Transitional cell carcinoma of the bladder (syn. urothelial carcinoma) (TCC) constitutes 90% of bladder cancers [1]. Depending on cancer penetration into the bladder wall muscle layer, it is categorized as non-muscle invasive (papillary) or muscle invasive (non-papillary). A majority of bladder TCC are non-muscle invasive on discovery. Being low-grade, this type of cancer has a better prognosis than the high-grade invasive type but is more likely to recur. However, without treatment, non-muscle invasive carcinoma will eventually progress into muscle-invasive type [1] [2].

In both men and women, the most widespread risk factor for developing bladder TCC is smoking [3]. The second major factor is workplace exposure to carcinogens, such as aromatic amines, polycyclic aromatic hydrocarbons, chlorinated hydrocarbons or heavy metals [4] [5]. Oral intake of arsenic is also associated with bladder cancer, with contaminated drinking water being the main source of exposure [6]. Iatrogenic causes of TCC include ionizing radiation and cyclophosphamide therapy [4].

Most patients with TCC display urinary signs and symptoms, predominantly painless hematuria. While usually visible, hematuria can sometimes be microscopic and intermittent, requiring repeated tests in order to be discovered. Additionally, patients can experience urgency or frequency of urination, in some cases accompanied by discomfort or pain. In advanced disease, flank pain, leg swelling or a palpable pelvic mass may occur; non-specific symptoms such as cachexia or bone pain may signal the presence of distant metastases [7].

• Asymptomatic

  As many benign and malignant glans lesions may be clinically similar, histologic study is necessary to correctly diagnose primary lesions and promptly detect underlying asymptomatic visceral malignancies initially presenting as Paget's disease. [ncbi.nlm.nih.gov]

  Physicians may consider cystoscopy and/or CT urography in patients 35 years with asymptomatic hematuria who also have risk factors for CIS. These procedures enable diagnostic evaluation of the entire urinary tract, as well as follow-up. [amboss.com]

  Eur Urol 57: 410–29 PubMed CrossRef Google Scholar Gray Sears CL, Ward JF, Sears ST et al. (2002) Prospective comparison of computerized tomography and excretory urography in the initial evaluation of asymptomatic microhematuria. [link.springer.com]

  Asymptomatic microhematuria and urologic disease. A population-based study. JAMA. 1986;256(2):224-229. 15. Golin AL, Howard RS. Asymptomatic microscopic hematuria. J Urol. 1980;124(3):389-391. 16. Koss LG, Deitch D, Ramanathan R, Sherman AB. [aafp.org]

  Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy--part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. [emedicine.medscape.com]

• Chills

  Other side effects include nausea, low-grade fever, and chills. These are caused by stimulation of the immune system. These effects are almost always temporary. [emedicinehealth.com]

• Pelvic Mass

  In advanced disease, flank pain, leg swelling or a palpable pelvic mass may occur; non-specific symptoms such as cachexia or bone pain may signal the presence of distant metastases. [symptoma.com]

  Pelvic pain occurs with advanced cancer, when a pelvic mass may be palpable. Cystoscopy with biopsy Urine cytology Bladder cancer is suspected clinically. Urine cytology, which can detect malignant cells, may be done. [merckmanuals.com]

  A palpable kidney or pelvic mass may be present in metastatic disease. [aafp.org]

• Abdominal Pain

  A 48-year-old male with a 30-pack year smoking history was admitted with abdominal pain, nausea, and vomiting. He also complained of a 50-lb weight loss and gross hematuria over one-year period. [ijcasereportsandimages.com]

  Urinary obstruction, abdominal pain, urinary tract infection, and weight loss are reported occasionally. Rare cases of paraneoplastic syndromes such as ectopic ACTH secretion and hypercalcemia have also been reported. [ccij-online.org]

• Subcutaneous Nodule

  He presented to our outpatient clinic with a 3-month history of skin lesions as multiple, rubbery subcutaneous nodules. [ncbi.nlm.nih.gov]

