Mariela R. Pow-Sang, MD, Victor Benavente, MD, Julio E. Pow-Sang, MD, Carlos Morante, MD, Luis Meza, MD, Mark Baker, MD, and Julio M. Pow-Sang, MD


Cancer Control. 2002;9(4) 

In This Article


The most important etiologic factor of penile cancer is the presence of an intact foreskin. Penile cancer is rarely seen in Jewish individuals, who are circumcised at birth.[6] In the United States, the risk of this disease in uncircumcised men is 3-fold higher than that of circumcised men and approaches the rate seen in some underdeveloped nations.[7]

Maden et al[7] reported a study of 110 men with penile cancer and 355 control subjects. The risk of penile cancer was 3.2 times greater among uncircumcised men compared with men circumcised at birth and 3.0 times greater among those who had been circumcised after the neonatal period.

Schoen and colleagues[8] evaluated the relationship between newborn circumcision and invasive penile cancer among adult men who were members of a large health maintenance organization. Of 89 men with invasive penile cancer whose circumcision status was known, 2 (2.3%) had been circumcised as newborns and 87 were not circumcised. This study confirms the highly protective effect of newborn circumcision against invasive penile cancer.

The protective effect of circumcision is likely due to the lack of accumulation of smegma that forms from desquamated epithelial cells. To date, the precise carcinogenic substance in smegma is not known. The protective effect of circumcision is diminished when performed later in life as evidenced by the higher incidence of penile carcinoma among Muslim men compared with Jewish men. Poor hygiene also contributes to the development of penile carcinoma through accumulation of smegma and other irritants. In populations that practice good hygiene but are uncircumcised, the incidence of penile carcinoma approaches that of circumcised populations.

A history of phimosis (ie, narrowness of the opening of the prepuce) is found in approximately 25% of penile cancer patients. Phimosis is strongly associated with invasive carcinoma of the penis.[9] Precancerous lesions are found in an additional 15% to 20% of patients.[10]

An ongoing focus of research in the study of penile cancer is the association of human papilloma virus (HPV) with both benign and malignant lesions of the penis. Rubin et al[11] evaluated the prevalence of HPV DNA in different histological subtypes of penile carcinoma, dysplasia, and condyloma. HPV DNA was detected in 42% of cases of penile carcinoma, in 90% of cases of dysplasia, and in 100% of cases of condyloma.

Many studies have shown the presence of HPV types 16 and 18 in penile carcinoma.[12,13,14,15] In an examination of 30 specimens of penile cancer by polymerase chain reaction and in situ hybridization assays from 23 patients, the HPV-16 genome was found in 15 patients (65%), HPV-30 in 3 patients (13%), and HPV-6 or HPV-11 in 2 patients (9%).[14] Recently Bezerra et al[15] detected HPV DNA in 25 of 82 samples (30.5%). HPV-16 was the most frequent type detected (13 of 25, 52%).

The mechanism by which HPV leads to malignant transformation is likely mediated through two viral genes, E6 and E7, which are actively transcribed in HPV infected cells. The E6 and E7 proteins bind to and inactivate the host cell's tumor suppressor gene products p53 and pRb (retinoblastoma gene), both of which are known negative regulators of cellular proliferation, leading to uncontrolled growth.[16]

Based on a review of the epidemiology of invasive penile cancer identified by a MEDLINE search of scientific publications from 1966-2000, Dillner et al[17] evaluated the etiology of squamous cell carcinoma of the penis. In this study, strong risk factors (>10) identified by case-control studies included phimosis, chronic inflammatory conditions (eg, balanoposthitis and lichen sclerosus et atrophicus), and treatment with psoralen and ultraviolet A photochemotherapy (PUVA). A consistent association was found between penile cancer and smoking that was dose-dependent and not explained by confounding factors such as sexual history. Sexual history and self-reported history of condyloma were associated with a 3-5-fold increase in penile cancer risk. The authors also cite a case-control study showing that circumcision neonatally, but not after the neonatal period, was associated with a 3-fold decreased risk of penile cancer. Finally, in a large number of case series, HPV DNA was positive in invasive penile cancer in 40% to 50% of cases.


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