Abstract
Besides worse prognosis of bladder cancer with squamous differentiation (pure squamous cell carcinoma (SCC) or mixed urothelial carcinoma (UC/SCC)), high-grade non-keratinising squamous differentiation is difficult to identify in haematoxylin–eosin stainings. This study aims to validate routine immunohistochemical markers for squamous differentiation in a larger cohort of patients. Tissue microarrays of 89 pure SCCs and mixed UC/SCCs, 66 urothelial carcinomas (UC), precursor lesions and normal urothelium were stained for cytokeratin (CK) 5/6, CK 5/14, CK 7, CK 20 and uroplakin III. Electron microscopy was performed to confirm the differentiation. Pure SCCs displayed staining throughout the epithelium for CK 5/6 (76.6% (36/47)) and CK 5/14 (95.8% (46/48)), focal staining for CK 7 (28.9% (13/45)) and no staining for CK 20 and uroplakin III (both 0% (0/48)). UCs exhibited a basal or diffuse staining for CK 5/6 (30.2% (16/53)) and CK 5/14 (57.1% (32/56)), focal positivity for CK 7 (83.6% (46/55)), CK 20 (50.9% (29/57)) and uroplakin III (21.8% (12/55)). Each marker discriminated SCC and UC significantly (p < 0.01). A third subgroup rarely showed full epithelial staining for CK 5/6 (14.3% (1/7)) and CK 5/14 (28.6% (2/7)), focal staining for CK 7 (85.7% (6/7)) and no staining for CK 20 and uroplakin III (both 0% (0/7)). Electron microscopy could prove both, SCC and UC characteristics, revealing a transient type. A staining pattern with CK 5/6- and CK 5/14-positivity plus CK 20- and uroplakin III-negativity identified squamous differentiation in bladder tumours and revealed a third type of squamous transdifferentiation.
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References
Ferlay J, Bray F, Pisani P, Parkin DM (2004) GLOBOCAN 2002 cancer incidence, mortality and prevalence worldwide. IARC Cancer Base No 5, version 2.0. IARC, Lyon
Parkin DM (2008) The global burden of urinary bladder cancer. Scand J Urol Nephrol 42(Suppl 218):12–20
Shanks JH, Iczkowski KA (2009) Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics. Histopathology 54:885–900
Erdemir F, Tunc M, Ozcan F, Parlaktas BS, Uluocac N, Kilicaslan I, Gokce O (2007) The effect of squamous and/or glandular differentiation on recurrence, progression and survival in urothelial carcinoma of bladder. Int Urol Nephrol 39:803–807
Lopez-Beltran A, Sauter G, Gasser T, Hartmann A, Schmitz-Dräger BJ, Helpap B, Ayala AG, Tamboli P, Knowles MA, Sidransky D, Cordon-Cardo C, Jones PA, Cairns P, Simon R, Amin MB, Tyczynski JE (2004) Infiltrating urothelial carcinoma. In: 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, pp 93–109
Lopez-Beltran A, Requena MJ, Alvarez-Kindelan J, Quintero A, Blanca A, Montironi R (2007) Squamous differentiation in primary urothelial carcinoma of the urinary tract as seen by MAC387 immunohistochemistry. J Clin Pathol 60:332–335
Lagwinski N, Thomas A, Stephenson AJ, Campbell S, Hoschar AP, Eö-Gabry E, Dreicer R, Hansel DE (2007) Squamous cell carcinoma of the bladder: a clinicopathological analysis of 45 cases. Am J Surg Pathol 31(12):1777–1787
Chu P, Wu E, Weiss LM (2000) Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol 13(9):962–972
Harnden P, Mahmood N, Southgate J (1999) Expression of cytokeratin 20 redefines urothelial papillomas of the bladder. Lancet 353:974–977
Kaufmann O, Volmerig J, Dietel M (2000) Uroplakin III is a highly specific and moderately sensitive immunohistochemical marker for primary and metastatic urothelial carcinomas. Am J Clin Pathol 113(5):683–687