• Meningism

  Gadolinium-enhanced magnetic resonance images (MRI), however, demonstrated multifocal 1-cm nodules in the brain parenchyma and enhancement of the meninges. Meningeal carcinomatosis was confirmed by lumbar puncture. [ncbi.nlm.nih.gov]

• Hematuria

  Most patients with TCC display urinary signs and symptoms, predominantly painless hematuria. While usually visible, hematuria can sometimes be microscopic and intermittent, requiring repeated tests in order to be discovered. [symptoma.com]

  We report a case of amyopathic dermatomyositis in a patient whose painless gross hematuria was due to transitional cell carcinoma of the bladder as well as review this association. [ncbi.nlm.nih.gov]

• Dysuria

  […] urothelial cancer References: [1] [2] [3] [4] [6] [7] [8] [9] Clinical features Location Symptoms Features of advanced/ metastatic disease Bladder carcinoma Painless gross hematuria throughout micturition (most common) Irritative voiding symptoms ( dysuria [amboss.com]

  Adults aged 60 and over and have unexplained non visible haematuria and either dysuria or a raised white cell count on a blood test. [patient.info]

  Patients present with urinary frequency, dysuria or urgency. Microscopic hematuria is very common but gross hematuria is present in an occasional patient. [med-ed.virginia.edu]

  Irritative voiding symptoms (dysuria, burning, frequency) and pyuria are also common at presentation. Pelvic pain occurs with advanced cancer, when a pelvic mass may be palpable. [merckmanuals.com]

• Pelvic Pain

  Bladder cancer care at Mayo Clinic Symptoms Bladder cancer signs and symptoms may include: Blood in urine (hematuria) Painful urination Pelvic pain If you have hematuria, your urine may appear bright red or cola colored. [mayoclinic.org]

  Pelvic pain: Hypofractionated radiotherapy, nerve block or palliative chemotherapy may be options for those with pelvic pain caused by incurable bladder cancer. [patient.info]

  Pelvic pain occurs with advanced cancer, when a pelvic mass may be palpable. Cystoscopy with biopsy Urine cytology Bladder cancer is suspected clinically. Urine cytology, which can detect malignant cells, may be done. [merckmanuals.com]

  Dysuria, frequency, urge incontinence, urgency Obstructive symptoms Decreased force of stream, feeling of incomplete voiding, intermittent stream, straining Signs and symptoms of metastases or advanced disease Abdominal, bone, flank, or pelvic pain; [aafp.org]

  Prognosis Untreated bladder cancer produces significant morbidity, including the following: Hematuria Dysuria Irritative urinary symptoms Urinary retention Urinary incontinence Ureteral obstruction Pelvic pain The recurrence rate for superficial TCC of [emedicine.medscape.com]

• Urinary Incontinence

  Orthotopic bladders have a risk of urinary incontinence. Prognosis The recurrence rate for superficial transitional cell cancer of the bladder is high (70% within five years). As many as 80% of patients have at least one recurrence. [patient.info]

  Prognosis Untreated bladder cancer produces significant morbidity, including the following: Hematuria Dysuria Irritative urinary symptoms Urinary retention Urinary incontinence Ureteral obstruction Pelvic pain The recurrence rate for superficial TCC of [emedicine.medscape.com]

• Macroscopic Hematuria

  Visible blood in the urine is referred to as gross, or macroscopic, hematuria. Bladder cancer often causes no symptoms until it reaches an advanced stage that is difficult to cure. [emedicinehealth.com]

Cystoscopy and bimanual examination are the golden standards for diagnosis in suspected bladder cancer. Aside from enabling tumor detection and visualization, cystoscopy provides an opportunity for biopsy of the observed abnormalities through all bladder wall layers. The obtained samples can give information on the cell type in addition to cancer stage and grade [8]. Difficulties arise in cystoscopic detection of carcinoma in situ (CIS), which is either invisible or mimics inflammation (appears in red-velvety flat patches) [9]. CIS can be detected through cytology analysis of voided urine. While urine cytology demonstrates high accuracy in diagnosis of CIS and high-grade lesions, its sensitivity is inadequate for low-grade malignancies, which yield too few cells per urine sample. Urine tumor marker analysis, such as fluorescence in situ hybridization (FISH) can increase sensitivity and specificity in TCC detection [10]. In the case of positive cytology, but negative cystoscopy findings, mapping biopsy along with additional diagnostic procedures (e.g. imaging) are recommended for investigation of CIS and upper urinary tract malignancies, respectively [9].

