Megan M. Merrill, DO
Surena F. Matin, MD, FACS
BASICS
DESCRIPTION
• Carcinoma in situ (CIS) of the bladder is a flat, multifocal, “velvety” lesion of the urothelium
– CIS is a flat, high-grade tumor that are confined to the mucosa
– Can be occult and diagnosed by random biopsies of normal appearing mucosa
– Although can occur alone, most often seen with concomitant high-grade papillary lesions
• Classified as nonmuscle-invasive bladder cancer (NMIBC) similar to stage Ta and T1, however CIS is considered high grade and aggressive with a propensity to invade the bladder wall and metastasize
EPIDEMIOLOGY
Incidence
True incidence not known given the flat superficial nature of this lesion, which can be destroyed by cautery effect during transurethral resection of bladder tumor (TURBT)
Prevalence
• Occurs as isolated CIS in 3–5% cases
• Estimated 5–10% of patients with noninvasive urothelial carcinoma have CIS (1)
• 45–65% patients with invasive urothelial carcinoma have CIS (2)
RISK FACTORS
• No risk factors specific for CIS beyond that of urothelial carcinoma
• Tobacco smoking-cigarettes
• Occupational exposure
– Organic chemicals: Aromatic amines, benzenes, aniline dyes
– High-risk occupations: Petroleum, chemical, rubber, textile workers, hairdressers
• Medications
– Phenacetin-containing analgesics
– Cyclophosphamide
• Pelvic radiation
Genetics
• p53 mutation most important deletion/mutation found with CIS (2)
• Chromosome 9q deletions common
• Loss of CDKN2/p16 (tumor suppressor gene)
PATHOPHYSIOLOGY
• CIS usually multifocal and can occur in the upper tracts, prostatic ducts, and urethra as well as the bladder
• Natural history—highly aggressive
– Progression to MIBC in 54–83% of untreated cases (3,4)
– Increase risk of recurrence if found with NMIBC papillary lesions
• Bacillus Calmette-Guerin (BCG) reduces risk of progression by 35% compared with other intravesical therapies (1,3)
• BCG confers disease-free rate approximately 51% at 3.75 yr (1)
• If concomitant muscle-invasive lesion, prognosis and treatment depends on invasive lesion
ASSOCIATED CONDITIONS
• NMIBC (Ta,T1)
• Invasive bladder cancer (T2,T3,T4)
GENERAL PREVENTION
• Smoking cessation
• Increased fluid intake
• Avoid occupational exposures
DIAGNOSIS
HISTORY
• Age and sex
• Presence of gross hematuria
• Irritative voiding symptoms—dysuria commonly occurs with CIS
• History of bladder cancer
• Family history of bladder cancer
• Smoking history
• Occupational risk factors
PHYSICAL EXAM
• Usually unremarkable
• Bimanual exam should be performed at time of cystoscopy/TURBT—If CIS is found in presence of advanced stage/invasive bladder cancer may appreciate palpable mass
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urinalysis, including microscopic evaluation
• Urine cytology—highly specific and sensitive (>90%) for detecting CIS and high-grade urothelial carcinoma (5)
• UroVysion, HA-HAase, and BLCA-4 have a high sensitivity to detect CIS however should not replace classic urine cytology (1) (Grade B)
Imaging
• No imaging specific for diagnosing CIS
• Renal/bladder ultrasound (US): Detects hydronephrosis that may be caused by ureteral obstruction from bladder tumor; bladder US can visualize larger bladder tumors
• Computed tomography (CT) urogram: Triple phase CT abdomen/pelvis is the gold standard for evaluation of painless gross hematuria; can detect more advanced bladder tumors, hydronephrosis, and upper tract filling defects that may represent upper tract urothelial carcinoma
Diagnostic Procedures/Surgery
• Cystoscopy with bladder biopsy
– Appearance can be flat, grossly erythematous, granular or cobblestone mucosa or visually normal
– May be performed in office at initial visit
– TURBT under general or spinal anesthesia may be required if papillary bladder tumor present
– Retrograde pyelography also should be performed to assess the upper tracts if not already evaluated with a CT urogram
– Positive cytology with no visible tumor and negative random bladder biopsies suggests disease outside of bladder
Biopsy of prostatic urethra indicated
Selective cytology from upper tracts; evaluate for urothelial carcinoma/CIS of renal pelvis or ureters. CIS of upper tracts suspected in absence of solid tumor and with positive cytology, rarely able to obtain adequate biopsy to confirm CIS histologically
• Fluorescent “Blue light” cystoscopy
– More sensitive than conventional white light cystoscopy for detecting CIS
In a prospective study additional detection rate of 20% for all tumors and 23% for CIS (6)
– False-positives can result in the presence of inflammation, recent TUR, or BCG instillation
Pathologic Findings
• Arises from surface uroepithelium
• Severe cytologic atypia and nuclear aplasia (2)
– Large, irregular hyperchromatic nuclei
– Mitotic activity common
• Thought to be a precursor of invasive disease
• Some pathologists use the term “severe dysplasia” to describe CIS
DIFFERENTIAL DIAGNOSIS
• Nonurothelial cancers (squamous cell carcinoma, adenocarcinoma)
• Inflammatory lesion from prior radiation, interstitial cystitis, infection
TREATMENT
GENERAL MEASURES
• Resection of all visible tumor followed by intravesical therapy
• For BCG-refractory CIS: Radical cystectomy
MEDICATION
First Line
• BCG—live suspension of the attenuated Mycobacterium bovis vaccine strain
– Standard of care for CIS
