2683 Risk Factors for Squamous Cell Carcinoma of the Penis— Population-Based Case-Control Study in Denmark Birgitte Schu¨tt Madsen,1 Adriaan J.C. van den Brule,2 Helle Lone Jensen,3 Jan Wohlfahrt,1 and Morten Frisch1 1Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, Denmark; 2Department of Pathology, VU Medical Center, Amsterdam and Laboratory for Pathology and Medical Microbiology, PAMM Laboratories, Michelangelolaan 2, 5623 EJ Eindhoven, the Netherlands;and 3Department of Pathology, Gentofte University Hospital, Niels Andersens Vej 65, Hellerup, Denmark Abstract Few etiologic studies of squamous cell carcinoma female sex partners, number of female sex partners (SCC) of the penis have been carried out in populations before age 20, age at first intercourse, penile-oral sex, a where childhood circumcision is rare. A total of 71 history of anogenital warts, and never having used patients with invasive (n = 53) or in situ (n = 18) penile condoms. Histories of phimosis and priapism at least 5 SCC, 86 prostate cancer controls, and 103 population years before diagnosis were also significant risk controls were interviewed in a population-based case- factors, whereas alcohol abstinence was associated control study in Denmark. For 37 penile SCC patients, with reduced risk. Our study confirms sexually tissue samples were PCR examined for human papil- transmitted HPV16 infection and phimosis as major lomavirus (HPV) DNA. Overall, 65% of PCR-examined risk factors for penile SCC and suggests that penile- penile SCCs were high-risk HPV-positive, most of oral sex may be an important means of viral transmis- which (22 of 24; 92%) were due to HPV16. Penile SCC sion. The association with priapism was unexpected risk was positively associated with measures of early and needs replication. (Cancer Epidemiol Biomarkers and high sexual activity, including lifetime number of Prev 2008;17(10):2683–91) Introduction In the Western world, squamous cell carcinoma (SCC) of case-control study in Denmark, a country with a largely the penis is a rare malignancy occurring mainly among uncircumcised male population (19) to further address elderly men above age 60 years (1, 2) and with a the etiology of penile SCC. standardized annual incidence of <2 per 100,000 men (1- 4). In some developing countries, penile SCC is more common and affects a somewhat wider age range (5-9). Material and Methods The etiology of penile SCC remains incompletely understood (7, 10). Studies have consistently reported Participants. Three study groups were identified, neonatal or childhood circumcision to be associated with including case patients diagnosed with invasive or reduced risk (1, 4, 6, 10-12), which corresponds geo- in situ penile SCC between 1993 and 1998 and two graphically with reduced rates of penile SCC in frequency-matched control groups consisting of male populations practicing neonatal circumcision (13). The population controls and patients diagnosed with adeno- protective effect of childhood circumcision, but not of carcinoma of the prostate in the same time period as the circumcision in adulthood (4, 11), seems to be attribut- penile SCC patients. Information about newly diagnosed able to the elimination of inflammatory conditions cases of penile SCC and prostate cancer was obtained related to poor genital hygiene (2, 8-10), such as phimosis every third month from the files of the Danish Cancer (3, 4, 14-16) and balanitis (14). Accordingly, an intact Registry and the Danish Pathology Registry, as well as foreskin has been shown not to be associated with through manual searches in the files of pathology increased penile SCC risk in the absence of phimosis (4). departments across Denmark. Overall, we identified Other previously suggested risk factors include infection 259 men with penile SCC (215 invasive and 44 in situ with high-risk types of sexually transmitted human cases) diagnosed between 1993 and 1998. Before inviting papillomaviruses (hrHPV;refs. 4, 11, 17) and current these men to participate in the study, we contacted the tobacco smoking (4, 11, 18). We undertook a nationwide hospital department or the private practitioner respon- sible for their treatment to ensure that each eligible participant had been fully informed about his diagnosis, that he had no other health-related reason for nonpartic- Received 5/19/08;revised 7/14/08;accepted 7/18/08. ipation known to the doctor (e.g., psychosis, hearing Grant support: Danish Cancer Society (grant no. 96-100-17), Dagmar Marshall’s Foundation, Manufacturer Einar Willumsen’s Memorial Foundation and the Danish impairment), and that he was a Danish-speaking person. Medical Research Council. Of the original 259 invasive or in situ penile SCC patients, Requests for reprints: Birgitte Schu¨tt Madsen, MSc, Department of Epidemiology 88 patients (34%) had died, for 47 patients (18%), we Research, Statens Serum Institut, Artillerivej 5, Dk-2300 Copenhagen S, Denmark. Phone: 45-32683951;Fax: 45-32683165. E-mail: [email protected]. received no reply from the hospital department or Copyright D 2008 American Association for Cancer Research. private practitioner responsible for the patient’s treat- doi:10.1158/1055-9965.EPI-08-0456 ment, and 3 patients (1%) were inaccessible due to Cancer Epidemiol Biomarkers Prev 2008;17(10). October 2008 Downloaded from cebp.