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Urothelial neoplasms-noninvasive

Carcinoma in situ

Reviewer: Monika Roychowdhury, M.D., University of Minnesota Medical Center (see Reviewers page)
Revised: 16 May 2011, last major update May 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.


● Flat lesion composed of cells in mid to upper epithelium with high cytologic grade
● By definition, no invasion into lamina propria
● Note: high grade non-invasive papillary lesions are NOT designated carcinoma in situ to avoid confusion


● Also known as high grade intraurothelial neoplasia (HG IUN), severe dysplasia (sometimes)


● De novo CIS constitutes less than 3% of all urothelial neoplasms, but occurs in 45% with concurrent invasive bladder carcinoma

Clinical features

● Symptoms are similar to cystitis; hematuria is common
● 20-80% of CIS patients develop invasive disease if left untreated
● Confers poorer prognosis in patients with coexisting noninvasive papillary urothelial carcinoma
● Often involves urothelium in other areas of GU tract
● Associated with multifocal high grade invasive carcinoma
● Presence should be included in pathology reports

Prognostic factors

● Multifocality, involvement of prostatic urethra, and response to bCG (J Natl Compr Canc Netw 2009;7:48)

Case reports

● CIS and coexisting small cell carcinoma with identical p53 mutations (Hum Pathol 2008;39:1258)


● bcg therapy (Eur Urol 2010;57:410) or intravesical hyperthermia and mitomycin-C (World J Urol 2009;27:319)
● Local resection or total cystectomy

Gross description

● Flat, grossly erythematous, granular or cobblestone mucosa
● No mass
● May involve large areas of mucosal surface, ureters, urethra

Micro description

● Flat lesion composed of cells with large, irregular, hyperchromatic nuclei, prominent nuclear pleomorphism, high N/C ratio, mitotic figures in mid to upper epithelium
● Atypia may not be full thickness
● Epithelium is often denuded
● Nuclear size is 5x that of lymphocytes vs 2x lymphocytes for normal urothelium (Hum Pathol 2001;32:997)
● Also (but less important) loss of polarity, nuclear crowding, irregular thickness of urothelium
● Cells are not cohesive, leading to shedding into urine
● Occasionally present in prostatic ducts, spreads by intramucosal extension
● Note: high grade non-invasive papillary lesions are NOT designated as carcinoma in situ to avoid confusion


● Large cells with pleomorphism, large cells without pleomorphism, small cell, clinging (single layer of atypical cells on denuded urothelium), cancerization of urothelium (pagetoid - Hum Pathol 1993;24:1199, undermining or overriding)
● Pattern need not be included in surgical pathology report
● Microinvasion (2 mm or less) demonstrates invasive cells with retraction artifact mimicking vascular invasion (77% of cases of microinvasion)
● Also nests or irregular cords, rarely invades as isolated single cells with or without desmoplasia (Am J Surg Pathol 2001;25:356)

Micro images

Series of images (images 2-9)

Lack of maturation and detachment of the tumor cells on the superficial portion

Markedly atypical cells

Small cell pattern

Clinging pattern

Carcinoma in situ: partial denudation is characteristic of these lesions

Carcinoma in situ, pagetoid variant

Involvement of Brunn’s nests

Carcinoma in situ in the urethral stump: multiple sections of the urethrectomy specimen are usually required to detect the focal carcinoma in situ

Carcinoma in situ undermining adjacent urothelium: the interface between neoplastic and normal urothelium is indicated by the arrows

Carcinoma in situ: in this example, the superficial cell layer is partially preserved

H&E, CK20, p53 and Ki-67

Other images: #1; #2; #3; #4; pagetoid pattern


● Cytology is 95% sensitive for carcinoma in situ
● Nuclear changes of carcinoma with minimal pleomorphism
● Numerous high-grade neoplastic cells
● Relatively clean background
● Image analysis of bladder wash cytology may be comparable to “expert” cytologic review (Mod Pathol 1997;10:976)

Cytology images

Carcinoma in situ in the urethral stump: these lesions are usually detected in cytologic specimens such as this, where the tumor cells have hyperchromatic, eccentric nuclei and relatively high nuclear-cytoplasmic ratios

Carcinoma in situ: high-grade malignant tumor cells are readily identified in most cytologic specimens



Positive stains

● Keratin 34betaE12 labels all urothelial layers, compared to only basal labeling in dysplasia (Hum Pathol 2000;31:745)
● Typical pattern for CIS is CK20+, p53+, Ki-67+, CD44- (Mod Pathol 2003;16:187)
● E-cadherin positive (Hum Pathol 2002;33:996)
● Strong p16(INK4) staining (Hum Pathol 2008;39:527)
● Frequent HER2+ amplification (Hum Pathol 1995;26:970)


● Monoclonal with aneuploid DNA and more abnormal microsatellites than corresponding invasive carcinoma, if present (Hum Pathol 2009;40:988)
● Has somatic mismatch repair protein down-regulation and accumulation of tumor suppressor gene microsatellite abnormalities
● Molecular pattern of CIS is divergent from coexistent muscle invasive urothelial carcinoma
● Deletion of 9p21 or polysomy of #9 (Hum Pathol 2008;39:527)

Differential diagnosis

Denuding cystitis: cells may look malignant
Dysplasia: less severe atypia although distinction may be difficult
Post-topical therapy for high grade urothelial carcinoma: still has capillaries
Radiation effect: cells still cohesive, may have distinctive nuclear borders, may resemble pagetoid variant of CIS
Reactive atypia: less pleomorphic nuclei than CIS; patchy CK20 in umbrella cells only, p53 weak/negative, CD44 diffusely or focally positive vs. CIS which is intensely CK20+ (81%), p53+ (57%), CD44- (100%, Am J Surg Pathol 2001;25:1074)

Additional references


End of Bladder > Urothelial neoplasms-noninvasive > Carcinoma in situ

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