Urothelial (Transitional Cell) Carcinoma In Situ (including flat hyperplasia and dysplasia)
Definition
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
Immunohistology
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
Grading
Urothelial carcinoma in situ is not graded
It is by definition high grade
Staging
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)
Clinical
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
Metastatic/direct spread of non-bladder adenocarcinomas
Bibliography
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.
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