Stanford School of Medicine

Surgical Pathology Criteria

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Urothelial (Transitional Cell) Carcinoma In Situ (including flat hyperplasia and dysplasia)


  • Flat non-invasive high grade urothelial neoplasm

Alternate/Historical Names

  • The term Urothelial is preferred over Transitional as is is more specific and includes neoplasms with non-transitional differentiation arising in urothelium
  • High grade and severe dysplasia as well as some moderate dysplasia are included in carcinoma in situ
  • (While non-invasive papillary urothelial neoplasms are technically also in situ, they are not referred to as carcinoma in situ)

Diagnostic Criteria

  • The only clearly significant and reproducible distinction is between carcinoma in situ (CIS) and lesions that fall short of malignancy
    • Essentially, all lesions short of CIS, except perhaps flat hyperplasia, require clinical followup, while CIS justifies intravesical chemotherapy or cystectomy
  • The following non-malignant atypical lesions have been described
    • Flat urothelial hyperplasia
      • Reserved only for markedly thickened urothelium
        • Normal urothelium is 2-4 cells thick when distended, 4-7 if contracted
      • May be seen adjacent to papillary neoplasms
      • No clinical significance has been shown for isolated hyperplasia
    • Reactive atypia is non-neoplastic
      • Acute or chronic inflammation
      • Retention of polarity and orderly maturation
      • Uniform nuclear enlargement
      • Uniform single central nucleolus
      • Fine or vesicular chromatin
      • Mtotic figures may be present but not atypical
      • No progression to neoplasm but inflammation may coexist with neoplasm
    • Dysplasia (low grade intra-urothelial neoplasm)
      • Significant atypia but falling short of CIS
        • Nuclear membrane irregularities
        • Dense, clumped chromatin
        • Nuclei may be 2x size of lymphocytes but few reach 5x size of lymphocytes
      • Loss of polarity
      • Lack of significant inflammation
      • Frequently seen adjacent to carcinoma
      • This diagnosis should be made with great caution in the absence of a conconcurrent or prior urothelial neoplasm
        • This restriction severely limits the utility of this diagnosis
    • Atypia of unknown significance
      • Features compatible with dysplasia (above) but in the presence of significant inflammation or lacking a history of urothelial neoplasm
  • Carcinoma in situ (high grade intraurothelial neoplasm)
    • Cytologically malignant cells
      • Features that if papillary would be diagnosed as high grade urothelial neoplasm
      • Large irregular hyperchromatic nuclei
        • Nuclear membrane irregularities
        • Dense, clumped chromatin
        • ≥25% of nuclei should be large enough to contain ≥5 lymphocyte nuclei
      • Mitotic figures are frequently seen and may be atypical
    • Loss of polarity and disordered maturation
    • Other features may be helpful but not required:
      • Full thickness atypia
      • High nuclear:cytoplasmic ratio
      • Loss of umbrella cell layer
    • Loss of intercellular cohesion may lead to sloughing and denudation
      • This should always prompt close examination
      • Cytologic atypia as above is still required
      • Sloughing may also be seen with inflammatory processes
    • Correlation with bladder wash cytology is very important
      • It is unusual for a biopsy to be positive when the concurrent bladder wash is negative
        • Extra caution should be used in such cases
      • Sampling error may explain the converse situation, when the biopsy is negative with a positive cytology study
        • It may be useful to explain this in the pathology biopsy report
    • Carcinoma in situ is by definition high grade, thus grading is not necessary
      • There is no such thing as low grade CIS
    • Various patterns may be seen (described in Amin & McKenney)
      • Large cell pleomorphic (usual pattern)
      • Large cell monomorphic
        • Nucleli uniformly large and atypical
        • May be deceptive due to lack of pleomorphism
      • Small cell
        • Same large uniformly atypical nuclei but scant cytoplasm
      • Clinging/discohesive with shedding
        • Few cells may be left attached for diagnosis
          • Requires same cytologic features of malignancy
          • Correlation with bladder wash cytology is especially important
        • Inflammation may also lead to discohesion and shedding
      • Pagetoid cancerization
      • Undermining cancerization
      • Glandular differentiation may rarely be seen
      • These types do not need to be reported
        • Their recognition may aid in diagnosis

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates: 10/20/12

Supplemental studies


  • CK20
    • Stains only umbrella cells in normal and reactive urothelium
    • May stain diffusely in dysplasia
    • Stains diffusely in most cases of CIS
  • p53
    • Negative in normal and reactive urothelium
    • May stain diffusely in dysplasia
    • Stains diffusely in most cases of CIS
  • CD44
    • Only basal cells stain in normal and hyperplastic
    • Diffuse or patchy staining in reactive and atypia of unknown significance
    • Negative in dysplasia and CIS
  • Utility of markers is limited by lack of characterization of borderline cases
  • We do not use these markers routinely for diagnosis of CIS

