Does a Subset of Localized Chronic Fibrosing Vasculitis Represent Cutaneous Manifestation of IgG4-Related Disease/a Histologic Pattern of IgG4-Related Skin Disease? A Reappraisal of an Enigmatic Pathologic Entity.

Localized chronic fibrosing vasculitis (LCFV) is a rare cutaneous fibroinflammatory and vasculitic process of poorly defined etiology. Furthermore, controversy remains as to whether LCFV represents a primary pathologic process or a histologic pattern. The current case documents a 52-year-old male patient with a scrotal mass and clinical history of a retroperitoneal mass as well as a previously resected tumor of the right submandibular salivary gland displaying morphologic features of eosinophilic angiocentric fibrosis. Histologic examination of the resected scrotal mass revealed a tumefactive lesion characterized by focally storiform fibrosis, obliterative phlebitis, tissue infiltration by IgG4-positive plasma cells, and leukocytoclastic vasculitis. Apart from the leukocytoclastic vasculitis, the scrotal lesion demonstrated characteristic morphologic features of an IgG4-related disease (IgG4-RD). In recognition of the combined histologic findings of both LCFV and IgG4-RD in the scrotal mass, it was postulated that a subset of LCFV cases might represent cutaneous manifestations of IgG4-RD or a new histologic pattern of IgG4-related skin disease (IgG4-RSD). The literature analysis of previously reported LCFV cases appeared to lend credence to this hypothesis. Pathologists should be aware of this new histologic pattern of IgG4-RSD as judicious consideration for additional studies might potentially detect an unexpected systemic IgG4-RD in the patient, particularly in cases of LCFV displaying storiform fibrosis associated with plasma cell infiltrate.

Aspects of Langerhans cells and TNF-α in the cutaneous immunity of anogenital warts.

BACKGROUND: Anogenital warts are the leading sexually transmitted infection in patients seeking care at specialized clinics. They may display a vast array of forms, according to the interaction of the virus with the host's immunity. Cellular immunity is the epithelium's main form of defense against the virus, involving an active participation of the Langerhans cells and pro-inflammatory cytokines such as TNF-α. OBJECTIVE: To assess the epithelial immune response of anogenital warts in males, according to the number of lesions presented. METHODS: This is a prospective, cross-sectional study carried out at the dermatology outpatient clinic in a tertiary hospital. We included male patients over 18 years of age without comorbidities who had anogenital condylomata and no previous treatments.In order to evaluate the local epithelial immunity, the lesions were quantified, then removed and employed in CD1a immunohistochemistry assays for assessing the morphometry and morphology of Langerhans cells; TNF-α; reaction was used for determining cytokine positivity in the epithelium. RESULTS: 48 patients were included in the study. There was no statistically significant difference as to the number of Langerhans cells, in their morphology, or the presence of TNF-α. However, patients presenting with more Langerhans cells in the lesions had cells with a star-like and dendritic morphology, whereas in those with a lower cell count had cells with a rounded morphology and no dendrites (p<0.001). STUDY LIMITATIONS: Small number of patients analyzed. CONCLUSION: There was no difference in epithelial immunity between patients having few or many anogenital condyloma lesions as measured by the morphology and morphometry of Langerhans cells and TNF-α; positivity. Such an assessment employing immunity markers differing from the usual ones is expected to yield useful results.

Aspects of Langerhans cells and TNF-α in the cutaneous immunity of anogenital warts

Abstract Background: Anogenital warts are the leading sexually transmitted infection in patients seeking care at specialized clinics. They may display a vast array of forms, according to the interaction of the virus with the host's immunity. Cellular immunity is the epithelium's main form of defense against the virus, involving an active participation of the Langerhans cells and pro-inflammatory cytokines such as TNF-α. Objective: To assess the epithelial immune response of anogenital warts in males, according to the number of lesions presented. Methods: This is a prospective, cross-sectional study carried out at the dermatology outpatient clinic in a tertiary hospital. We included male patients over 18 years of age without comorbidities who had anogenital condylomata and no previous treatments.In order to evaluate the local epithelial immunity, the lesions were quantified, then removed and employed in CD1a immunohistochemistry assays for assessing the morphometry and morphology of Langerhans cells; TNF-α; reaction was used for determining cytokine positivity in the epithelium. Results: 48 patients were included in the study. There was no statistically significant difference as to the number of Langerhans cells, in their morphology, or the presence of TNF-α. However, patients presenting with more Langerhans cells in the lesions had cells with a star-like and dendritic morphology, whereas in those with a lower cell count had cells with a rounded morphology and no dendrites (p < 0.001). Study limitations: Small number of patients analyzed. Conclusion: There was no difference in epithelial immunity between patients having few or many anogenital condyloma lesions as measured by the morphology and morphometry of Langerhans cells and TNF-α; positivity. Such an assessment employing immunity markers differing from the usual ones is expected to yield useful results.

