Lipschütz genital ulcer revisited: is juvenile gangrenous vasculitis of the scrotum the male counterpart?

Since its first description as ulcus vulvae acutum by Benjamin Lipschütz in 1912, the etiopathogenesis of this peculiar genital ulcer remains incompletely understood. In his original description, two different types of genital ulcers were observed and proposed, which were not precisely defined and distinguished in most subsequent reports. The first type is characterized by acute excruciating genital ulcers of first-time onset with self-limited non-recurrent course in association with gravely symptomatic systemic infections, in which a primary Epstein-Barr virus (EBV) infection is later identified to be probably the most common aetiology. The second type of ulcer usually refers to little painful ulcers of unknown etiopathogenesis in the absence of fever or chills and with a slow torpid progression and recurrent nature. Differentiation from idiopathic aphthous ulcers is unclear. The changes of the cervicovaginal microbiota and microbiome in diseased state deserve further clarification. Acute genital ulcers associated with primary EBV infection in women have drawn attention since 1970s, while the corresponding penile ulcers in men were already known in 1950s. First presented in 1973, juvenile gangrenous vasculitis of the scrotum with an acute painful scrotal ulcer preceded by symptomatic pharyngeal infections can be considered as the male counterpart of ulcus vulvae acutum, and the future clinical survey should include primary EBV infection.

[Circumcision reduces the incidence of human papillomavirus infection in men].

OBJECTIVE: To investigate the association of circumcision with the incidence of human papillomavirus (HPV) infection in men. METHODS: We collected the samples from the surface of the coronal sulcus, glans penis, penile shaft and scrotum of 351 males examined for HPV infection in our hospital from January 2016 to August 2017, of whom 118 had received circumcision while the other 233 had not. We compared the incidence rate of HPV infection between the circumcision and non-circumcision groups and analyzed the association of the age of circumcision with the incidence of HPV infection. RESULTS: HPV infection was found in 135 (38.46%) of the males, 29 (24.58%) in the circumcision group and 106 (45.49%) in the non-circumcision group, significantly lower in the former than in the latter (χ² = 14.48, P < 0.01). The incidence rate of HPV infection was also remarkably lower in the males circumcised at ≤17 years (13.16% ï¼»5/38ï¼½) than in those circumcised at >17 years of age (30.0% ï¼»24/80ï¼½) (χ² = 3.942, P = 0.047). CONCLUSIONS: Male circumcision helps reduce the incidence rate of HPV infection in men and earlier surgery may achieve even better effect.

Human papillomavirus type 6/11 identified in an epidermoid cyst of the scrotum.

To date, epidermoid cysts associated with human papillomavirus (HPV) infection have been described mainly in palmoplantar locations, and have involved HPV types 60 and 57. In contrast, HPV-6/11 is a major cause of condyloma acuminatum. Here, we report the case of a healthy 31-year-old man who presented to our clinic with a 1-month history of a 1-cm, reddish-brown, cystic scrotal tumor with a punctum. The lesion was studied histologically, immunohistochemically and by DNA-DNAin situ hybridization. Histology revealed an epidermoid cyst with vacuolated keratinocytes with shrunken nuclei (koilocytes) in the cyst wall. Immunostaining was positive for HPV antigens and in situ hybridization revealed HPV-6/11 DNA in the koilocytes. This is the first report of an HPV-6/11-associated epidermoid cyst in the anogenital skin of an immunocompetent individual.

Genital Human Papillomavirus Infection in Indian HIV-Seropositive Men Who Have Sex With Men.

