Abstract
BackgroundTherapeutic targeting of the PI3K-AKT-mTOR pathway may benefit patients with advanced penile squamous cell carcinoma (PSCC).ObjectivesTo determine the prevalence of PIK3CA copy number gain and correlate this with the activity status of PI3K-AKT-mTOR pathway in pre-malignant penile intraepithelial neoplasia (PeIN) and invasive PSCC.Materials and methodsArchival tissue blocks were obtained from 58 PeIN and 244 primary PSCC patients treated at St George’s Hospital. PIK3CA copy number status (CNS) was assessed by fluorescence in-situ hybridisation. High-risk HPV DNA was detected with INNO-LiPA assay. p16INK4A, p-AKT and p-mTOR protein expression were assessed using immunohistochemistry (IHC).ResultsIncreased prevalence of PIK3CA copy number gain was seen in PSCC in comparison to PeIN (84/199 (42%) vs. 10/58 (17%); p = 0.0009). Analysis of the p-AKT and p-mTOR revealed a tendency to a more common expression of cytoplasmic p-AKT (p = 0.1318), nuclear p-AKT (p<0.0001) and cytoplasmic mTOR (p = 0.0006) in PeIN than PSCC. A significant association between p-AKT cytoplasmic immunoexpression and PIK3CA CNS (p = 0.0404) was found in PeIN.ConclusionOverall, PIK3CA copy number gain correlated with activation of the PI3K-AKT-mTOR pathway in PeIN and activation of this pathway is primarily involved in early penile carcinogenesis. Based on these results therapeutic targeting of this pathway in advanced PSCC is unlikely to produce significant clinical benefit. Future studies will need to focus on alternative therapeutic targets.
Highlights
Penile squamous cell carcinoma (PSCC), though uncommon with an incidence of less 1 per 100,000 men in Europe and USA [1], poses significant physical and psychological stress to those afflicted [2]
Increased prevalence of PIK3CA copy number gain was seen in PSCC in comparison to penile intraepithelial neoplasia (PeIN) (84/199 (42%) vs. 10/58 (17%); p = 0.0009)
PIK3CA copy number gain correlated with activation of the PI3K-AKT-mTOR pathway in PeIN and activation of this pathway is primarily involved in early penile carcinogenesis
Summary
Penile squamous cell carcinoma (PSCC), though uncommon with an incidence of less 1 per 100,000 men in Europe and USA [1], poses significant physical and psychological stress to those afflicted [2]. With PSCC two distinct patient groups exist, the first a large cohort with a high cure rate (80%) and excellent long-term survival in those with organ-confined disease with no or minimal regional lymph node involvement [2]. The second is a smaller patient cohort with highly aggressive disease with significant propensity to metastasise and poor prognosis [4]. Management of the latter group with aggressive and advanced tumours still remains difficult as most are chemo/ radio-resistant with limited treatment options available when first line options fails [5]. Therapeutic targeting of the PI3K-AKT-mTOR pathway may benefit patients with advanced penile squamous cell carcinoma (PSCC)
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