Progression of urothelial carcinoma in situ of the urinary bladder: a switch from luminal to basal phenotype and related therapeutic implications

The stratification of bladder cancer into luminal and basal tumors has recently been introduced as a novel prognostic system in patient cohorts of muscle-invasive bladder cancer or high-grade papillary carcinomas. Using a representative immunohistochemistry panel, we analyzed luminal and basal marker expression in a large case series (n = 156) of urothelial carcinoma in situ (CIS), a precancerous lesion that frequently progresses to muscle-invasive disease. The majority of CIS cases was characterized by a positivity for luminal markers (aberrant cytokeratin (CK) 20 85% (132/156), GATA3 median Remmele score (score of staining intensity (0-3) multiplied with percentage of positive cells (0-4)): 12, estrogen receptor (ER) β Remmele score > 2: 88% (138/156), human epidermal growth factor receptor 2 (Her2) Dako score 3+ 32% (50/156), Her2 Dako score 2+ 33% (51/156)), and marginal expression of basal markers (CK5/6+ 2% (3/156), CK14+ 1% (2/156)). To further investigate phenotypic stability during disease progression, we compared 48 pairs of CIS and invasive tumors from the same biopsy. A highly significant loss of luminal marker expression (p < 0.001) was observed in the course of progression whereas an increase of basal marker expression (p < 0.01) was noted in the invasive compartment. Importantly, 91% of CIS cases demonstrated a positivity for at least one of the two predictive markers Her2 and ERβ, indicating that the analysis of Her2 and ERβ may help to identify CIS-patient subgroups prone to more efficient targeted treatment strategies. Larger prospective and biomarker-embedded clinical trials are needed to confirm and validate our preliminary findings.

Virchows Archiv : an international journal of pathology. 2018 Apr 13 [Epub ahead of print]

Isabella Barth, Ursula Schneider, Tobias Grimm, Alexander Karl, David Horst, Nadine T Gaisa, Ruth Knüchel, Stefan Garczyk

Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany., Department of Urology, LMU Munich University, Munich, Marchioninistraße 15, 81377, Munich, Germany., Institute of Pathology, LMU Munich University, Munich, Thalkirchner Str. 36, 80337, Munich, Germany., Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. .