BACKGROUND: The incidence of penile cancer in Indian men is high. Little is known about genital human papillomavirus (HPV) infection in Indian HIV-seropositive men who have sex with men (MSM), a population that may be at particularly high risk for genital HPV infection and, potentially, penile cancer. In this study, we assessed the prevalence and risk factors for genital HPV infection in this population. DESIGN AND METHODS: Three hundred HIV-seropositive MSM were recruited from 2 clinical sites in India. They were tested for genital HPV infection using L1 HPV DNA polymerase chain reaction with probes specific for 29 types and a mixture of 10 additional types. Participants received an interviewer-administered questionnaire that included questions on demographics and behaviors. RESULTS: Human papillomavirus data were available from 299 participants. The prevalence of any HPV type in the penis and scrotum was 55% and 54%, respectively. Human papillomavirus type 35 was the most common oncogenic HPV type followed by HPV-16. In multivariate analysis, being the insertive partner with 100+ male partners increased the odds of any penile HPV infection compared with not being insertive with any partners (odds ratio, 2.5; 95% confidence interval, 1.3-5.1). Circumcision was protective against penile HPV infection (odds ratio, 0.39; 95% confidence interval, 0.19-0.76). CONCLUSIONS: The prevalence of penile and scrotal HPV infection was high among Indian HIV-seropositive MSM. The most common oncogenic HPV type in this population, HPV-35, is not included in any currently available HPV vaccines. Insertive anal sex with men and lack of circumcision were the primary risk factors for penile HPV infection in this population.

Prevalence and distribution of 15 high-risk human papillomavirus types in squamous cell carcinoma of the scrotum.

Which subtype(s) of high-risk human papillomavirus (hrHPV) are involved in squamous cell carcinoma (SCC) of the scrotum is unknown. Twenty-seven cases of SCC of the scrotum were retrieved, and all 15 subtypes of hrHPV and their viral loads were assessed using multiplex real-time polymerase chain reaction. The results were correlated with the histopathologic features, p16 expression, and in situ hybridization for hrHPV. hrHPV was identified in 18 (67%) of 27 of the cases, including HPV16 (n=8), HPV35 (n=7), HPV31 (n=5), HPV59 (n=5), HPV33 (n=3), HPV18 (n=2), HPV51 (n=2), HPV39 (n=1), HPV56 (n=1), and HPV82 (n=1). Of the 18 cases, 10 (56%) were infected by multiple hrHPV subtypes. In situ carcinomas had higher viral loads than invasive (50M versus 2M in average). The average age of HPV-positive and -negative cases was similar, 55 and 51, respectively. Of 11 cases of invasive carcinoma, 5 (45%) were positive for hrHPV versus 13 of 16 (81%) of in situ carcinomas. The highest proportion of hrHPV-positive cases was seen in basaloid type (7/7; 100%) and warty type (4/4; 100%), followed by usual type (7/16; 44%). Of 18 of the HPV-positive cases, 9 (50%) were also positive for p16 by immunohistochemistry and 6 of 18 (33%) were positive by in situ hybridization. Similar to SCC of the vulva and penis, the most frequently HPV-positive tumors are basaloid and warty types. However, a proportion of SCC usual type are also positive for hrHPV. Our results show that 8 (44%) of 18 of cases are associated with hrHPV subtypes other than 16 and 18. Additionally, 7 (70%) of 10 of hrHPV16/18-positive cases are coinfected with other subtypes.

Alcohol consumption and prevalence of human papillomavirus (HPV) infection among US men in the HPV in Men (HIM) study.

OBJECTIVES: Moderate alcohol consumption can impair host defence against viral infections. The objective of this cross-sectional analysis was to assess the association between alcohol intake and prevalent human papillomavirus (HPV) infection among US men enrolled in the HPV in Men (HIM) study using quantitative alcohol intake measured from a Food Frequency Questionnaire. METHODS: The HIM study is a prospective, multinational study of the natural history of HPV infection. For this report, we restricted our analyses to men from the US cohort (N = 1313). Samples from the corona of glans penis, penile shaft and scrotum were combined for HPV DNA testing. Self-reported alcohol intake was quantified by grams of alcohol intake per day. Multivariable prevalence ratios (mPRs) were used to assess the association between alcohol intake and HPV infections. RESULTS: Prevalent infections were significantly higher among men in the highest quartile of alcohol intake and multivariable models revealed that the highest quartile of alcohol intake was associated with significantly increased risks for any (mPR = 1.13; 95% CI 1.00 to 1.27) HPV types and oncogenic (mPR = 1.35; 95% CI 1.08 to 1.68) HPV types. The fourth quartile of alcohol intake was associated with elevated risks for prevalent HPV infection across all strata of number of sexual partners and among never-smokers and current smokers, but not among former smokers. CONCLUSIONS: These results demonstrate that high intake of alcohol is associated with an increased risk for prevalent HPV infections among men. The biological role that alcohol plays in genital HPV infection remains understudied and limited epidemiological data exist, especially among men.