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. 2684 Risk Factors of Penile Cancer emigration. Thus, we invited 121 (47%) penile SCC HPV-positive samples were subsequently analyzed for patients who had been informed about their cancer (or their HPV types using the reverse line blotting method. carcinoma in situ) and were alive at the time we aimed to The following hrHPV types were detected and identified approach them between 1997 and 2000. Prostate cancer as follows: HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, controls were frequency matched to penile SCC patients 66, and 68;low-risk HPVs detected were HPV 6, 11, 26, on year of diagnosis and birth year (F5 y). From the Civil 34, 40, 42, 43, 44, 53, 54, 55, 57, 61, 70, 71 (CP8061), 72, 73, Registration System, a nationwide demographic database 81 (CP8304), 82/MM4, 82/IS39, 83 (MM7), 84 (MM8), (20), we obtained a list of all Danish men born on two and CP6108. specific dates for each year between 1911 and 1963. As Statistical Analysis. To ensure comparable exposure patients with penile cancer were invited to participate in ascertainment periods in all 3 groups of study partic- the study, this list was used to select possible population ipants, we assigned a pseudo-year of diagnosis between controls, by means of frequency matching to invited 1993 and 1998 to population controls according to the penile SCC patients on year of birth. We anticipated distribution of year of diagnosis among penile SCC somewhat lower participation rates among population patients. Specifically, the distribution of pseudo-year of controls, so to obtain the intended case-cancer control diagnosis among population controls was similar to the and case-population control ratios of 1:1, we invited distribution of year of diagnosis among penile SCC cases more population controls than patients with penile (i.e., similar proportions of population controls having cancer. Potential participants (121 penile SCC cases, 136 pseudo-year of diagnosis in 1993, 1994, 1995, 1996, 1997, prostate cancer controls, and 172 population controls) received a letter of invitation with information about the and 1998 as penile SCC patients with year of diagnosis in study and were asked to sign and return a consent form 1993, 1994, 1995, 1996, 1997, and 1998, respectively). We in a prepaid envelope to participate in the study. considered only those exposures that preceded the All consenting participants underwent a structured pseudo-year of diagnosis to be relevant in population telephone interview between March 1997 and April 2000. controls, similar to the situation in penile SCC cases and prostate cancer controls, for whom only exposures that The interviews, conducted according to written guide- preceded the year of cancer diagnosis counted as lines by six trained female medical students who were exposures of potential etiologic relevance. unaware of the study hypotheses and who were kept blinded to the case or control status of the participants, Univariate Analyses. Because most risk factors are covered a broad range of topics including basic school similar for both diagnostic entities (4), we considered as attendance and postschool education, weight and height, our case group all patients with invasive or in situ penile tobacco and alcohol consumption, issues related to SCC. Initially, we calculated univariate odds ratios (OR) general and genital health, fertility, and details about separately for penile SCC patients versus each of the two sexual experiences and hygiene as well as venereal control groups, adjusting only for age at diagnosis in 10-y history. Patients with prostate cancer were chosen as a age groups (< 40, 40-49,..., z70 y). ORs obtained with supplementary control group because most examined either of the two control groups were generally similar, risk factors for penile SCC are not suspected to be risk so we subsequently tested the appropriateness of factors for prostate cancer. Consequently, information combining the two control groups by doing a logistic provided by these control subjects was anticipated to be regression analysis restricted to prostate cancer controls comparable with the information obtained from popula- and population controls, with adjustment for age in 10-y tion controls. Moreover, we anticipated the reliability of age groups. This analysis revealed that none of the answers to be high among prostate cancer controls examined explanatory variables were associated with becausethesemenwereexpectedtobesimilarly statistically significantly increased risk of prostate cancer, motivated as case patients to provide honest answers so to reduce complexity and gain statistical power, we with respect to sexual and venereal history, genital combined the two control groups in all subsequent hygiene, and other sensitive matters.