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Bladder
WHO/ISUP classification
Carcinoma in situ
Author: Nat Pernick, M.D. (see Authors page)
Revised: 15 December 2009, last major update - December 2009, UPDATE IN PROGRESS
Copyright: (c) 2002-2009, PathologyOutlines.com, Inc.
Definition
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● 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
Terminology
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● Also known as high grade intraurothelial neoplasia (HG IUN), severe dysplasia (sometimes)
Epidemiology
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● De novo CIS constitutes less than 3% of all urothelial neoplasms, but occurs in 45% with concurrent invasive bladder carcinoma
Sites
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Etiology
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Clinical features
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● 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
● Include its presence in pathology reports
Prognostic factors
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● Multifocality, involvement of prostatic urethra, and response to BCG (J Natl Compr Canc Netw 2009;7:48)
Case reports
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● CIS and coexisting small cell carcinoma with identical p53 mutations (Hum Pathol 2008;39:1258)
Treatment
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● bcg therapy (Eur Urol 2009 Nov 13 [Epub ahead of print]) or intravesical hyperthermia and mitomycin-C (World J Urol 2009;27:319)
● Local resection or total cystectomy
Clinical images
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Gross description (Macroscopy)
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● Flat, grossly erythematous, granular or cobblestone mucosa
● No mass
● May involve large areas of mucosal surface, ureters, urethra
Gross images
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Micro description (Histopathology)
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● Flat lesion composed of cells with large, irregular, hyperchromatic nuclei, prominent nuclear pleomorphism, high N/C ratios, 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 Path 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
Patterns
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● Large cells with pleomorphism, large cells without pleomorphism, small cell, clinging (single layer of atypical cells on denuded urothelium), cancerization of urothelium (pagetoid-Hum Path 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 (AJSP 2001;25:356)
Micro images
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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
CARCINOMA IN SITU, SMALL CELL VARIANT
Clinging pattern
CARCINOMA IN SITU, PAGETOID VARIANT
Involvement of Brunn’s nests
A: H&E
B: diffusely CK20+ throughout urothelial thickness
C: intensely p53+
D: Ki-67+
CARCINOMA IN SITU Partial denudation is characteristic of these lesions #1; #2
CARCINOMA IN SITU In this example, the superficial cell layer is partially preserved
Other images without thumbnails: #1; #2; #3; #4; pagetoid pattern
Cytology description
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● 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 Path 1997;10:976)
Cytology images
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CARCINOMA IN SITU High-grade tumor cells in the urinary cytology.
Most of the cells appear singly or in small groups. Papanicolaou stain. 400X magnification.
Videos
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● YouTube
Positive stains
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● 34betaE12 labels all urothelial layers, compared to only basal labeling in dysplasia (Hum Path 2000;31:745)
● Typical pattern is CK20+, p53+, Ki-67+, CD44- (Mod Path 2003;16:187)
● E-cadherin positive (Hum Path 2002;33:996)
● Strong p16(INK4) staining (Hum Pathol 2008;39:527)
● Frequent HER2+ amplification (Hum Path 1995;26:970)
Negative stains
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Electron microscopy descriptions
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Electron microscopy images
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Molecular / cytogenetics description
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● 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)
Molecular / cytogenetics images
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Differential Diagnosis
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● 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%, AJSP 2001;25:1074)
Additional references
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End of Bladder > WHO/ISUP classification > Carcinoma in situ
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