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Bladder Cancer Differential Diagnoses

  • Author: Gary David Steinberg, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
Updated: Jun 02, 2016

Diagnostic Considerations

Any patient with gross or microscopic hematuria should undergo urologic evaluation. Patients with bladder cancer may have spontaneous resolution of gross or microscopic hematuria, which may lull the patient and the clinician into erroneously believing that no significant entity is present.

The presentation in bladder cancer may resemble urinary tract infection (UTI), or the 2 conditions may coexist. Both UTIs and bladder cancer cause hematuria, and bacteriuria occurs in about 50% of patients with squamous cell carcinoma (SCC). UTIs are usually associated with irritative voiding symptoms (eg, dysuria, frequency, urgency). Irritative voiding symptoms may also be caused by carcinoma in situ (CIS) or muscle-invasive bladder cancer; patients with CIS may present with irritative voiding symptoms only.

CIS is often misdiagnosed as a bladder infection and treated as such. Patients with irritative voiding symptoms that do not resolve with treatment for UTI require further evaluation. The investigation should include urine cultures for fungi and tuberculosis, as well as cytology studies.

Cystoscopy in patients with CIS may reveal a characteristic red, velvety appearance that resembles an area of inflammation. In some cases, however, CIS is not visible on gross inspection.

Diagnostic tests include a urine cytology test and/or tests for one of several available bladder cancer markers. These tests are highly sensitive in detecting CIS. Bladder biopsies are needed to firmly establish a diagnosis. Urinary cytology is highly specific for urothelial bladder cancer, with improved sensitivity for high-grade tumors and cytology obtained by bladder wash or barbotage.

Unfortunately, urinary cytology is not especially helpful in early diagnosis of SCCs. Most of these tumors are not diagnosed until they are at an advanced stage.

With small cell carcinoma, the main differential diagnoses are high-grade urothelial carcinoma, lymphoma, and sarcoma. Additionally, metastatic small cell carcinoma should be ruled out based on the available clinical information. Because small cell carcinoma of the urinary bladder is often mixed with urothelial carcinoma and because any presence of small cell carcinoma is justifiable to render the diagnosis, it is important to thoroughly examine the tumor tissue.

Differential Diagnoses

Contributor Information and Disclosures

Gary David Steinberg, MD, FACS The Bruce and Beth White Family Professor and Vice Chairman of Urology, Director of Urologic Oncology, Section of Urology, Department of Surgery, The University of Chicago Medical Center and Cancer Center

Gary David Steinberg, MD, FACS is a member of the following medical societies: American Association for Cancer Research, Society of Laparoendoscopic Surgeons, American Society of Clinical Oncology, Societe Internationale d'Urologie (International Society of Urology), American College of Surgeons, American Urological Association, Society of Urologic Oncology

Disclosure: Received consulting fee from Abbott Molecular for consulting; Received consulting fee from Endo Pharmaceuticals for consulting; Received consulting fee from Bioniche for consulting; Received consulting fee from Tengion for consulting; Received consulting fee from Archimedes for review panel membership; Received consulting fee from PhotoCure for review panel membership; Received consulting fee from Taris Biomedical for review panel membership; Received none from Cold Genesys for other; Received h for: Photocure; Taris Biomedical; Heat Biologics: Cold Genesys; Merck; Roche/Genentech; Karl Storz; Mdx Health, Telesta.


Kush Sachdeva, MD Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner

Disclosure: Nothing to disclose.

Bagi RP Jana, MD Associate Professor of Medicine (Genitourinary Oncology), Division of Hematology and Oncology, University of Texas Medical Branch

Bagi RP Jana, MD is a member of the following medical societies: American Cancer Society, American Medical Association, SWOG, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

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, Society of Laparoendoscopic Surgeons, Society of University Urologists, Association of Military Osteopathic Physicians and Surgeons, American Urological Association, Endourological Society

Disclosure: Nothing to disclose.


Sujeet S Acharya, MD Resident Physician, Department of Surgery, Section of Urology, University of Chicago Division of the Biological Sciences, The Pritzker School of Medicine

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.

Edward M Gong, MD Fellow, Department of Surgery, Division of Urology, Children's Hospital Boston

Disclosure: Nothing to disclose.

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.

