Different immunohistochemical and ultrastructural phenotypes of squamous differentiation in bladder cancer

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.

Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup

“…Tissue microarrays (TMA) of previously characterized formalin-fixed, paraffin-embedded squamous differentiated bladder cancer specimens were used [25]. The residual TMAs contained 34 cases of pure squamous cell carcinomas (5 pT2, 24 pT3, 5 pT4) and 39 cases with mixed squamous and urothelial differentiation (5 pT2, 31 pT3, 3 pT4).…”

Normal and neoplastic urothelial stem cells: getting to the root of the problem

“…34 In a study that analyzed 48 pure bladder SCCs and 56 mixed (SCC and urothelial carcinoma) tumours, 96% of pure SSCs stained strongly positively for CK5 and CK14 markers and negative for CK20. 67 By comparison, 86–93% of mixed tumours stained strongly positive for CK5 and CK14, negative for uroplakin, and rarely positive for CK20. 67 Another study analyzed 20 micropapillary variants of urothelial carcinomas and demonstrated that these cancers stained positive for both 343E12 (basal cell marker) and CK20.…”

Consequences of Disrupted Notch Signaling in Bladder Cancer

“…These include how its effects on normal urothelial cell and tissue differentiation are mediated, which ligands of the NOTCH receptors are active in the normal urothelium and how they change in cancers, and whether NOTCH1 and NOTCH2 mutations have equivalent consequences. Specifically, Notch signaling deserves closer investigation in the various forms of squamous cell carcinoma of the bladder [10]. Importantly, further studies in larger cohorts are required to evaluate the impact of Notch pathway inactivation on patient prognosis and on response to targeted and conventional chemotherapy in bladder cancer.…”