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315 INVESTIGATIVE REPORT Risk Factors for Penile Intraepithelial Neoplasia: A Population- based Register Study in Sweden, 2000–2012 Sinja KRISTIANSEN 1 , Åke SVENSSON 1 , Linda DREVIN 2 , Ola FORSLUND 3 , Christian TORBRAND 4 and Carina BJARTLING 5 Department of Dermatology and Venereology and 5 Department of Obstetrics and Gynaecology, Lund University, Skåne University Hospital, Malmö, 2 Regional Cancer Centre Uppsala-Örebro, Uppsala University Hospital, Uppsala, 3 Department of Medical Microbiology Laboratory Medicine, Lund University, Lund, and 4 Department of Urology, Helsingborg General Hospital, Lund University, Helsingborg, Sweden 1 Studies on risk factors for penile intraepithelial neo­ plasia have been small in size, have not distinguished penile intraepithelial neoplasia from invasive cancer, and have relied on self-reported information. This study investigated risk factors for penile intraepithe- lial neoplasia in a cohort of 580 penile intraepithelial neoplasia cases and 3,436 controls using information from 7 Swedish registers. Cases with penile intraepi­ thelial neoplasia had increased odds ratios (ORs) for inflammatory skin diseases (14.7, 95% CI 6.5–33.4) including lichen planus (12.0, 95% CI 3.0–48.0), in- dicating lichen planus to be an important risk factor. Increased ORs were also observed for diseases of the prepuce (4.0, 95% CI 2.2–7.4), immunosuppressive drugs (5.0, 95% CI 2.5–9.8), penile surgical proce- dures (4.8, 95% CI 2.2–10.8), balanitis (9.2, 95% CI 5.0–16.8), genital warts (9.9, 95% CI 4.3−22.7) and organ transplantation (7.0, 95% CI 2.4–20.8). This study demonstrates important risk factors for penile intraepithelial neoplasia, providing knowledge that can help prevent the development of penile cancer. Key words: PeIN; penile intraepithelial neoplasia; penile cancer in situ; CIS; penile cancer; risk factors: lichen planus. Accepted Nov 14, 2018; E-published Nov 14, 2018 Acta Derm Venereol 2019; 99: 315–320. Corr: Sinja Kristiansen, Department of Dermatology and Venereology, Skåne University Hospital, SE-214 28 Malmö, Sweden. E-mail: Sinja.Kris- [email protected] P enile cancer is a rare type of cancer with an age- adjusted incidence in Sweden of 2.1/100,000 (1). In Europe, the incidence is 0.45–1.7/100,000 (2), and in the USA 0.58/100,000 (3). The highest incidence is reported from Brazil, with 2.9–6.8/100,000 (4), and Uganda with 3.3/100,000, although in Uganda recent data has shown a significant decrease in incidence to 1.2/100,000 (5). In contrast, increasing incidence is seen both in the Nether- lands (6) and the UK (7). In Sweden, the incidence was stable between 2000 and 2012 (1). In more than 95% of cases, penile cancer is classified as squamous cell carci- noma (SCC) (8). Penile intraepithelial neoplasia (PeIN) is a premalignant precursor lesion of invasive penile SCC, a SCC in situ, where the squamous epithelium shows dysplastic changes with an intact basement membrane (9). Each year approximately 150 penile cancer cases are diagnosed in Sweden, approximately 30% are diagnosed SIGNIFICANCE Non-invasive penile cancer is a precursor to invasive pe- nile cancer. Studies on risk factors have been small in size and have relied on self-reported information. This study looked at risk factors for non-invasive penile cancer in 580 men and 3,436 cancer-free controls in Swedish medical re- gisters. It found that inflammatory skin diseases, diseases of the prepuce, taking immunosuppressive drugs, having had penile surgery, inflammation of the glans, genital warts and being organ transplanted all are risk factors for non- invasive penile cancer. Increased knowledge on risk factors for non-invasive penile cancer will help in the prevention of development of invasive penile cancer. with PeIN (1). PeIN are morphologically divided into 4 subgroups, with differentiated PeIN being the most predominant, followed by warty-basaloid, basaloid and warty morphology (10). In 2016, the World Health Orga- nization (WHO) introduced a new pathological classifica- tion of PeIN based on aetiology, with 2 main pathways for malignant transformation, one pathway being a human papillomavirus (HPV)-induced carcinogenesis, named “undifferentiated PeIN”, and the other being an inflam- matory pathway derived from lichen sclerosus (LS) and lichen planus (LP), named “differentiated PeIN” (9, 11). Data on how often premalignant lesions transform to invasive cancer are scarce. According to published data the transformation occurs in 10–30% of cases in PeIN, with the glans and inner prepuce having the highest risk of malignant transformation (12, 13). The overall 5-year relative survival rate in Sweden is 82% (1). The prevalence of HPV in manifest penile cancer is approximately 47%, ranging between 24 and 82% (14, 15). HPV is assumed to be a major risk factor for penile cancer. In PeIN, HPV prevalence is more common, bet- ween 87–100% of cases (16, 17). Inflammatory skin di- sease, such as LS, is present in 28–55% of cases of penile cancer and is thought to be the other major risk factor for invasive penile cancer (18–20). Balanitis and phimosis increases the relative risk of invasive penile cancer 9.5 times (21). Circumcision in infancy is known to protect from developing penile cancer (22, 23). Smoking is as- sociated with a 4.5% increased risk of invasive penile cancer (22). Overweight and obesity are more prevalent among patients with invasive penile cancer, indicating This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3083 Acta Derm Venereol 2019; 99: 315–320