Urothelial neoplasms-noninvasive
Carcinoma in situ

Author: Monika Roychowdhury, M.D. (see Authors page)

Revised: 12 July 2016, last major update December 2014

Copyright: (c) 2003-2016,, Inc.

PubMed Search: Bladder carcinoma in situ [title]
Cite this page: Carcinoma in situ. website. Accessed October 25th, 2016.
Definition / General
  • 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
Case Reports
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

Images hosted on Pathout server:

Case of the Week #331:

Various images

Additional images

Images hosted on other servers:

Low power (H&E and CK20)

Markedly atypical cells

Clinging pattern

Involvement of von Brunn nests

Pagetoid involvement


Loss of polarization, H&E

Broadened urothelium, H&E

Narrowed urothelium, H&E

Pagetoid pattern, H&E

Cytology Description
  • 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)

Positive Stains
Molecular / Cytogenetics Description
  • 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)