Evaluation of Patch Test Findings in Patients With Anogenital Dermatitis.

Importance: Contact dermatitis in the anogenital area is associated with sleep disturbance and dyspareunia and can profoundly affect quality of life. The literature on anogenital contact dermatitis and culprit allergens is limited. The last large-scale study on common, relevant allergens in patients with anogenital dermatitis was published in 2008. Objectives: To characterize patients with anogenital dermatitis referred for patch testing by the North American Contact Dermatitis Group, to identify common allergens, and to explore sex-associated differences between anogenital dermatitis and allergens. Design, Setting, and Participants: A retrospective, cross-sectional analysis was conducted of the North American Contact Dermatitis Group database among 28 481 patients who underwent patch testing from January 1, 2005, to December 31, 2016, at outpatient referral clinics in the United States and Canada. Exposure: Patch testing for allergens. Main Outcomes and Measures: Currently relevant allergic patch test reactions in patients with anogenital dermatitis. Results: Of 28 481 patients tested during the study period, 832 patients (336 men and 496 women; mean [SD] age, 50.1 [26.5] years) had anogenital involvement and 449 patients (177 men and 272 women; mean [SD] age, 49.6 [17.4] years) had anogenital dermatitis only. Compared with those without anogenital involvement, there were significantly more male patients in the group with anogenital dermatitis (177 [39.4%] vs 8857 of 27 649 [32.0%]; relative risk, 1.37; 95% CI, 1.14-1.66; P < .001). In the group with anogenital involvement, female patients were significantly less likely than male patients to have allergic contact dermatitis as a final diagnosis (130 [47.8%] vs 107 [60.5%]; relative risk, 0.78; 95% CI, 0.64-0.94; P = .01), whereas a final diagnosis of other dermatoses (eg, lichen planus, lichen sclerosus, or lichen simplex chronicus) was more frequent for female patients than for male patients (67 [24.6%] vs 28 [15.8%]; relative risk, 1.54; 95% CI, 1.02-2.31; P = .03). Of the 449 patients in the group with anogenital involvement only, 227 (50.6%) had 1 or more relevant reaction with patch testing. Allergens that were statistically significantly more common in patients with anogenital involvement compared with those without anogenital involvement included medicaments such as dibucaine (10 of 250 patients tested [4.0%] vs 32 of 17 494 patients tested [0.2%]; relative risk, 22.74; 95% CI, 11.05-46.78; P < .001) and preservatives such as methylchloroisothiazolinone and methylisothiazolinone (30 of 449 patients tested [6.7%] vs 1143 of 27 599 patients tested [4.1%]; relative risk, 1.61; 95% CI, 1.14-2.41; P = .008). A total of 152 patients met the definition for anogenital allergic contact dermatitis, which is defined as anogenital involvement only, allergic contact dermatitis as the only diagnosis, and 1 or more positive reaction of current clinical relevance. Conclusions and Relevance: For patients with anogenital involvement only who were referred for patch testing, male patients were more likely to have allergic contact dermatitis, whereas female patients were more likely to have other dermatoses. Common allergens or sources consisted of those likely to contact the anogenital area. For individuals with anogenital involvement suspected of having allergic contact dermatitis, reactions to preservatives, fragrances, medications (particularly topical anesthetics), and topical corticosteroids should be tested.

Highlighting a Potential Pitfall: Positive Treponema pallidum Immunohistochemical Stain in a Patient Without Syphilis.

The Treponema pallidum antibody immunohistochemical (IHC) stain has improved our ability to detect the organism histologically. We present a case of a man with genital condyloma acuminatum with a positive T. pallidum IHC stain but negative T. pallidum serologies and no syphilitic symptoms. It has been shown that the T. pallidum antibody IHC can cross-react, staining other spirochetes, including Borrelia burgdorferi and the Brachyspira family of intestinal spirochetes. Because of the proximity of our patient's lesions to the anus, and the persistently negative T. pallidum serologies, we believe nontreponemal spirochetes colonized the condyloma, giving a false-positive T. pallidum IHC. This cross-reactivity is a potential diagnostic pitfall and is important for the dermatopathologist to recognize, thereby avoiding false diagnosis of syphilis.

Levels of different cytokines in women and men with asymptomatic genital infection caused by Chlamydia.

INTRODUCTION: Immune response to genital Chlamydia trachomatis infection is involved in both immunity and pathology. The cytokine profile during infection has been implicated in the disease outcome, either resolution or severe sequelae. METHODOLOGY: In total, 3900 patients were analyzed for presence of genital infections caused by Chlamydia using molecular assays. Interleukins (IL) IL-10, IL-17, IL-6, IL-2 and chemokine IP-10 were estimated by ELISA in urine, cervical swabs and semen samples. Statistical analysis was performed using the T student test. RESULTS: A total of 47 out of 3900 samples (1.2%) were found to be positive for Chlamydia trachomatis based on the Real Time (RT) PCR results. Statistical analysis revealed that the differences between Chlamydia trachomatis positive and negative samples regarding levels of cytokines were not significant. CONCLUSIONS: Our results demonstrated that no significant difference in cytokine concentrations exists in Chlamydia trachomatis infected patients when compared to healthy controls. In further study, we aim to test on a greater number of positive samples a greater number of cytokines involved in the immune response to Chlamydia trachomatis infections.

Variants in immune-related genes and genital HPV 16 persistence in men.

OBJECTIVES: While most human papillomavirus (HPV) infection clears on its own, persistent HPV infection can cause genital warts and anal, penile and oropharyngeal cancers in men. We conducted genetic analysis in a sub-cohort of the HPV infection in men (HIM) study to test the hypothesis that differences in host genes influence HPV persistence in men. METHODS: Baseline and longitudinal genital HPV status at the genitals was measured every 6-months using the Linear Array assay amplified HPV L1 gene fragment using the PGMY09/11 L1 consensus primer system. DNA was extracted from peripheral blood and single nucleotide polymorphisms (SNPs) in the customized genome-wide genotyping array, the "TxArray," were examined using logistic regression in a case-control study design to assess the association with HPV16 persistence/clearance. RESULTS: Of the total of 737,742 autosomal SNPs in the array, 605,885 passed basic quality control and were examined between 40 men (cases) with > 18 months persistent genital HPV 16 infection vs. 151 controls who were HPV 16-positive, but whose infections cleared in < 18 months. The logistic regression analysis from this case-control study showed variants in several gene regions associated with genital HPV 16 persistence, with the strongest association detected with SNPs on chromosomes 20 (p < 5.72 × 10-6) and 15 (p < 5.89 × 10-6), after adjusting for age, smoking status, number of sex partners and four principal components (ancestral background). CONCLUSIONS: Our results provide a preliminary basis for understanding the biological mechanism of oncogenic HPV 16 pathogenesis at the genitals in men. Some of the genes flanking the top hit SNPs are consistent with previous findings in both HPV related and non-related cancers but further genetic studies in larger cohorts are warranted to confirm these and identify novel major susceptibility genes involved in the pathogenesis of genital HPV persistence in men.

Ageing and inflammation in the male reproductive tract.

Ageing is usually characterised by a mild chronic proinflammatory state. Despite the tight association between both processes, the phenomenon has recently been termed inflammageing. Inflammation in the male reproductive tract is frequently linked with bacterial or virus infections but also with a broad range of noninfectious processes. Prostatitis, epididymitis and orchitis, among others, can lead to infertility. However, in spite of the inflammation theory of disease, chronic inflammation in male urogenital system does not always cause symptoms. With advancing age, inflammatory processes are commonly observed in the male reproductive tract. Nevertheless, the incidence of inflammation in reproductive organs and ducts varies greatly among elderly men. Inflammageing is considered a predictor of pathogenesis and the development of age-related diseases. This article briefly summarises the current state of knowledge on inflammageing in the male reproductive tract. Yet, the precise aetiology of inflammageing in the male urogenital system, and its potential contribution not only to infertility but most importantly to adverse health outcomes remains almost unknown. Thus, further investigations are required to elucidate the precise cross-links between inflammation and male reproductive senescence, and to establish the impact of anti-inflammatory drug treatments on elder men's general health status.

Characterization of scrotal involvement in children and adolescents with IgA vasculitis.

OBJECTIVE: To characterize scrotal involvement in children and adolescents with IgA vasculitis. METHODS: A cross-sectional retrospective study included 296 IgA vasculitis (EULAR/PRINTO/PRES criteria) patients, 150/296 (51%) were males and assessed by demographic/clinical/laboratory and treatments. Scrotal involvement was defined by the presence of scrotal edema and/or pain/tenderness in physical examination and/or testicular Doppler ultrasound abnormalities. RESULTS: Scrotal involvement was observed in 28/150 (19%) IgA vasculitis patients. This complication was evidenced at IgA vasculitis diagnosis in 27/28 (96%). Acute recurrent scrotal involvement was observed in 2/150 (1%) and none had chronic subtype. Further analysis of patients with scrotal involvement at first episode (n = 27) compared to those without this complication (n = 122) revealed that the median age at diagnosis [4.0 (2.0-12) vs. 6 (1.3-13) years, p = 0.249] was similar in both groups. The frequency of elevated serum IgA was significantly lower in IgA vasculitis patients with scrotal involvement versus without this manifestation (18% vs. 57%, p = 0.017), whereas glucocorticoid (93% vs. 49%, p < 0.0001) and ranitidine use (63% vs. 30%, p = 0.003) were significantly higher in the former group. CONCLUSIONS: The scrotal involvement occurred in almost one fifth of IgA vasculitis patients and was commonly evidenced as acute subtype at diagnosis. Scrotal signs/symptoms improved after a prompt use of glucocorticoid and was associated with low frequency of elevated IgA serum levels.

[EFFECTIVENESS OF COMBINED TREATMENT OF HPV INFECTION].

This study evaluates the effectiveness of immunomodulating drug isoprinosine in a comprehensive treatment of genital warts in men. Most of the patients were aged 20-30 years. The combination therapy was found to have long term effectiveness. In the group of patients undergoing only destructive methods of treatment relapse after 8 month follow-up was diagnosed in 32% and in patients of the combination therapy group (destruction plus isoprinosine) - in 7% of patients. The pharmacological action of the drug (immunostimulating, antiviral) and the effectiveness of its combination with destructive therapies justify the use of inosine pranobex (isoprinosine) both in the complex therapy of genital warts and for the prevention of the disease recurrence.

A giant primary sclerosing lipogranuloma of the scrotum.

Sclerosing lipogranuloma is a rare, benign disease that can affect several organs, particularly of genitourinary system in males. The majority of the cases are secondary to exogenous foreign bodies. The masses are composed of granulomatous tissue formed around an either exogenous or endogenous lipomatous substance. We describe a 47-year-old male patient who presented with a growing, painless scrotal mass on physical examination. The mass was in 20 cm diameter and the laboratory findings were in normal limits. Pathologic evaluation confirmed the diagnosis of scrotal sclerosing lipogranuloma. To the best of our knowledge, this is the biggest scrotal sclerosing lipogranuloma case in the literature. We aimed with this presentation to keep in mind this benign lesion and also to assist the algorithmic approach.

Differential leucocyte detection by flow cytometry improves the diagnosis of genital tract inflammation and identifies macrophages as proinflammatory cytokine-producing cells in human semen.

Genital tract inflammation is considered as a major cause of male infertility with leucocytospermia as widely used diagnostic marker. However, threshold of 10(6) leucocytes ml(-1) recommended by the WHO is a matter of debate. Moreover, leucocyte subpopulations and their impact cannot be identified by the routine peroxidase method (POM). Ejaculates of subfertile men (n = 47) were analysed by flow cytometry (FACS) using a bead-based method. Leucocytes were identified by CD18 and further divided into macrophages (HLA-Dr+/CD66abce-) and neutrophils (HLA-Dr-/CD66abce+). IL-1ß, TNF-α and IL-6 production was investigated in these subpopulations. It was found that CD18-positive cells correlated significantly with POM. However, only in samples with POM below 10(6) per millilitre, FACS detected significantly higher leucocyte numbers. Moreover, in 31% of these samples, FACS leucocyte detection reached threshold values greater than 1 × 10(6)  ml(-1) , fulfilling the criteria for diagnosis of leucocytospermia. Neutrophils were the predominating leucocyte population. Nevertheless, in 24% of samples, macrophages encountered more than 50% of leucocytes. Most interestingly, only macrophages produced significant amounts of IL-1ß, TNF-α and IL-6. It is concluded that FACS improves detection and functional differentiation of seminal leucocytes as one of the diagnostic hallmarks of male genital tract inflammation.

Human papillomavirus-related genital disease in the immunocompromised host: Part I.

Human papillomavirus (HPV) is responsible for common condyloma acuminata and a number of premalignant and malignant anogenital lesions. These conditions are of particular concern in immunocompromised individuals who have higher risk of malignant transformation and are more difficult to treat. This is part I of a two-part review that will highlight the cutaneous features of condyloma acuminata and vaginal, vulvar, penile, and anal intraepithelial neoplasias, with an emphasis on presentation of these HPV-mediated diseases in the immunocompromised host. Counseling patients about these conditions requires a thorough understanding of the epidemiology, natural history of HPV, transmission and infectivity, risk of malignancy, and the role of the host immune response in clearing HPV lesions. Part II will provide an updated review of available treatments, with a focus on recent advances and the challenges faced in successfully treating HPV lesions in immunocompromised patients.

