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WHO/ISUP classification

Carcinoma in situ

Reviewers: Sean Williamson, M.D. (see Reviewers page)
Revised: 23 June 2012, last major update June 2012
Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.


● Also called high-grade intraurothelial neoplasia (HG IUN), severe dysplasia
● By definition a flat lesion without true papillary architecture
● Often seen in conjunction with invasive carcinoma
● May shed atypical cells into urine, making cytology valuable for diagnosis (although false positives may occur with bladder contamination)
● Primary upper urinary tract involvement is rare in comparison to urinary bladder CIS
● Bladder CIS is a risk factor for recurrence in the upper urinary tract in some settings; however, utility of frozen section evaluation of ureter margin is unclear (presence of “skip” lesions and limited implications on survival and local morbidity, Cancer 2006;107:2167, J Urol 1997;158:768)

Micro description

● Flat lesion composed of increased, normal or decreased number of cell layers
● Cytologic features include nuclear enlargement, irregular nuclear contours, hyperchromasia, mitotic figures
● Atypia may not be full thickness (see Patterns below)
● In bladder, nuclear area 5x 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
● Note: high-grade non-invasive papillary lesions (pTa) are NOT referred to as carcinoma in situ (pTis) to avoid confusion

Micro images

Left two images: CIS
Right middle: black arrow-normal urothelium; red arrow-CIS
Right: black arrow - denuded urothelium adjacent to CIS


● Large cell CIS characterized by abundant cytoplasm
● Small cell CIS (scant cytoplasm and sometimes prominent nucleoli – does not connote neuroendocrine differentiation)
● Clinging CIS (or “denuding cystitis” in the bladder – rare attached atypical cells in background of denuded urothelium)
● Cancerization of urothelium (pagetoid, undermining or overriding growth – may have preservation of umbrella cell layer)
● Pattern need not be included in surgical pathology report
● Associated 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 as isolated single cells with or without desmoplasia (Am J Surg Pathol 2001;25:356)

Positive stains

● Typical pattern is CK20+, p53+, CD44-
● E-cadherin positive (Hum Pathol 2002;33:996)

Differential diagnosis

Denuded urothelium:
● Extensively denuded epithelium is often seen in CIS (“clinging CIS” or “denuding cystitis”)
● However residual malignant cells required for diagnosis
● Deeper sectioning of tissue block or examination of von Brunn nests may be helpful if epithelium is denuded

Reactive atypia:
● Patchy CK20 in umbrella cells only
● p53 weak/negative
● CD44 diffusely or focally positive vs. CIS with intense CK20 and p53 positivity in 81% and 57% of cases; CD44 negative in all cases (Am J Surg Pathol 2001;25:1074)

End of Ureters > WHO/ISUP classification > Carcinoma in situ

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