Penile Intraepithelial Neoplasia and Penile Cancer. Risk Factors and Treatment.

AbstractPenile cancer and its precursor, penile intraepithelial neoplasia (PeIN), are rare malignancies. Data on risk factors, incidence, and treatment of PeIN is scarce. The prevalence of human papillomavirus (HPV) varies substantially between studies of penile cancer.The aims of this thesis were to explore the incidence, risk factors and treatment of PeIN; to analyse the prevalence of HPV and skin diseases in circumcised preputium; to investigate the prevalence of HPV in penile cancer compared to age-matched controls; and in HPV16-positive cases, to analyse viral activity.Risk factors for PeIN, studied in a case-control study of 580 cases and 3436 controls, showed increased odds ratios for lichen sclerosus (LS), lichen planus (LP), genital warts, balanoposthitis, taking immunosuppressive drugs, penile surgical procedures and organ transplantation.The incidence of PeIN retrieved from the Swedish National Penile Cancer Register over 20 years, revealed an increased standardised incidence rate of 2.37 from 2019 to 2000. A comparison of given treatment for PeIN in the last five years, compared to the first five years of the period studied, showed surgery to be more common than laser treatment and, topical imiquimod and 5-FU to be more common than local destructive methods.Analysis of symptomatic foreskin (N=351) showed HPV in 17.1% of cases, high-risk (HR) HPV types in 9.1% with HPV16 in only 2.3%. Histologically, LS, LP and lichenoid dermatitis were seen in 73.5% and PeIN in 2%, despite no clinical suspicion of malignancy.In penile cancers (N=135) HPV was detected in 38.5% of cases and HPV16 was present in 27.4%. Among cases and age-matched controls (N=105) HR HPV types were found in 34.3% (48/135) of tumours and in 4.8% (5/105) of controls (p<0.001). Among tumours and controls, HPV16 was present in 27.4% (37/135) and 1% (1/105), respectively (p< 0.001). Viral activity (HPV16 mRNA) among HPV16-positive cases was more common in the tumour (86.5%) compared to adjacent to the tumour (21.7%) (p<0.001).In conclusion, this thesis provides knowledge about risk factors, change in incidence, and treatment methods over 20 years for PeIN. For penile cancer, HR HPV types were significantly more common in penile cancer cases than in age-matched controls. The finding of active HPV16 in penile cancer suggests that HPV16 is an oncogenic driver of the disease

Penile intraepithelial neoplasia, penile cancer precursors and human papillomavirus prevalence in symptomatic preputium : a cross-sectional study of 351 circumcised men in Sweden

Objectives: To investigate the prevalence of pathological disease and spectrum of human papillomavirus (HPV) types among symptomatic foreskin tissue. Patients and Methods: Consecutively excised symptomatic foreskins from 351 men were sent for histopathological evaluation. During the surgical procedure, a fresh biopsy was taken for HPV analysis by modified general primer polymerase chain reaction. A medical questionnaire regarding medication, smoking habits, number of lifetime sexual partners, former diseases and surgery performed on penis was completed by all participants. Results: The most common clinical diagnosis and cause for circumcision was phimosis, seen in 85.2%. Histopathologically inflammatory dermatological conditions were present in 87% of the men. The most common histopathological diagnosis was lichen sclerosus (LS) observed among 58.7%. Notably, penile intraepithelial neoplasia (PeIN) was present in 2% without former clinical suspicion. Overall, HPV was detected in 17.1% of the men and 28 different HPV types were found. High-risk (HR) HPV types were identified in 9.1% and HPV16 was present in 2.3%. Current smoking increased the risk of HPV (crude odds ratio [OR] 2.8, confidence interval [CI] 1.4–5.6; P = 0.005). Having >15 lifetime sexual partners increased the risk of HPV (crude OR 2.6, 95% CI 1.4–5.1; P = 0.003) and when adjusted for current smoking the OR was substantially increased (OR 6.0, 95% CI CI 2.2–16.8; P < 0001). Conclusions: Histopathological evaluation of circumcised symptomatic foreskin revealed PeIN in 2% of the men without any clinical suspicion of malignancy and that treatable dermatological conditions were present in 87%, LS being the most common. HR-HPV types were present in 9%. Due to risk of malignant development both in PeIN and in inflammatory skin diseases we recommend sending all excised foreskins from patients with symptoms for histopathological evaluation as guidance for further clinical management