Moll R, Achtstätter T, Becht E, Balcarova-Ständer J, Ittenson M, Franke WW (1988) Cytokeratins in normal and malignant transitional epithelium. Maintenance of expression of urothelial expression features in transitional cell carcinomas and bladder carcinoma cell culture lines. Am J Pathol 132(1):123–144
Reis-Filho JS, Simpson PT, Martins A, Preto A, Gärtner F, Schmitt FC (2003) Distribution of p63, cytokeratins 5/6 and cytokeratin 14 in 51 normal and 400 neoplastic human tissue samples using TARP-4 multi-tumor tissue microarray. Virchows Arch 443:122–132
Harnden P, Southgate J (1997) Cyokeratin 14 as a marker of squamous differention in transitional cell carcinomas. J Clin Pathol 50:1032–1033
Moll R, Löwe A, Laufer J, Franke WW (1992) Cytokeratin 20 in human carcinomas. Am J Pathol 140(2):427–447
Ramos-Vara JA, Miller MA, Boucher M, Roudabush A, Johnson GC (2003) Immunohistochemical detection of uroplakin III, cytokeratin 7, and cytokeratin 20 in canine urothelial tumours. Vet Pathol 40:55–62
Liang F-X, Bosland MC, Huang H, Romih R, Baptiste S, Deng F-M, Wu X-R, Shapiro E, Sun T-T (2005) Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement. JBC 171(5):835–844
Moll R, Wu X-R, Lin J-H, Sun T-T (1995) Uroplakins, specific membrane proteins of urothelial umbrella cells, as histological markers of metastatic transitional cell carcinoma. Am J Pathol 147:1383–1397
Ogawa K, St John M, Luiza de Oliveira M, Arnold L, Shirai T, Sun TT, Cohen SM (1999) Comparison of uroplakin expression during urothelial carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in rats and mice. Toxicol Pathol 27(6):645–651
Wu R-L, Osman I, Wu X-R, Lu M-L, Zhang Z-F, Liang F-X, Hamza R, Scher H, Cordon-Cardo C, Sun T-T (1998) Uroplakin II gene is expressed in transitional cell carcinoma but not in bilharzial bladder squamous cell carcinoma: alternative pathways of bladder epithelial differentiation and tumour formation. Cancer Res 58:1291–1297
Suo Z, Holm R, Nesland JM (1993) Squamous cell carcinomas. An immunohistochemical study of cytokeratins and involucrin in primary and metastatic tumours. Histopathology 23:45–54
Gee JR, Montoya RG, Khaled HM, Sabichi AL, Grossman HB (2003) Cytokeratin 20, AN43, PGDH, and COX-2 expression in transitional and squamous cell carcinoma of the bladder. Urol Oncol 21(4):266–270
Chu PG, Weiss LM (2002) Expression of cytokeratin 5/6 in epithelial neoplasma: an immunohistochemical study of 509 cases. Mod Pathol 15(1):6–10
Achtstätter T, Moll R, Moore B, Franke WB (1985) Cytokeratin polypeptide patterns of different epithelia of the human male urogenital tract: immunofluorescence and gel electrophoretic studies. J Histochem Cytochem 33(5):415–426
Sakamoto N, Tsuneyoshi M, Enjoji M (1992) Urinary bladder carcinoma with a neoplastic squamous component: a mapping study of 31 cases. Histopathology 21:135–141
Acknowledgement
The authors are grateful to Stella Koufou for the sample recruitment and to Marina Molitor as well as Ursula Schneider for the technical support. Furthermore, they like to thank Daniela Smeets, Hiltrud Königs and Rudolf Jung for the excellent sample preparation.
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Gaisa, N.T., Braunschweig, T., Reimer, N. et al. Different immunohistochemical and ultrastructural phenotypes of squamous differentiation in bladder cancer. Virchows Arch 458, 301–312 (2011). https://doi.org/10.1007/s00428-010-1017-2
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DOI: https://doi.org/10.1007/s00428-010-1017-2