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Prognostic impact of immunohistochemical classification of bladder cancer according to luminal (Uroplakin III) and basal (Cytokeratin 5/6) markers

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Sources of Funding: none

Introduction

Recent genomic studies suggest that urothelial carcinoma (UC) can be grouped into luminal and basal subtypes. Basal bladder cancers are enriched with squamous features and are associated with worse prognosis. Previously, we reported that Desmocollin2 (DSC2) is an immunohistochemical (IHC) marker of squamous differentiation (SD) in UC, that correlates significantly with advanced tumor stage and poor prognosis. Here, we examined the subtype classification of bladder cancer based on Uroplakin III (UPK3) and Cytokeratin 5/6 (CK5/6) expression.

Methods

Expression of UPK3, CK5/6 and DSC2 was measured by IHC in 57 cases of bladder cancer treated with cystectomy (data set-1:previously reported in IHC of DSC2), which included 39 cases of pure UC and 18 cases of UC with SD. Next, we confirmed the result in the other data set of 77 cases of muscle invasive bladder cancer treated with cystectomy from 2006 to 2015 (data set-2).

Results

In dataset-1, the positivity of UPK3, CK5/6 and DSC2 in pure UC was 46%, 21% and 0%, while the positivity in UC with SD was 0%, 83% and 100%, respectively. CK5/6 expression correlated with DSC2 expression, and UPK3 expression was mutually exclusive of both CK5/6 and DSC2 expression. In addition, the positivity of UPK3 and CK5/6 in papillary tumors was 43% and 14%, respectively, and in flat and non-papillary tumors was 28% and 49%, respectively. In normal urothelium, UPK3 expression was observed only in umbrella cells, while CK5/6 expression was detected only in the basal layer. The intermediate layer showed no staining with either marker. UPK3 positive cases had the most favorable cancer specific survival (CSS at 5 years; 83%), while CK5/6 positive cases had the worst prognosis (55%), and cases negative for both markers had an intermediate prognosis (68%)._x000D_ In dataset-2, the expression of UPK3 and CK5/6 in papillary UC was 57% and 4%, respectively, while expression in flat and non-papillary UC was 11% and 39%, respectively. CSS at 5 years was 95% in UPK3 positive, 49% in CK5/6 positive and 59% in marker-negative cases. _x000D_

Conclusions

While genomic subtyping of UC requires clustering of large datasets derived from an entire cohort of patients, our simple IHC with two markers of luminal and basal differentiation is capable of stratifying prognosis on an individual patient basis. IHC classification of UC lends itself to easy adoption in routine clinical practice.

Funding

none

Authors
Tetsutaro Hayashi
Kazuhiro Sentani
Shinji Kakumoto
Htoo Zarni Oo
Naoya Sakamoto
Kazuaki Mutaguchi
Kohei Kobatake
Keisuke Goto
Shogo Inoue
Jun Teishima
Peter Black
Akio Matsubara
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