cystectomy, open diverticulectomy) rather than a simple resection followed by surveillance.
    • Further investigate efflux of blood from either ureteral orifice with retrograde pyelography, ureteroscopy, or both.
  • Urine cytology
    • Perform urine cytology at the same time as cystoscopy, although its routine use for screening is controversial.
    • Urine cytology is associated with a significant false-negative rate, especially for low-grade carcinoma (10-50% accuracy rate).
    • The false-positive rate is 1-12%, but it has a 95% accuracy rate for diagnosing high-grade carcinoma and CIS.
    • The sensitivity of urine cytology can be increased by obtaining a bladder barbotage cytology (70%) as opposed to a voided cytology (30%).
    • With a normal finding on cystoscopic examination, further evaluate a positive cytology result on urine study with an upper-tract study and random biopsies of the bladder. Obtain biopsy samples of the prostatic urethra in men.
  • Other urine markers for bladder cancer
    • The use of additional urine markers such as UroVysion (FISH), BTA, and NMP-22 in the initial diagnosis of bladder cancer is controversial. All of these assays may yield false-positive and false-negative results.
    • These other tests should not replace urine cytology and cystoscopy, with or without biopsy, for the diagnosis of bladder cancer. However, they may be useful adjuncts to urine cytology and cystoscopy.

Histologic Findings

More than 90% of bladder cancer cases are TCC, approximately 5% are SCC, and less than 2% are adenocarcinoma. Both the stage and tumor grade correlate independently with prognosis.

Staging

The International Union Against Cancer and the American Joint Committee on Cancer Staging developed the tumor, node, and metastases (TNM) staging system, which is used to stage bladder cancer (see below). Ta and T1 tumors and CIS were once considered superficial bladder tumors. T2, T3, and T4 tumors were traditionally described as invasive bladder cancer. However, urologic oncologists now recommend avoiding the term superficial bladder cancer to describe Ta, T1, and CIS tumors because it is a misnomer and tends to group patients who may require different treatments and who may have differing prognoses. Urothelial carcinoma is histologically graded as low grade (formerly graded 1-2) or high grade (formerly graded 3). CIS is characterized by full mucosal thickness and high-grade dysplasia of the bladder epithelium and is associated with a poorer prognosis.

The following is the TNM staging system for bladder cancer:

  • CIS - Carcinoma in situ, high-grade dysplasia, confined to the epithelium
  • Ta - Papillary tumor confined to the epithelium
  • T1 - Tumor invasion into the lamina propria
  • T2 - Tumor invasion into the muscularis propria
  • T3 - Tumor involvement of the perivesical fat
  • T4 - Tumor involvement of adjacent organs such as prostate, rectum, or pelvic sidewall
  • N+ - Lymph node metastasis
  • M+ - Metastasis

More than 70% of all newly diagnosed bladder cancers are non–muscle invasive, approximately 50-70% are Ta, 20-30% are T1, and 10% are CIS. Approximately 5% of patients present with metastatic disease, which commonly involves the lymph nodes, lung, liver, bone, and central nervous system. Approximately 25% of affected patients have muscle-invasive disease at diagnosis.

  • Clinically stage a patient who has muscle-invasive disease with CT scanning of the abdomen and pelvis, chest radiography, and serum chemistries.
  • If the patient is asymptomatic with normal calcium and alkaline phosphatase levels, a bone scan is unnecessary.
  • As many as 50% of patients with muscle-invasive bladder cancer may have occult metastases that become clinically apparent within 5 years of initial diagnosis.
  • Most patients with overt metastatic disease die within 2 years despite chemotherapy.
  • Approximately 25-30% of patients with only limited regional lymph node metastasis discovered during cystectomy and pelvic lymph node dissection may survive beyond 5 years.

More on Bladder Cancer

Overview: Bladder Cancer
Differential Diagnoses & Workup: Bladder Cancer
Treatment & Medication: Bladder Cancer
Follow-up: Bladder Cancer
Multimedia: Bladder Cancer
References
Further Reading
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Keywords

urothelial cancer, urothelial carcinoma, bladder cancer, transitional cell cancer, transitional cell carcinoma, TCC, bladder tumor, leiomyosarcoma, rhabdomyosarcoma, hematuria, urothelial tumors, carcinoma in situ, CIS, squamous cell carcinoma, SCC, urothelial carcinoma, indwelling Foley catheter, bladder stones, Schistosoma haematobium, S haematobium, primary bladder lymphoma, smoking, aromatic amines, radiation treatment of the pelvis, nitrosamine, 2-naphthylamine, 4-aminobiphenyl, chemotherapy with cyclophosphamide, acrolein, muscle-invasive bladder cancer, urinary tract infection, superficial transitional cell carcinoma, superficial TCC

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Contributor Information and Disclosures

Author

Gary David Steinberg, MD, FACS, Professor and Vice Chairman of Urology, Director of Urologic Oncology, Section of Urology, Department of Surgery, The University of Chicago Cancer Research Center
Gary David Steinberg, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Urological Association, Société Internationale d'Urologie (International Society of Urology), Society of Laparoendoscopic Surgeons, and Society of Urologic Oncology
Disclosure: Spectrum Pharmaceuticals Consulting fee Consulting; Abbott Molecular Consulting fee Speaking and teaching; Endo Pharmaceuticals Consulting fee Consulting; Bioniche Consulting fee Consulting

Coauthor(s)

Mark H Katz, MD, Fellow in Urologic Oncology and Minimally Invasive Surgery, University of Chicago Medical Center
Mark H Katz, MD is a member of the following medical societies: Alpha Omega Alpha, American Urological Association, Endourological Society, and Society of Urologic Oncology
Disclosure: Nothing to disclose.

Kush Sachdeva, MD, Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner
Disclosure: Nothing to disclose.

Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Cancer Center
Brendan Curti, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, Oregon Medical Association, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Bagi RP Jana, MD, Assistant Professor, University of Central Florida College of Medicine; Attending Physician, Department of Medicine, Florida Hospital Cancer Institute, Orlando
Bagi RP Jana, MD is a member of the following medical societies: American Medical Association and American Society of Clinical Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Dan Theodorescu, MD, PhD, Paul Mellon Professor of Urologic Oncology, Department of Urology, University of Virginia Health Sciences Center
Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Gyrus-ACMI Honoraria Speaking and teaching

Chief Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

 
 
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