Incidence of penile intraepithelial neoplasia and treatment strategies in Sweden 2000–2019

Objectives: To analyse the incidence, treatment strategies and complications associated with penile intraepithelial neoplasia (PeIN) in Sweden over a period of 20 years. Materials and methods: Data on PeIN from the Swedish National Penile Cancer Register were analysed regarding treatment in relation to age, size of the PeIN lesion, localization of the PeIN lesion and complications using chi-squared tests and logistic regression. The incidence of PeIN was calculated and age-standardized according to the European Standard population. Results: Between 2000 and 2019 a total of 1113 PeIN cases were reported. The age-standardized incidence of PeIN was 1.40 per 100 000 men (95% confidence interval [CI] 1.32–1.49). An increase in incidence over time was seen, with a standardized incidence rate of 2.37 (95% CI 1.56–3.70) in 2019 compared to the baseline year, 2000. Surgical or topical treatments were given in 75.0% and 14.6% of cases, respectively. The complication rate was higher in laser surgery (12.1%, 7/58) compared to local surgery (4.6%, 16/348; P = 0.03) with an age-adjusted odds ratio (OR) of 2.82 (95% CI 1.10–7.19; P = 0.03). Local surgery was more common than laser surgery in the last 5 years compared to the first 5 years of the study period: OR 5.75 (95% CI 2.94–11.27). Treatments with imiquimod and topical 5-fluorouracil (5-FU) were more common than destructive methods such as photodynamic therapy, cryotherapy, curettage and electrocautery in the last 5 years compared to the first 5 years: OR 9.48 (95% CI 2.29–39.24). Conclusions: A twofold increase in the age-standardized incidence of PeIN was seen in Sweden over 20 years. Complications were three times more common in laser surgery compared to local surgery. Changes in treatment showed an increase of treatment strategies such as local surgery and treatment with imiquimod and topical 5-FU over time

Risk Factors for Penile Intraepithelial Neoplasia : A Population-based Register Study in Sweden, 2000-2012

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 intraepithelial neoplasia in a cohort of 580 penile intraepithelial neoplasia cases and 3,436 controls using information from 7 Swedish registers. Cases with penile intraepithelial 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), indicating 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 procedures (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

Increased prevalence of human papillomavirus in fresh tissue from penile cancers compared to non-malignant penile samples : a case-control study

Background: HPV has been detected in approximately 50% of invasive penile cancers but with a large span between 24 and 89%, most likely due to different types of tumors and various methods for HPV analysis. Most studies of HPV in penile cancer have been performed using paraffin-embedded tissue, argued to be at risk for contaminated HPV analysis. Viral activity of HPV, by the use of HPV mRNA expression is well studied in cervical cancer, but seldom studied in penile cancer. The aim was to determine prevalence of HPV types in fresh tissue of penile cancers compared to non-malignant age-matched penile controls. Additional aims were to analyze the viral expression and copy numbers of HPV16-positive tumors and 10 mm adjacent to the tumor. Methods: Fresh tissue from penile cancer cases was biopsied inside the tumor and 10 mm outside the tumor. Controls were males circumcised for non-malignant reasons, biopsied at surgery. PCR and Luminex assays were used for identification of HPV types. HPV16-positive samples were investigated for copy numbers and expression of HPV16-mRNA. Results: Among tumors (n = 135) and age-matched controls (n = 105), HPV was detected in 38.5% (52/135) and 11.4% (12/105), respectively (p < 0.001), adjusted odds ratio 12.8 (95% confidence interval 4.9–33.6). High-risk HPV types were found in 35.6% (48/135) of tumors and 4.8% (5/105) of controls (p < 0.001). Among tumors and controls, HPV16 was present in 27.4% (37/135) and 1% (1/105), respectively (p < 0.001). Among HPV16-positive penile cancers, mean HPV16 viral copy/cell was 74.4 (range 0.00003–725.4) in the tumor and 1.6 (range 0.001–14.4) 10 mm adjacent from the tumor. HPV16-mRNA analysis of the tumors and 10 mm adjacent from the tumors demonstrated viral activity in 86.5% (32/37) and 21.7% (5/23), respectively. Conclusions: The prevalence of HPV was significantly higher in penile cancer (38.5%) than among age-matched non-malignant penile samples (11.4%). HPV16 predominates (27.4%) in penile tumors. HPV16 expression was more common in penile cancer than in adjacent healthy tissue, strongly suggesting an etiological role for HPV16 in the development of penile cancer