Squamous neoplasia of the scrotum: a series of 29 cases.

The current epidemiology and clinicopathologic features of squamous cell carcinoma (SCC) of the scrotum are largely unknown because of its low incidence. We describe the histopathologic features, immunohistochemistry, and human papillomavirus (HPV) status of 29 patients with scrotal SCC. The mean age at presentation was 55 years (range, 30 to 74 y). White to black ratio was 1.9:1. There was no predominant occupation, with the majority being white-collar professionals. Clinical history of condylomas was present in 5 patients, and 7 patients had a history of multiple skin cancers including melanoma, basal cell carcinoma, and other SCCs. Other comorbidities included human immunodeficiency virus infection (n=2), kidney transplant (n=1), leukemia/lymphoma (n=2), hidradenitis suppurativa (n=1), chronic scrotal infections with abscess (n=1), inflamed epidermal inclusion cyst (n=1), and lichen planus (n=1). One patient had a history of regular tanning bed use. Morphologically, the majority was usual type (n=17), followed by basaloid (n=7) and warty (n=5). Nineteen cases were in situ, and 10 were invasive. Three patients had inguinal lymphadenopathy; in 1, metastasis was confirmed. Suprabasal nuclear staining for Ki67 was considered positive. For p16, a continuous band of nuclear and cytoplasmic staining was considered positive, and a noncontinuous or absence of staining was considered negative. p16 was positive in 10 cases; high-risk HPV was confirmed in 7 cases. Ki67 was positive in 8/17 (47%) usual, 6/7 (85.7%) basaloid, and 3/5 (60%) warty type. p53 was positive in 5/17 (29.4%) usual, 2/7 (28.6%) basaloid, and 1/5 (20%) warty type. All patients were treated with local excision only; 13 had positive margins. Three patients were treated with imiquimod after local excision. The median follow-up was 30 months. Three patients recurred and were treated with re-excision; 1 patient received radiotherapy. Overall, the morphologic, immunohistochemical, and HPV studies show that, similar to SCC of the vulva or penis, the SCC of the scrotum can be divided into 2 major groups. Group 1 (38.5%): positive for p16 and elevated Ki67. This group is associated with HPV infection and displays predominantly a basaloid or warty morphology, although a number of them are of usual type. Group 2 (61.5%): negative for p16. This group has variable Ki67 expression, is consistently negative for HPV, and displays predominantly usual-type morphology. SCC of the scrotum in the United States currently affects primarily white-collar professionals. The majority present with in situ lesions, and the high rate of positive margins at first excision suggests that they are clinically ill-defined lesions. No longer are occupational exposures to carcinogens the major etiology of scrotal SCC. Rather in contemporary times, common risk factors include HPV infection, immunocompromised states, and chronic scrotal inflammatory conditions.

Incidence, clearance, and disease progression of genital human papillomavirus infection in heterosexual men.

BACKGROUND: In this analysis, we examine the incidence and clearance of external genital human papillomavirus (HPV) infection among heterosexual males aged 16-24 years. METHODS: A total of 1732 males aged 16-24 years old in the placebo arm of a quadrivalent HPV vaccine trial were included in this analysis. Participants were enrolled from 18 countries in Africa, the Asia-Pacific region, Europe, Latin America, and North America. Subjects underwent anogenital examinations and sampling of the penis, scrotum, and perineal/perianal regions. RESULTS: The incidence rate of any HPV DNA genotype 6, 11, 16, and/or 18 detection was 9.0 cases per 100 person-years. Rates of HPV DNA detection were highest in men from Africa. Median time to clearance of HPV genotypes 6, 11, 16, and 18 DNA was 6.1, 6.1, 7.7, and 6.2 months, respectively. Median time to clearance of persistently detected HPV 6, 11, 16, and 18 DNA was 6.7, 3.2, 9.2, and 4.7 months, respectively. CONCLUSION: The study results suggest that the acquisition of HPV 6, 11, 16, and/or 18 in males is common and that many of these so-called infections are subsequently cleared, similar to findings for women. Nevertheless, given the high rate of HPV detection among young men, HPV vaccination of males may reduce infection in men and reduce the overall burden of HPV-associated disease in the community.

Male circumcision and the incidence and clearance of genital human papillomavirus (HPV) infection in men: the HPV Infection in men (HIM) cohort study.

BACKGROUND: Reported associations of male circumcision (MC) with human papillomavirus (HPV) infection in men have been inconsistent. METHODS: 4,033 healthy men were examined every six months for a median of 17.5 months. In each study visit, exfoliated cell specimens from the coronal sulcus/glans penis, penile shaft, and scrotum were collected and combined into one sample per person for HPV DNA detection. Samples were tested for 37 HPV types. Cox proportional hazards models were used to evaluate the association between MC and the incidence and clearance of HPV infections and specific genotypes. RESULTS: The overall incidence of new HPV infections did not differ by MC status (for any HPV, adjusted hazard ratio (aHR) 1.08, 95% confidence interval (CI) 0.91-1.27). However, incidence was significantly lower among circumcised versus uncircumcised men for HPV types 58 (p = 0.01), 68 (p < 0.001), 42 (p = 0.01), 61 (p < 0.001), 71 (p < 0.001), 81 (p = 0.04), and IS39 (p = 0.01), and higher for HPV types 39 (p = 0.01) and 51 (p = 0.02). Despite the lack of an overall association in the risk of HPV clearance by MC (for any HPV, aHR 0.95, 95% CI 0.88-1.02), median times to clearance were significantly shorter among circumcised than uncircumcised men for HPV types 33 (p = 0.02) and 64 (p = 0.04), and longer for HPV types 6 (p < 0.001), 16 (p < 0.001), and 51 (p = 0.02). CONCLUSIONS: MC is not associated with the incidence and clearance of genital HPV detection, except for certain HPV types. The use of a single combined sample from the penis and scrotum for HPV DNA detection likely limited our ability to identify a true effect of MC at the distal penis.

Verrucous herpetic infection of the scrotum and the groin in an immuno-competent patient: Case report and review of the literature.

Atypical presentations of genital herpes are more commonly described among immuno-compromised patients. Furthermore, verrucous lesions may be attributed to acyclovir resistant strains of herpes simplex virus as well as co-infection with fungi and other viruses in this patient population. We describe the first case of verrucous genital herpes infection in an immuno-competent patient.

Smoking and human papillomavirus (HPV) infection in the HPV in Men (HIM) study.

BACKGROUND: The influence of smoking on the natural history of HPV infection in men is not well understood. Smoking could influence the incidence and persistence of HPV infections by suppressing local immune function, increased cellular proliferation, upregulated proinflammatory factors, or induced host DNA damage resulting in increased susceptibility to infection. The purpose of this analysis is to assess prevalent HPV infections by smoking status in men, and to determine baseline risk of HPV infection associated with smoking. METHODS: The HPV in Men (HIM) study is a multinational prospective study of the natural history of HPV infections in men. Samples from the coronal sulcus, glans penis, shaft, and scrotum were combined for HPV DNA testing. Multivariable logistic regression was used to assess the association between smoking and any-, oncogenic-, and nononcogenic HPV infections. RESULTS: Our analyses revealed that current smoking was associated with an increased risk of any HPV infection (OR = 1.19; 95% CI: 1.01-1.41) and oncogenic HPV infection (OR = 1.24; 95% CI: 1.05-1.47). However, the association between smoking and any HPV infection (OR = 1.35; 95% CI: 1.05-1.73) and oncogenic HPV infection (OR = 1.46; 95% CI: 1.11-1.92) was only evident among men reporting fewer lifetime sexual partners. DISCUSSION: These results suggest that current smokers with the fewest number of sexual partners are associated with an increased risk for oncogenic HPV infection. IMPACT: The relationship between smoking and HPV infection remains understudied in men; these data shed new light on the interplay between smoking, sexual activity, and risk of HPV infection.

Race and prevalence of human papillomavirus infection among men residing in Brazil, Mexico and the United States.

Human papillomavirus (HPV) causes anal, penile and oropharyngeal cancers in men. Genital HPV prevalence in men appears to vary by world region with men residing in Asia having among the lowest prevalence. Unfortunately, there is little information on prevalence of HPV infection in men by race. The purpose of this study was to examine HPV prevalence by race across three countries. 3,909 men ages 18-70 years enrolled in an ongoing prospective cohort study of the natural history of HPV in men (The HIM Study) were included in the analysis. Participants completed risk factor questionnaires and samples were taken from the penile epithelium and scrotum for HPV detection. HPV testing of the combined DNA extract was conducted using PCR and genotyping. Asian/Pacific Islanders had the lowest HPV prevalence of 42.2% compared to Blacks (66.2%), and Whites (71.5%). The Asian/Pacific Islander race was strongly protective in univariate analysis (prevalence ratio (PR) = 0.59; 95% confidence interval (CI): 0.48-0.74) and multivariate analysis for any HPV infection (PR = 0.65; 95% CI: 0.52-0.8). Stratified analysis by lifetime number of female partners also showed strong inverse associations with the Asian/Pacific Islander race. We consistently observed the lowest prevalence of HPV infection among Asian/Pacific Islanders with moderate inverse associations even after various adjustments for potential confounding factors. Unmeasured behavioral factors, sexual mixing with low risk women, and/or race-specific differences in the frequency of germline variations among immune regulating genes may underlie these associations. Further studies among Asian populations that incorporate measures of immuno-genetics are needed to understand this phenomenon.

Clustering of human papillomavirus (HPV) types in the male genital tract: the HPV in men (HIM) study.

OBJECTIVE: To evaluate clustering patterns of prevalent infection with multiple human papillomavirus (HPV) types in 3677 men from the HPV in Men (HIM) study. METHODS: HPV testing was performed in samples combined from the glans penis/coronal sulcus, the shaft, and the scrotum by Linear Array methodology. Linear Array uses a mixed probe to assess HPV52 positivity, which limits the assay's ability to determine HPV52 status in the presence of HPV33, 35, or 58. Logistic regression was used to model type-specific HPV positivity, adjusted for age, study area, lifetime number of sexual partners, and specific HPV type prevalence. Participant-level random effects were added to represent unobservable risk factors common to all HPV types. RESULTS: The observed-to-expected ratio for infections with ≥ 3 types was 1.09 (95% credible interval, 1.04-1.14). For the majority of 2-type combinations, no evidence was found of a significant departure of the observed from the expected number. An apparent clustering of HPV52 with HPV35 or 58 was observed, because of limitation in the ability of Linear Array to define HPV52 positivity. CONCLUSIONS: Our study showed that, despite obvious anatomical differences, HPV coinfections do seem to occur at random in the male external genitalia as in the female cervix.

The prevalence of genital HPV and factors associated with oncogenic HPV among men having sex with men and men having sex with women and men: the HIM study.

BACKGROUND: Comparative studies of genital human papillomavirus (HPV) among men having sex with men (MSM), men having sex with women and men (MSWM), and men having sex with women (MSW) have not been conducted so far; however, such comparisons may be important for planning prevention strategies like vaccination. METHODS: Men, aged 18 to 70 years, were enrolled in a study of genital HPV in São Paulo, Brazil; Cuernavaca, Mexico; and Tampa, FL. Men were classified as MSM (n = 170), MSWM (n = 214), and MSW (n = 3326) based on self-reported sexual behavior. Genotyping for HPV was conducted on cells from the penis and scrotum. Prevalence data were adjusted by country. Factors potentially associated with genital HPV were assessed using multivariable Poisson regression. RESULTS: Genital HPV prevalence was typically higher among MSWM than among MSM or MSW for groups of HPV genotypes including nononcogenic types (51%, 36%, and 42%, respectively), and multiple types (37%, 24%, and 29%, respectively). Age and alcohol consumption in the past month were associated with oncogenic HPV among both MSM and MSWM; however, there were no statistically significant associations between sexual behaviors and genital HPV among MSM or MSWM. CONCLUSIONS: Prevalence of genital HPV may be higher among MSWM than among MSW or MSM. Number of female sex partners was associated with genital HPV among MSW, but number of male anal sex partners was not associated with genital HPV among MSM and MSWM.

Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study.

BACKGROUND: Human papillomaviruses (HPVs) cause genital warts and cancers in men. The natural history of HPV infection in men is largely unknown, and that information is needed to inform prevention strategies. The goal in this study was to estimate incidence and clearance of type-specific genital HPV infection in men, and to assess the associated factors. METHODS: Men (aged 18-70 years), residing in Brazil, Mexico, and the USA, who were HIV negative and reported no history of cancer were recruited from the general population, universities, and organised health-care systems. They were assessed every 6 months for a median follow-up of 27·5 months (18·0-31·2). Specimens from the coronal sulcus, glans penis, shaft, and scrotum were obtained for the assessment of the status of HPV genotypes. FINDINGS: In 1159 men, the incidence of a new genital HPV infection was 38·4 per 1000 person months (95% CI 34·3-43·0). Oncogenic HPV infection was significantly associated with having a high number of lifetime female sexual partners (hazard ratio 2·40, 1·38-4·18, for at least 50 partners vs not more than one partner), and number of male anal-sexual partners (2·57, 1·46-4·49, for at least three male partners vs no recent partners). Median duration of HPV infection was 7·52 months (6·80-8·61) for any HPV and 12·19 months (7·16-18·17) for HPV 16. Clearance of oncogenic HPV infection decreased in men with a high number of lifetime female partners (0·49, 0·31-0·76, for at least 50 female partners vs not more than one partner), and in men in Brazil (0·71, 0·56-0·91) and Mexico (0·73, 0·57-0·94) compared with the USA. Clearance of oncogenic HPV was more rapid with increasing age (1·02, 1·01-1·03). INTERPRETATION: The data from this study are useful for the development of realistic cost-effectiveness models for male HPV vaccination internationally. FUNDING: National Cancer Institute.

External genital human papillomavirus prevalence and associated factors among heterosexual men on 5 continents.

BACKGROUND: We examined the baseline prevalence of penile, scrotal, and perineal/perianal human papillomavirus (HPV) in heterosexual men (HM). We also evaluated baseline characteristics of HM to assess factors associated with prevalent HPV detection. METHODS: We tested serum samples from 3463 HM aged 16-24 years with 1-5 lifetime female sexual partners for antibodies to HPV 6, 11, 16, and 18. We collected baseline swab specimens for the detection of DNA of HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 from 3 areas: penile, scrotal, and perineal/perianal. Risk factors for prevalent HPV DNA detection were evaluated. RESULTS: The prevalence of any tested HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. Having >3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% confidence interval (CI) 2.1-4.9) for HPV 6, 11, 16, and 18; and OR 4.5 (95% CI 3.3-6.1) for all HPV types tested. HPV DNA detection was highest in Africa. Neither condom usage nor circumcision was associated with HPV DNA prevalence. CONCLUSION: Genital-HPV DNA detection is common in young, sexually active HM. We found HPV to be most prevalent in African men and least prevalent in men from the Asia-Pacific region. Increased numbers of sexual partners was an important risk factor for HPV DNA prevalence.

Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men.

BACKGROUND: We examined the baseline prevalence of penile, scrotal, perineal/perianal, and intra-anal human papillomavirus (HPV) infection in human immunodeficiency virus (HIV)-seronegative men who have sex with men (MSM). METHODS: Data were analyzed from 602 MSM aged 16-27 years with ≤ 5 lifetime sexual partners. Serum samples were tested for antibodies to HPV6/11/16/18. Swab samples were collected separately from several anogenital areas for detection of HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59 DNA. RESULTS: The prevalence of any tested HPV type was 18.5% at the penis, 17.1% at the scrotum, 33.0% at the perineal/perianal region, 42.4% in the anal canal, and 48.0% at any site. Overall, 415 MSM (69.7%) were negative to HPV 6, 11, 16, and 18 at enrollment by both serology and DNA detection. Men residing in Europe and Latin America had significantly increased risk of HPV infection at external genital sites and the anal canal compared to men from Australia. Tobacco use and greater number of lifetime sexual partners was associated with higher HPV infection prevalence. CONCLUSIONS: The prevalence of HPV infection is high among young sexually active MSM, with the anal canal being the most common site of infection. Lifetime number of sexual partners was the most important modifiable risk factor for anogenital HPV infection.