Imaging techniques, primarily computed tomography (CT) and magnetic resonance imaging (MRI) complement cystoscopy in the detection of carcinomas situated in bladder diverticula, disease staging (distinguishing invasive from non-invasive forms) and lymph node visualization [8]. MRI is superior in tumor staging, especially when contrast-enhanced, T2-weighted and diffusion-weighted techniques are combined [1] [11]. Shortcomings of CT and MRI include false positive and false negative findings due to small lymph nodes, reactive lymphadenopathy and variability in bladder wall thickening depending on the degree of bladder extension [1] [8]. [F-18]-Fluorodeoxyglucose positron emission tomography (FDG-PET) can be used for staging of pelvic lymph nodes, discovering distant metastases and differentiating the reactive from tumor tissue. Urinary excretion of FDG limits this method in the diagnosis of primary bladder TCC [12].

The exceptionally high recurrence rate of bladder TCC warrants periodic post-therapeutic surveillance, by using cystoscopy, urinary cytology (including FISH), FDG PET and other imaging techniques [1] [8] [10] [12].

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2. Pashos CL, Botteman MF, Laskin BL, Redaelli A. Bladder Cancer. Epidemiology, Diagnosis, and Management. Cancer Practice. 2002;10(6):311-322. doi:10.1046/j.1523-5394.2002.106011.x.
3. Freedman ND, Silverman DT, Hollenbeck AR. Association Between Smoking and Risk of Bladder Cancer Among Men and Women. Jama. 2011;306(7):737. doi:10.1001/jama.2011.1142.
4. Burger M, Catto JW, Dalbagni G, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. European Urology. 2013;63(2):234-241. doi:10.1016/j.eururo.2012.07.033.
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6. Baris D, Waddell R, Freeman LEB, et al. Elevated Bladder Cancer in Northern New England: The Role of Drinking Water and Arsenic. JNCI: Journal of the National Cancer Institute. 2016;108(9). doi:10.1093/jnci/djw099.
7. Soloway M, Carmack A, Khoury S. Bladder Tumors. Bladder Cancer: Epidemiology, Staging and Grading, and Diagnosis. In: 1St International Consultation on Bladder Tumors. Health Publication Ltd; 2004:14 - 64.
8. Vikram R, Sandler CM, Ng CS. Imaging and Staging of Transitional Cell Carcinoma: Part 1, Lower Urinary Tract. American Journal of Roentgenology. 2009;192(6):1481-1487. doi:10.2214/ajr.08.1318.
9. Babjuk M, Burger M, Zigeuner R, et al. EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2013. European Urology. 2013;64(4):639-653. doi:10.1016/j.eururo.2013.06.003.
10. Grossman HB, Soloway M, Messing E. Surveillance for Recurrent Bladder Cancer Using a Point-of-Care Proteomic Assay. Jama. 2006;295(3):299. doi:10.1001/jama.295.3.299.
11. Takeuchi M, Sasaki S, Ito M, et al. Urinary Bladder Cancer: Diffusion-weighted MR Imaging—Accuracy for Diagnosing T Stage and Estimating Histologic Grade. Radiology. 2009;251(1):112-121. doi:10.1148/radiol.2511080873.
12. Jadvar H, Quan V, Henderson RW, Conti PS. [F-18]-Fluorodeoxyglucose PET and PET-CT in diagnostic imaging evaluation of locally recurrent and metastatic bladder transitional cell carcinoma. International Journal of Clinical Oncology. 2008;13(1):42-47. doi:10.1007/s10147-007-0720-8.