Introduction: Penile cancer is not common in developed countries, although it is common in some Latin American countries. It is related to cervical cancer. Therefore, it is important to promote vaccination in young men. Given the clinical/oncological management, there are new treatment proposals based on immunotherapy (IT), which favor organ preservation. Pathology reports must be increasingly strict regarding classification, IHC markers, and therapeutic strategies.

Objectives: To evaluate the perspective on the use of established HPV and IT markers to establish their relevance; to determine the specificity and sensitivity of the markers through IHC focused on the B7 H3 protein.

Materials and methods: 27 penile cancer samples from patients in Paraguay underwent IHC at Bio SB, CA. USA, with 16 markers.

Results: The IHC markers HPV, B7H3, and HSP-27 were highly significant in the relationship between penile cancer and HPV. Based on our results, we recommend further investigation of the B7 homologous protein H3 and its potential as a target in immunotherapy and cancer.

Conclusion: Sample management should be performed by pathologists experienced in the pathogenesis, classification, and therapeutics of penile cancer. The function of B7-H3 as an immunoregulator and its practical use, the degree of involvement of agents and/or cofactors, and the local/systemic immune response remain to be elucidated, making it attractive and promising.