Factors associated with the seroprevalence of 26 cutaneous and two genital human papillomavirus types in organ transplant patients.

Viral skin infections are commonly present in organ transplant recipients (OTR). In this study, we aimed to identify factors associated with human papillomavirus (HPV) infections in OTR. Patients with solid-organ transplants were recruited from the outpatient nephrology and dermatology clinics in five European countries. Only patients with no current or past skin cancer were included in this analysis. Serum samples were analysed for antibodies to the L1 proteins of 26 cutaneous and two genital HPV types from five phylogenetic genera (α, ß, γ, µ and ν). The most consistent association was found between recreational sun exposure and the seroprevalence of all tested genera, except α. The antibody presence of any ß type was higher among people who had been transplanted at least 23 years prior to participation than in those who had been transplanted for less than 7 years. The prevalence of two γ-HPV types (60 and 65) and three ß-HPV types (15, 38 and 49) was associated with time since transplantation. The presence of a high number of warts was associated with the presence of any µ-PV or ν-PV types, and having greater than 50 keratotic skin lesions was almost significantly associated with the presence of antibodies to two or more γ-PV. Discrepancies in the results of the present study, as well as in previous reports, may depend on different methodologies and on geographical variations. Our results also indicate that further research with more standardized methods is needed to clarify the role of cutaneous HPV in OTR.

Serum antibody response following genital {alpha}9 human papillomavirus infection in young men.

Background. Although the prevalence of human papillomavirus (HPV) genital infection is similarly high in males and females, seroprevalence is lower in males. This study assessed rates and determinants of seroconversion after detection of genital HPV infection in young men. Methods. We investigated HPV type-specific seroconversion in a cohort of heterosexual male university students who had an α9 HPV type (HPV-16, -31, -33, -35, -52, -58, or -67) detected in the genital tract (n = 156). HPV DNA and antibodies were detected and typed using liquid bead-based multiplex assays. We calculated seroconversion using Kaplan-Meier survival analysis. Cox proportional hazards models with generalized estimating equations were used to examine associations with seroconversion. Results. Within 24 months of detecting genital HPV infection, type-specific seroconversion ranged from 4% for HPV-52 to 36% for HPV-31. HPV-16 seroconversion at 24 months was 13% (95% confidence interval [CI], 7%-25%). Among incident HPV infections, ever cigarette smoking and infection site(s) (shaft/scrotum and glans/urine vs shaft/scrotum or glans/urine only) were positively associated with type-specific seroconversion. Conclusions. For each of the α9 HPV types, type-specific seroconversion within 24 months was observed in 36% or less of infected men. Seroconversion might be related to cigarette smoking and genital site(s) infected.

Antimicrobial responses in the male reproductive tract of lipopolysaccharide challenged rats.

PROBLEM: Innate immune machinery including the Toll-like receptors (TLRs) confers the first line of defense mechanisms to counter pathogenic microorganisms that enter the body. The male reproductive tract is vulnerable to infection and the role of TLRs and the antimicrobial responses that operate to counter infections in this organ system are poorly understood. METHOD OF STUDY: Caput and cauda epididymides, testes and seminal vesicles were collected at 0, 3, 6, 9, 12, 15 and 24 h from rats injected intraperitoneally with a single dose of LPS. Plasma testosterone was measured using ELISA. Expression pattern of defensins and Spag11 isoforms were analysed using RT-PCR. Immunohistochemical analyses was performed to determine SPAG11E protein expression following LPS treatment. RESULTS: We provide the first line of evidence that the male reproductive tract induces the expression of Sperm Associated Antigen 11 (Spag11) mRNA variants and defensins when challenged with lipopolysaccharide (LPS) with a concomitant increase in protein expression. However, there was an inverse relationship between induction of antimicrobial gene expression and plasma testosterone. An increase in the mRNA levels of proinflammatory cytokines was observed parallel to the induction of Spag11 variants and majority of defensin expression in the male reproductive tract. CONCLUSION: The increase in Spag11 and defensin mRNA in response to LPS administration demonstrates their importance in protecting the male reproductive tract during infection. Results of this study help to understand male reproductive tract innate immune defense mechanisms and to design novel peptide antibiotics to prevent sexually transmitted diseases.