Immunology, imaging and treatment of advanced penile carcinoma

Penile cancer is introduced in chapter 1. Chapter 2 and 3 describe immunohistochemical studies. First, we looked at PD-L1 expression in different areas and patterns in the tumour-microenvironment. Forty-eight percent of the tumours expressed PD-L1, significantly associated with hrHPV- status. A marginal expression pattern was favourable in terms of lymph node metastases (LNM) and survival. Opposingly, diffuse PD-L1 expression had unfavourable associations. In chapter 3, more parameters were added: T cells, myeloid cells, and HLA class I. Upon multivariable analysis, hrHPV- and diffuse PD-L1+ tumours were significantly associated with poor DSS and only PD-L1+ with LNM. Whether penile tumours respond well to immunotherapy needs to be studied in clinical trials. Chapters 4 and 5 review staging and imaging of penile cancer, in particular the role of FDG-PET/CT, that was further studied in a retrospective cohort in chapter 6. There, FDG-PET/CT showed a high sensitivity (85%) and negative predictive value (90%) for staging pelvic LNM, and for detection of distant metastases a high positive predictive value (93%). With these properties, PET/CT can aid earlier detection and treatment of advanced penile carcinoma. Treatment is evaluated in the last part. Chapters 7 describes surgical and oncological outcomes in fifteen patients with locoregionally advanced penile SCC (LAPSCC) requiring reconstructive surgery with vascularized flaps. Thirteen experienced wound complications including five severe complications. The cure rate was only 27%, indicating that extensive surgery needs to be carefully thought trough beforehand. Chapter 8 provides preliminary results of a chemoradiationtherapy (CRT) trial for LAPSCC. With median follow-up 27 months 2-year progression free survival was 32%, and overall survival was 52%. CRT was generally well-tolerated although 40% experienced severe toxicity during therapy or follow-up. So far, CRT seems a feasible treatment alternative for LAPSCC. Chapter 9 provides a reflection on the findings of the research presented in this thesis and places our results in a larger perspective