Penile Cancer and Advances in Prognostic Factors: TP53 and HPV

Penile cancer is most common in sub-Saharan Africa and Latin America, where it is associated with human papillomavirus (HPV) infection. However it also occurs in high-income countries, where it is more often associated with a genetic mutation.

This text was authored by Natalia Rakislova, a physician specialised in pathological surgery at the Hospital Clínic de Barcelona and Assistant Research Professor at ISGlobal; Jaume Ordi, Research Professor at ISGlobal, and Vima Delgado, Project Manager at ISGlobal.

Penile cancer is a rare malignant tumour. Squamous cell carcinoma is by far the most common cancer affecting the penis. The incidence of penile squamous cell carcinoma has marked geographical variability, with the highest incidence occurring in sub-Saharan Africa and Latin America. This regional variability is due to the exposure of different populations to risk factors for this cancer, including poor hygiene and a higher incidence of inflammatory lesions such as lichen sclerosus, phimosis and HPV infection. HPV-association, better known for its determinant role in other cancers such as cervical, vaginal, vulvar, anal and throat cancers, is also well-established in penile cancer. This is the aspect that aroused the interest of our group, which is focused on HPV-associated cancers.

World incidence of penile squamous cell carcinoma. Nat Rev Dis Prim. 2021;7(1):11-34. https://www.nature.com/articles/s41572-021-00246-5

HPV and Penile Cancer: Differences and Prognosis

The important role played by HPV in the pathogenesis of penile cancer has been confirmed by the World Health Organisation (WHO), which classifies penile squamous cell carcinomas based on HPV status, as it does for cervical, vaginal, vulvar and throat cancers.

There are notable differences between the HPV-associated and HPV-independent penile cancers. HPV-related carcinomas affect men between the ages of 40 and 50, while HPV-independent carcinomas usually occur between the ages of 50 and 70 and are associated with conditions such as phimosis and lichen sclerosus.

There are also marked differences in prognosis because HPV-independent tumours are more aggressive. HPV-independent tumours are the most frequent type of penile cancers in high-income countries, such as Spain, while HPV-associated cancers constitute the vast majority of penile cancers in low- and middle-income countries. This difference was highlighted in a study we published recently in the journal Cancers, comparing the characteristics of penile cancers in patients in Spain and Mozambique.

TP53 Mutation Matters

A recent finding of our group has been that TP53 gene abnormality is an important factor in the carcinogenesis and prognosis of penile squamous cell carcinoma, especially in HPV-independent tumours. In an article published in the American Journal of Surgical Pathology, we correlated HPV and p53 status with prognosis in a very large series of patients with penile squamous cell carcinoma. The aim of the study was to assess the impact of HPV and p53 on prognosis in patients diagnosed and treated for penile cancer in three hospitals in Barcelona (Hospital Clínic de Barcelona, Hospital Vall de Hebron and Fundació Puigvert). The study showed that the presence of a p53 mutation had significant prognostic value: HPV-independent tumours in patients with altered p53 were more aggressive and virtually all the deaths from this cancer occurred in this group of patients.

Our findings have a number of implications: physicians must be particularly careful when diagnosing and treating these patients; p53 testing should be incorporated into the routine evaluation of these cancers; and more intensive treatments should be applied in patients who present HPV-independent cancers with abnormalities in p53 patterns (high-risk patients).