Cancer of the Penis

Epidemiology

Penile cancer is exceedingly rare in North America and Scandinavia and is far more prevalent in South America, Asia, and Africa. In the United States, approximately 2000 men were diagnosed with approximately 300 associated deaths in 2016. In industrialized nations, penile cancer affects between 1 and 9 per 1,000,000 men. In less developed nations such as sub-Saharan Africa and parts of South America, it represents as many as 10% of male malignancies. Incidence in Africa and Asia ranges between 10% and 20%. Possibly because of improving worldwide health conditions and increasing prevalence of circumcision, the incidence of penile cancer has been decreasing in recent years.

Etiology and Biologic Characteristics

There are many cited risk factors for penile cancer. Risk factors include phimosis, human papillomavirus (HPV) infection, genital warts, cigarette smoking, and trauma or balanitis. Twenty-five percent to 60% of penile cancer cases are associated with phimosis. Phimosis is a known risk factor for invasive carcinoma (odds ratio [OR], 16), but not for carcinoma in situ (CIS). Circumcision performed in the first year of life virtually eliminates the risk of invasive penile carcinoma. Older studies have shown that the risk of penile cancer is the same in men who are uncircumcised as in those circumcised after the first year of life. Cigarette smoking is a risk factor (OR, 1.44), especially in long-term smokers or those who smoke more than 10 cigarettes daily (OR, 2.1). Chewing tobacco (OR, 3.1) is a greater risk than cigarette smoking. History of trauma is a risk factor for CIS and invasive cancer, as is balanitis. Likewise, men with a personal history of anal or genital warts are at elevated risk for the disease (OR, 3.7).

In recent years, infection with HPV has been a subject of investigation as a major etiologic factor for penile cancer. HPV is highly prevalent worldwide in men, with up to 70% of all males infected. A systematic review of studies evaluating HPV prevalence in penile cancers found that 48% of evaluated tumors tested positive for HPV. Only 10% of men are infected with known oncogenic strains of HPV, however. Men with invasive penile cancer have a 24% to 62% rate of infection with high-risk HPV, whereas controls have a 12% rate. As many as 95% of penile cancers are associated with HPV-16 infection.

Evidence suggests that oncogenesis of penile cancer falls into two pathways—HPV associated and non–HPV associated. HPV-associated tumors are much more likely to be of the basaloid or warty subtypes. These tumors are similar in nature to tumors arising from the mucosa of the anal and oropharyngeal regions and most frequently occur on the glans. Non–HPV-associated cancers tend to be keratinizing squamous cell carcinoma (SCC), similar to what is seen on nongenital skin and tends to be well differentiated. Up to 30% of these tumors may contain HPV DNA, but it is uncertain if HPV plays an etiologic role in these tumors. Non–HPV-associated cancers tend to be associated with chronic inflammatory skin conditions such as lichen sclerosus.

Little is known about molecular alterations common in penile carcinoma owing to its rarity and its association with concomitant infection and inflammation. Observations have been made regarding certain DNA copy number gains (8q24, 16p11-12, 20q11-13, 22q, 19q13, 5p15) and deletions (13q21-22, q21-32). Increasing aneuploidy appears to be associated with a high risk of invasive cancer. E6, the oncogenic product of HPV, is known to bind to p53, causing suppression of its normal cell cycle inhibitory function. This results in increased cell proliferation, decreased apoptotic control, and loss of differentiation. Accordingly, the relationship of p53 expression to penile cancer prognosis has been investigated with contradictory results. Alternately, a positive or negative relationship between p53 expression and HPV infections has been seen. It has been suggested that late alteration of p53 may be associated with disease progression and metastasis.

Other HPV-associated pathways and genes that have been investigated include p16 ^INK4a /cyclin D/retinoblastoma, c-ras, MYC, PIK3CA, PTEN, BRAF, HRAS, KRAS, and NRAS. The general observation is that larger and more advanced tumors are associated with mutations in more of these pathways. HPV-18 has been found in metastatic tumor linked to mutations in p53 and c-ras. DNA methylation has been evaluated in penile cancer and hypermethylation found in DAPK, HIT, MGMT, p14ARF, p16INK4a, RAR-B, RASSF1A, and RUNX3. In another study, methylation of TSP-1 was associated with poorly differentiated tumor and increased risk of vascular invasion.

Research has identified the presence of programmed death ligand 1 (PD-L1) in penile cancer. In these studies, PD-L1 expression was significantly increased in tumors negative for high-risk HPV infection.

Prevention and Early Detection

Penile cancer is a disease with a relatively low prevalence in the industrialized world, so formal preventive programs have not been enacted. Discussion regarding prevention of penile cancer centers around the role of neonatal circumcision and prevention of oncogenic HPV.

Circumcision is a divisive topic in the medical literature, with strong proponents both for and against routine circumcision. Many political authorities are withdrawing public funding for circumcision based on evaluation of cost-effectiveness in preventing disease. Also, opponents of circumcision argue that the procedure is primarily cosmetic and is performed without the assent of the patient. A meta-analysis has suggested a significant decrease in the likelihood of development of invasive penile cancer in patients who underwent childhood or adolescent circumcision (OR, 0.33). Also, regardless of the direct goal of preventing penile cancer, circumcision reduces the transmission of high-risk HPV by up to 35% and of human immunodeficiency virus (HIV) by up to 60%.

Although HPV appears to have a significant role in the development of penile malignancy, vaccination of men against HPV for penile cancer prevention is considered unreasonable because of the low incidence of penile cancer. Many other cancers in both men and women, however, are associated with high-risk HPV, and some groups have proposed increased efforts to vaccinate against HPV on the basis of herd immunity. In 2011, the Advisory Committee on Immunization Practices (ACIP) recommended immunization of all boys of age 11 or 12 with the HPV4 vaccine on the basis of risk reduction for anal, pharyngeal, and penile cancer and to prevent genital warts. In a 2015 update, the ACIP recommended routine male vaccination at age 11 or 12 with either quadrivalent or 9-valent vaccine, and also for males aged 13 to 21 who have not completed a three-dose cycle. Males 22 to 26 may be vaccinated, particularly immunocompromised men and men who have sex with men.

Pathology and Pathways of Spread

There are many dermatologic processes that manifest on the penis, most of which are associated with benign disease. It is a particular challenge to health care providers to be vigilant for a low-incidence disease such as penile cancer in the background of a diverse range of visible dermatologic manifestations that may be benign. It should be recognized by providers that skin lesions of the penis can be quite disturbing to patients, but at the same time embarrassment often causes them to avoid seeking treatment. Therefore when a patient has a complaint about a penile skin lesion, a diligent effort should be made for diagnosis.