Analysis of papillary urothelial carcinomas of the bladder with grade heterogeneity: supportive evidence for an early role of CDKN 2A deletions in the FGFR 3 pathway

• Published in: Histopathology Vol. 70; no. 2; pp. 281 - 289
• Main Authors: Downes, Michelle R, Weening, Berber, van Rhijn, Bas W G, Have, Cherry L, Treurniet, Kilian M, van der Kwast, Theodorus H
• Format: Journal Article
• Language: English
• Published: 01.01.2017
• ISSN: 0309-0167; 1365-2559
• DOI: 10.1111/his.13063

Aims The dual pathway model of urothelial carcinogenesis does not fully explain grade and stage progression in patients with initial low‐grade, non‐muscle invasive urothelial carcinomas. Fibroblast growth factor receptor 3 ( FGFR 3 ) mutations are a hallmark of the low‐grade pathway, with subsequent progression to muscle invasion occurring when FGFR 3 mutant tumours exhibit a homozygous CDKN 2A deletion. We hypothesized that grade heterogeneity represents the morphological manifestation of molecular changes associated with disease progression. Methods and results We identified retrospectively 29 non‐muscle invasive papillary urothelial carcinomas with grade heterogeneity (<20% high grade). Nineteen had sufficient material for immunohistochemistry, CDKN 2A fluorescence in‐situ hybridization and FGFR 3 mutation analysis. Eight pure low‐grade urothelial carcinomas ( PLGUC ) were also analysed. FGFR 3 mutation was seen in 10 of 19 cases. A homozygous CDKN 2A deletion was identified in the low‐grade areas of eight of nine (88%) technically suitable FGFR 3 mutant cases (including five pT a cancers), in five of nine FGFR 3 wild‐type carcinomas and in none of the PLGUC . Increased MIB ‐1 expression was seen in low‐grade areas of 12 of 19, in high‐grade areas of 17 of 19 cases with grade heterogeneity and in none of the PLGUC . p53 staining was increased in one of 19 low‐grade and seven of 19 high‐grade areas. Conclusion Our findings show that grade heterogeneity in urothelial carcinoma is characterized by increased MIB ‐1 labelling, and particularly in the FGFR 3 mutant pathway, with homozygous deletions of CDKN 2A in low‐ and high‐grade areas. This would suggest that CDKN 2A deletion occurs prior to grade progression and supports the current convention to assign the highest grade to urothelial carcinomas with grade heterogeneity.