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Hum Pathol. 2019 Jul 4. pii: S0046-8177(19)30121-2. doi: 10.1016/j.humpath.2019.07.002. [Epub ahead of print]

The co-expression of fibroblast activation protein (FAP) and basal-type markers (CK 5/6 and CD44) predicts prognosis in high-grade invasive urothelial carcinoma of the bladder.

Author information

1
Service of Medical Oncology, University Hospital Puerta del Mar, Cádiz, Spain.
2
Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV-EHU), Leioa, Spain; Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, Barakaldo, Spain.
3
Service of Pathology, University Hospital of Getafe, Getafe, Madrid, Spain.
4
Service of Urology, University Hospital of Getafe, Getafe, Madrid, Spain.
5
Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, Barakaldo, Spain; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
6
Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, Barakaldo, Spain; Ikerbasque, The Basque Foundation for Science, Bilbao, Spain.
7
Biomarkers in Cancer Unit, Biocruces-Bizkaia Institute, Barakaldo, Spain; Service of Pathology, Cruces University Hospital, Barakaldo, Spain; Department of Medical-Surgical Specialties, Faculty of Medicine and Nursing, University of the Basque Country (UPV-EHU), Leioa, Spain. Electronic address: jilpath@gmail.com.
8
Service of Urology, University Hospital of Getafe, Getafe, Madrid, Spain; Clinical Department, Faculty of Biomedical Sciences, European University of Madrid, Laureate Universities, Madrid, Spain.

Abstract

High-grade urothelial carcinoma (UC) of the bladder is a heterogeneous disease with dismal prognosis. Bladder tumors with basal phenotype are intrinsically aggressive and morphological parameters that define disease staging remain main prognosticators. We intend to evaluate the role of cancer associated fibroblasts (CAF) in the prognosis of bladder cancer and its association with basal and luminal phenotypes. Clinical and pathological parameters, including the immunohistochemical expression of fibroblast activation protein (FAP) and markers of basal (CK5/6, CD44) and luminal (CK20, GATA3) phenotypes, have been investigated in a series of 121 patients with UC of the bladder treated by radical cystectomy with lymph node dissection and their implication in long-term cancer-specific survival has been evaluated. A cytoplasmic immunostaining of FAP in CAFs implies worse disease-specific survival (HR=1.68; P=.048). FAP expression is associated with tumor staging (P<.0001), with best discrimination at T2a/T2b level, and with negative expression of markers of luminal phenotype, such as CK20 (P<.0001) and GATA3 (P=.005). In the multivariate analysis, simultaneous expression of FAP, CK5/6 and CD44 is a strong prognosticator of disease-specific survival (HR=2.3; P=.001), together with nodal invasion (HR=3.47; P<.0001) and bladder infiltration up to deep muscle or beyond (HR=2.47; P=.02). There is not association between positive FAP expression in primary tumor and nodal disease (P=.22). FAP expression in CAFs favors tumor invasion in high-grade invasive UC of the bladder with basal phenotype. This new immunohistochemical marker could be added to the routine immunohistochemical protocol to predict clinical behavior in these patients.

KEYWORDS:

Basal Phenotype; Bladder Neoplasia; Fibroblast Activation Protein; Prognosis; Survival; Transitional Cell Carcinoma; Tumor Microenvironment

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