Hyung L Kim, MD Associate Professor, Cedars-Sinai Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Dan Theodorescu, MD, PhD Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer 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: Key Genomics Ownership interest Co-Founder-50% Stock Ownership; KromaTiD, Inc Stock Options Board membership

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In an ileal conduit, a small segment of ileum is taken out of continuity with the gastrointestinal tract but is maintained on its mesentery. Ureters are anastomosed to one end of this ileal segment, and the other end is brought out as a stoma to the abdominal wall.
In an Indiana pouch, a urinary reservoir is created from detubularized right colon and an efferent limb of terminal ileum. Terminal ileum is plicated and brought to the abdominal wall. The continence mechanism is the ileocecal valve.
In an orthotopic neobladder, a segment of ileum is used to construct a neobladder, which is connected to the urethra. Orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder.
The classic appearance of carcinoma in situ as a flat, velvety patch. However, using special staining techniques such as 5-aminolevulinic acid, it has been shown that significant areas of carcinoma in situ are easily overlooked by conventional cystoscopy. Courtesy of Abbott and Vysis Inc.
Papillary bladder tumors such as this one are typically of low stage and grade (Ta-G1). Courtesy of Abbott and Vysis Inc.
Sessile lesions as shown usually invade muscle, although occasionally a tumor is detected at the T1-G3 stage prior to muscle invasion. Courtesy of Abbott and Vysis Inc.
Photograph in which fluorescence in situ hybridization centromere staining identifies aneuploidy of chromosome 3. Multiple instances of overexpression of the chromosome (note the multiple red dots, which identify centromeres of this chromosome) prove aneuploidy.
Cross-section through the bladder, uterus, and vagina with squamous cell carcinoma of the bladder infiltrating through the bladder wall into the vaginal wall.
High power, Pap stain showing high grade urothelial carcinoma on a bladder wash cytology.
Intermediate power, H and E stain of urothelial carcinoma in situ. The superficial cells shed into the urine and correlate with those seen in cytologic bladder washing or urine cytology.
High power, H and E stain of high grade urothelial carcinoma. This tumor is now invasive into the muscularis propria (smooth muscle seen in center of image).
Histopathology of bladder shows eggs of Schistosoma haematobium surrounded by intense infiltrates of eosinophils and other inflammatory cells.
(A) When infused into the bladder, the optical imaging agent hexaminolevulinate (Cysview) accumulates preferentially in malignant cells. (B) On blue-light cystoscopy, the collection of hexaminolevulinate within tumors is visible as bright red spots. Courtesy of Gary David Steinberg, MD, FACS.
Table 1. Clinical Findings and Recommended Action in Patients with Negative Cystoscopy
Cystoscopy Findings Urine Cytology Findings FISH* Findings Action
Negative Negative Negative† Routine follow-up
Negative Negative Positive‡ Increased frequency of surveillance, whether FISH findings are false positive or anticipatory positive
Negative Positive Negative or positive Cancer until proven otherwise
  • Upper tract imaging with contrast
  • Cystoscopy with retrograde pyelography, washings, and/or ureteroscopy
  • Evaluate urethra
  • Increased frequency of surveillance upon negative findings
*FISH - Fluorescent in situ hybridization.

†Negative predictive value 95%.

‡Positive predictive value 30%.

Table 2. Recurrence and Progression Rates at 5 Years for Ta, T1, and CIS TCC of the Bladder Treated With BCG
Stage Recurrence, % Progression, %
Ta 55 11
T1 61 31
CIS 45 23
G1 61 2-4
G2 56 5-7
G3 50-70 30-40
Table 3. Most Common Complications of Radical Cystectomy
Early Complications Rate, % Late Complications Rate, %
Ileus 10 Small-bowel obstruction 7.4
Wound infection 5.5 Ureteroenteric stricture 7.0
Sepsis 4.9 Renal calculi 3.9
Pelvic abscess 4.7 Acute pyelonephritis 3.1
Hemorrhage 3.4 Parastomal hernia 2.8
Wound dehiscence 3.3 Stomal stenosis 2.8
Bowel obstruction 3.0 Incisional hernia 2.2
Enterocutaneous fistula 2.2 Fistula 1.3
Rectal injury 2.2 Rectal complications < 1
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