Differential Diagnosis

  • Principal differential diagnosis is vs reactive atypia
Urothelial Carcinoma In Situ Reactive Atypia
Cytologically malignant Generally more uniform atypia, not clearly malignant
≥25% of nuclei ≥5x size of lymphocytes Nuclei only 2x size of lymphocytes
Nucleoli if present usually variable, excentric Nucleoli usually uniform and centrald
Inflammation variably present Inflammation always present, acute or chronic
Mitotic figures may be atypical Mitotic figures may be frequent but not atypical
Both may be either hyperplastic or largely denuded due to sloughing
  • Other diagnoses are generally resolved with additional sections, obtaining history of treatment, or careful attention to detail
    • Radiation may result in full thickness atypia
      • Frequently results in bizarre multinucleated cells
      • Cytoplasm frequently vacuolated
      • Stroma radiation fibroblasts may be present
    • Intravesicular chemotherapy may produce markedly atypical surface epithelium
      • Deeper cells are not affected
    • Treated papillary carcinoma may lose tops of papillae resulting in largely flat lesions
      • Most often seen with Mitomycin C and Thiotepa

Grading / Staging


  • Urothelial carcinoma in situ is not graded
    • It is by definition high grade


  • Urothelial carcinoma in situ is staged as Tis
    • (While non-invasive papillary urothelial neoplasms are technically also in situ, they are staged as Ta and are not referred to as carcinoma in situ)


  • Primary hyperplasia, reactive atypia and atypia of unknown significance have not been shown to progress to malignancy
  • The proper treatment and follow up for primary dysplasia is not clear
    • There are widely varying reports of behavior for this diagnosis
      • Some studies find 15-20% progression to CIS or carcinoma
    • To some extent this may be due to poor agreement in making the diagnosis
  • About 50% of patients with CIS will progress to invasive carcinoma within five years

Classification / Lists

Flat Lesions of the Urinary Bladder

Papillary Lesions of the Urinary Bladder

Subtypes of High Grade Urothelial Carcinoma

Inverted Lesions of the Urinary Bladder

Glandular Lesions of the Urinary Bladder


  • Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder and Related Urinary Structures, Atlas of Tumor Pathology, AFIP Fourth Series, Fascicle 1, 2004
  • Eble JN, Sauter G, Epstein JI, Sesterhenn IA eds. World Health Organization Classification of Tumors. Pathology and genetics of tumors of the Urinary System and Male Genital Organs. IARC Press: Lyon 2004.
  • Amin MB, McKenney JK. An approach to the diagnosis of flat intraepithelial lesions of the urinary bladder using the World Health Organization/ International Society of Urological Pathology consensus classification system. Adv Anat Pathol. 2002 Jul;9(4):222-32.
  • McKenney JK, Gomez JA, Desai S, Lee MW, Amin MB. Morphologic expressions of urothelial carcinoma in situ: a detailed evaluation of its histologic patterns with emphasis on carcinoma in situ with microinvasion. Am J Surg Pathol. 2001 Mar;25(3):356-62.
  • Epstein JI. Diagnosis and classification of flat, papillary, and invasive urothelial carcinoma: the WHO/ISUP consensus. Int J Surg Pathol. 2010 Jun;18(3 Suppl):106S-111S.
  • Humphrey PA. Urothelial carcinoma in situ of the bladder. J Urol. 2012 Mar;187(3):1057-8.
  • McKenney JK, Desai S, Cohen C, Amin MB. Discriminatory immunohistochemical staining of urothelial carcinoma in situ and non-neoplastic urothelium: an analysis of cytokeratin 20, p53, and CD44 antigens. Am J Surg Pathol. 2001 Aug;25(8):1074-8.
  • Miyamoto H, Miller JS, Fajardo DA, Lee TK, Netto GJ, Epstein JI. Non-invasive papillary urothelial neoplasms: the 2004 WHO/ISUP classification system. Pathol Int. 2010 Jan;60(1):1-8.
  • Samaratunga H, Makarov DV, Epstein JI. Comparison of WHO/ISUP and WHO classification of noninvasive papillary urothelial neoplasms for risk of progression. Urology. 2002 Aug;60(2):315-9.
  • Williamson SR, Lopez-Beltran A, Montironi R, Cheng L. Glandular lesions of the urinary bladder:clinical significance and differential diagnosis. Histopathology. 2011 May;58(6):811-34.


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