Introduction: Penile squamous cell carcinoma (SCC) is a tumor with a high metastatic potential. In penile SCC_x000D_ the attributable fraction to human papillomavirus (HPV) infection is not well established, and the usefulness of_x000D_ p16INK4a immunohistochemical expression as a surrogate marker of high-risk HPV (hrHPV) infection needs_x000D_ further investigation. There is also very limited data about the role of mTOR signaling pathway in penile SCC_x000D_ carcinogenesis._x000D_ Aims: 1. To provide novel data about the prevalence of HPV infection in a large series of penile intraepithelial_x000D_ neoplasia (PeIN) and invasive penile SCC from a Mediterranean population, correlating the results with the_x000D_ histologic subtype, p16INK4a immunostaining, and prognosis. 2. To assess a possible role of mTOR signaling_x000D_ pathway as potential predictive biomarker of outcome and therapeutic target for penile cancer. 3. To evaluate the_x000D_ role of abnormal p53 expression in penile SCC and correlate it with HPV status and other clinico-pathological_x000D_ data._x000D_ Material and methods: A total of 82 penile SCC were retrospectively included in the study, 69 invasive and 13_x000D_ PeINs. HPV detection was performed by PCR with SPF-10 broad-spectrum primers followed by DNA enzyme_x000D_ immunoassay and genotyping with a reverse hybridization line probe assay. Tissue microarrays were constructed_x000D_ including invasive tumors, PeINs, matched normal tissues, and 8 lymph node metastases. Immunohistochemical_x000D_ staining was performed for p16 INK4a, p53, phosphorylated (p) mTOR, pERK, p4E-BP1, eIF4E and peIF4E. The_x000D_ expression was evaluated using a semiquantitative score on a scale from 0 to 300 (H-score). Statistical analysis_x000D_ was performed using Windows Statistical Package for Social Sciences version 17 (SPSS, Chicago, IL)._x000D_ Results: HPV DNA was identified in 28% of invasive penile SCC and 90% of PeINs. In 80% of cases HPV-16_x000D_ was identified. High-risk HPV was associated with some histologic subtypes (mostly basaloid and warty)._x000D_ Moreover, most hrHPV-positive tumors had an adjacent undifferentiated PeIN. Strong p16INK4a immunostaining_x000D_ correlated with hrHPV infection and undifferentiated PeIN. Both hrHPV-positive and p16INK4a-positive tumors_x000D_ showed a better overall survival without reaching statistical significance. PmTOR, p4E-BP1, eIF4E and peIF4E_x000D_ expression were increased in penile tumors when compared with normal tissues, indicating an activation of_x000D_ mTOR signaling in penile tumorigenesis. Moreover, pmTOR, peIF4E and p53 overexpression were significantly_x000D_ associated with poor outcome (recurrence, metastases and/or disease-specific death). PmTOR and an intense p53_x000D_ expression were associated with HPV-negative tumors._x000D_ Conclusions: Our results give support to the bimodal etiopathogenic hypothesis that distinguishes two different_x000D_ subsets of penile SCC (HPV-related penile SCC and penile SCC nonrelated to HPV). Moreover, most hrHPVpositive_x000D_ penile SCC develop from an undifferentiated hrHPV-positive PeIN. P16INK4a immunostaining may be_x000D_ useful in identifying both etiologically related hrHPV positive tumors and those with better outcome. Activation_x000D_ of mTOR signaling may contribute to tumor progression and aggressive behavior in penile SCC. Targeting_x000D_ mTOR or its downstream signaling targets such as peIF4E may be a valid therapeutic strategy. P53 is an_x000D_ excellent marker of poor outcome.
Penile squamous cell carcinoma: Study of clinicopathological and molecular factors implicated in its pathogenesis and prognosis.
Ferrandiz Pulido, C. (Author). 13 Dec 2013
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis