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Virchows Arch. 2018 Nov;473(5):607-614. doi: 10.1007/s00428-018-2404-3. Epub 2018 Aug 11.

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor.

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Department of Urology, Faculty of Medicine, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil.
CIPE - A.C. Camargo Cancer Center, São Paulo, Brazil.
Department of Surgery and Orthopedics and Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, UNESP, Botucatu, São Paulo, Brazil.
Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos and Diagnósticos da América (DASA), São Paulo, São Paulo, Brazil.
Department of Urology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Beriderbakken 4, 7100, Vejle, Denmark.


Androgen receptor (AR) is a member of the steroid and nuclear family receptor that acts as transcription factor. AR signaling plays pivotal role in the development and progression of prostate cancer. However, the role of AR in penile cancer (PeCa) is poorly explored. Our previous molecular studies unveiled frequent AR mRNA loss in PeCa, which was further predicted as a major driver alteration in this neoplasm. Herein, we assessed the AR protein expression in 59 usual PeCa tissues and 42 surrounding normal tissues (SNT) by immunohistochemistry using a tissue microarray. In a paired analysis, we found a total absence of nuclear AR expression in PeCa while 95.2% of SNT samples presented strong nuclear AR expression (P < 0.001). Interestingly, 17 of 42 PeCa presented weak or moderate cytoplasmic AR staining, contrasting with 5 of 42 SNT (P = 0.008). Increased levels of AR cytoplasmic expression were related with poor prognosis features including advanced clinical staging (P = 0.044), compromised surgical margins (P = 0.005), and pathological inguinal node status (P = 0.047). Furthermore, AR cytoplasmic expression was also related with shorter overall survival (P = 0.032). In conclusion, the frequent loss of nuclear AR protein levels suggests a potential function in PeCa development. Based on this result, the androgen deprivation therapy is not indicated for PeCa patients. In addition, the AR cytoplasmic expression found in a significant number of cases (40.5%) showed prognostic value and pathways activated by the non-genomic AR signaling may represent a promising therapeutic strategy.


Androgen receptor; Cytoplasmic AR expression; Immunohistochemistry; Penile carcinoma

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