– Therapy initiated no earlier than 2–4 wk after TURBT/biopsy to give uroepithelium time to heal and prevent systemic complications of BCG
– Administered as induction therapy—6 consecutive weekly bladder instillations; then maintenance treatment recommended for at least 1 yr (1) (Grade A)
– BCG has the highest complete response rate and durable disease-free rate among all intravesical treatments (1) (Grade A)
– Initial response rates approximately 70–90%, however up to 1/2 of patients will recur
– Response to BCG instillation should be assessed at 3 mo
If no response can give another 6-wk course of BCG vs. proceed to radical cystectomy
Approximately 50% will respond to second course of BCG (1) (Grade B)
Second Line
• Intravesical chemotherapy
– Mitomycin C—an alternative for patients who cannot tolerate BCG
– Valrubicin—an option for poor surgical candidates with BCG-refractory disease
– Gemcitabine
SURGERY/OTHER PROCEDURES
• TURBT—Resection of all visible papillary bladder tumors is essential prior to BCG therapy
• For CIS refractory to intravesical therapy—radical cystectomy
– Disease-specific survival rates excellent if cystectomy performed early (instead of BCG instillation), however 40–50% could be overtreated (4) (Grade A)
ADDITIONAL TREATMENT
Radiation Therapy
No role in treatment of CIS
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Depends on stage of concomitant invasive papillary urothelial lesion
• CIS alone or with NMIBC—high rate of progression to muscle-invasive disease if untreated
– See “Pathophysiology”
– BCG reduces risk of recurrence and progression to muscle-invasive disease
• CIS of prostatic urethra unfavorable (1)
– Prostatic tissue stromal invasion worst prognosis—cystoprostatectomy advised
• Disease-specific survival rates excellent if cystectomy performed early (instead of BCG instillation), however 40–50% could be overtreated (4) (Grade A)
COMPLICATIONS
• BCG toxicity
– Low, but serious risk of systemic BCG infection (BCGosis)—avoid treatment in presence of recent TURBT, hematuria, foley trauma, or urinary tract infection
– Has side effect of dysuria and can be intolerable in some patients
Usually experienced within the first 6 mo of treatment
FOLLOW-UP
Patient Monitoring
At 3 mo patients should have cystoscopy and urine cytology. If negative, this should be repeated every 3 mo × 2 yr, every 6 mo thereafter until year 5 and then yearly (3)
Patient Resources
American Cancer Society—Bladder Cancer http://www.cancer.org/acs/groups/cid/documents/webcontent/003085-pdf.pdf
REFERENCES
1. van der Meijden AP, Sylvester R, Oosterlinck W, et al. EUA guidelines on the diagnosis and treatment of urothelial carcinoma in situ. Eur Urol. 2005;48:363–371.
2. Nese N, Gupta R, Bui MH, et al. Carcinoma in situ of the urinary bladder: Review of clinicopathologic characteristics with an emphasis on aspects related to molecular diagnostic techniques and prognosis. J Natl Compr Canc Netw. 2009;7:48–57.
3. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 2011;59:997–1008.
4. Sylvester R, van der Meijden AP, Witjes JA, et al. High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology. 2005;66(Suppl 1):90–107.
5. Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: Results of a comprehensive literature review and meta-analysis. Urology. 2003;61:109–118.
6. Kausch I, Sommerauer M, Montorsi F, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: A systematic review and cumulative analysis of prospective studies. Eur Urol. 2010;57:595–606.
ADDITIONAL READING
• EAU Guidelines on Non-muscle-invasive (TaT1 and CIS) Bladder Cancer http://www.uroweb.org/gls/pdf/07_Bladder%20Cancer_LR%20II.pdf, Accessed January 28, 2014.
• Guideline for the Management of Nonmuscle Invasive Bladder Cancer: (Stages Ta, T1, and Tis): Update (2007) (Reviewed and validity confirmed 2010). AUA Clinical Practice Guidelines. http//www.auanet.org/content/clinical-practice guidelines/clinicalguidelines.cfm?sub=bc, Accessed November 2013.
See Also (Topic, Algorithm, Media)
• BCG Sepsis/BCGosis
• Bladder Cancer, General
• Bladder Cancer, Intravesical Agents (table)
• Bladder Cancer, Nonmuscle-invasive Bladder Cancer (Ta, T1)
• Bladder Cancer, Urothelial, Metastatic (Clinical and Pathologic N+, M+)
• Bladder Cancer, Urothelial, Muscle Invasive (Clinical and Pathologic T2/T3/T4) (MIBC)
• Bladder Cancer, Urothelial, Superficial Carcinoma In Situ (CIS) (NMIBC) Image 
• Bladder Tumor Algorithm 
• Bladder Tumors, Benign, and Malignant, General
• Bladder Tumors, Benign and Malignant, General Considerations
• Reference Tables: TNM Classification: Urinary Bladder Cancer
CODES
ICD9
233.7 Carcinoma in situ of bladder
ICD10
D09.0 Carcinoma in situ of bladder
CLINICAL/SURGICAL PEARLS
• Urine cytology is the best marker (>90% sensitivity/specificity) for diagnosis of CIS.
• Positive cytology in absence of visible bladder lesions—differential includes CIS bladder, prostatic urethra, or upper tract urothelial carcinoma.
• BCG is the treatment of choice for CIS of the bladder; highest response rate and most durable disease-free rates of all intravesical therapies.
• To prevent systemic complications of BCG do not administer after TURBT until urothelium healed (approximately 2 wk).
• For BCG refractory CIS: A second induction course BCG can be administered vs. proceeding immediately to radical cystectomy.