More than 95% of penile cancers are squamous cell carcinomas (SCCs). There are several recognised subtypes of penile SCC with different clinical features and natural history. Penile SCC usually arises from the epithelium of the inner prepuce or the glans.

Penile cancer incidence varies across the world. In industrialised countries, penile cancer is uncommon, with an overall incidence of around 0.94/100,000 males in Europe and 0.5 in the USA. In contrast, in South America, Southeast Asia and parts of Africa, the incidence is much higher and can account for 1–2% of malignant disease in men.

The annual age-adjusted incidence is 0.7–3.0 in India, 8.3 in Brazil (per 100,000, respectively) and is higher in parts of Africa such as Uganda. In Europe, there is considerable variation across countries. Data from Norway showed an increase in the age-standardised incidence rates in 5-year periods from 2001-2015 compared to the previous periods (0.65/100,000 in 1956–60 vs. 0.91/100,000, in 2011-2015) with an Estimated Annual Percent Change of +0.80%. In the United Kingdom, the age-standardised incidence rate increased 28% between 1993 and 2018.

This trend was seen in age groups from 50–79 years old. Incidence rates remained unchanged for both age extremes (< 50 and > 79 years). Based on 16 cancer registries in France, incidence rates between 2009 and 2011 were 0.59 per 100,000 men (95% CI: 0.50–0.68) and these rates have remained stable since 1989 [16]. In the USA, the incidence of penile cancer is affected by race and ethnicity, with the highest incidence in white Hispanics (1.01), followed by Alaskans and Native American Indians (0.77), African Americans (0.62) and white non-Hispanics (0.51), per 100,000 males, respectively. The overall age-adjusted incidence rate decreased between 1973 and 2002; per decade from 0.84 (1973–1982), to 0.69 (1983–1992), and 0.58 (1993–2002) per 100,000 males, respectively.

An increasing trend, slightly surpassing the previous incidence rates, was described using the Surveillance, Epidemiology and End Result (SEER) 2000–2016 data, showing an estimated annual percent change of +3.5% from 2004-2016. The incidence increases with age, with a peak in the sixth decade but it does occur in younger men. Penile cancer is common in regions with a high prevalence of human papillomavirus (HPV), and approximately one-third to half of cancer cases are attributed to HPV-associated carcinogenesis. There are no reports linking this cancer to human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).

In summary, it seems that a slight increase in incidence is seen in Western/developed countries, most likely caused by higher infection rates of HPV which is a trend also observed in oropharynx carcinoma.

Several risk factors for penile cancer have been identified, such as phimosis, chronic penile inflammation, lichen sclerosus, smoking, ultraviolet A phototherapy, and low socio-economic status, amongst others.

Patient outcome is influenced by clinical and histologic features. United States SEER data from 18 cancer registries indicated an overall 5-year relative survival of 67% with no significant changes when comparing 5-year spans between 2000–2014. Patients with localised disease showed the best outcome with up to 81% 5-year relative survival. Patients with distant metastases have the worst outcomes with only 16% 5-year relative survival. Human papilloma virus infection is the main risk factor for penile cancer. Human papilloma virus deoxyribonucleic acid (DNA) has been identified in intraepithelial neoplasia and invasive penile cancer tissue samples. The HPV virus interacts with oncogenes and tumour suppressor genes (p16, P53, Rb genes).

The rate of HPV-positivity differs between different histological subtypes of penile SCC. Human papilloma virus is a co-factor in the carcinogenesis of some subtypes of penile SCC, while others are not related to HPV. The risk of penile cancer is increased in patients with condyloma acuminata. A SR of 52 studies concluded that the overall HPV prevalence in penile cancer is 50.8% (95% CI: 44.8–56.7).

Among HPV-associated carcinomas, basaloid carcinoma showed the highest prevalence (84%) followed by warty-basaloid carcinoma (75.7%) and warty carcinomas (58.7%). In histologically HPV-independent carcinomas, HPV prevalence was 19.4%. The most frequent HPV genotypes were HPV16 (68.3%, 95% CI: 58.9–77.1), followed by the low-risk HPV6 genotype (8.1%, 95% CI: 4.0–13.7). In early studies, HPV has shown an inconsistent association with prognosis.

In one study, a significantly better 5-year disease-specific survival (DSS) was reported for HPV-positive vs. HPV-negative cases (93% vs. 78%), while no difference in lymph node (LN) metastases and 10-year survival was reported in another study. This variable relationship with outcome remains unexplained but some studies suggested that it can be related to specific treatment and linked to different histologic subtypes. A meta-analysis published in 2018 reported a pooled HR of 0.61 for penile cancer HPV-positive cases, which is in line with head, neck.

Positivity for p16 immunohistochemistry (IHC), a surrogate for HPV activity, showed a prognostic value for DSS (hazard ratio [HR]: 0.45) based on two meta-analyses. Female sexual partners of patients with penile cancer have not been found to have an increased incidence of cervical cancer.

At present, except in a limited number of countries, there is no general recommendation for HPV vaccination in males because of the different HPV-associated risk patterns in penile- and cervical cancer. A meta-analysis showed that the incidence of anal (risk ratio [RR]: 0.42), oral (RR: 0.16), and cervical HPV infections (RR: 0.22) were reduced in vaccinated groups when compared against control groups, indicating that HPV vaccination leads to the prevention of HPV infection.

Human papilloma virus vaccination in males showed more than 50% efficacy against anal intraepithelial lesions but no meaningful estimates were obtained for penile, anal, and head and neck invasive carcinomas.

Since up to 50% of invasive penile carcinomas and 80% of preneoplastic lesions are HPV-associated, HPV vaccination is encouraged. Phimosis is strongly associated with invasive penile cancer, due to associated chronic infections. However, smegma is not a carcinogen. The incidence of lichen sclerosus is relatively high in penile cancer patients but is not associated with adverse histopathological features, including penile intraepithelial neoplasia (PeIN).

Other epidemiological risk factors are cigarette smoking, low socio-economic status, and a low level of education. Neonatal circumcision reduces the incidence of penile cancer; however, it does not seem to reduce the risk of PeIN. The lowest incidence of penile cancer is reported in Israeli Jews (0.3/100,000/year). One matched-pair case-control study reported that the protective effect of neonatal circumcision against invasive penile cancer (OR: 0.41) was much weaker when the analysis was restricted to men without a history of phimosis (OR: 0.79, 95% CI: 0.29–2).