The possible role of human papillomavirus infection in the development of lichen sclerosus.

Lichen sclerosus (LS) is a chronic inflammatory skin disease of unknown origin predominantly affecting the anogenital area that causes pruritus and pain and is associated with an increased risk of malignancy. In some cases, LS vanishes after application of imiquimod, raising the question whether human papillomavirus (HPV) may have an etiopathogenic role in anogenital LS. The databases MEDLINE and Embase were systematically searched using the PRISMA guidelines. Twenty-seven papers were included that reported the prevalence of HPV in LS and in LS associated with neoplasia. HPV was identified in 0-80% (median 22%) of all LS cases. The prevalence of HPV was higher among male patients with LS (median 29%) than among female patients (median 8%). HPV16 was the most prevalent genotype, but the distribution of genotypes indicates that even low-risk HPV can cause LS. The diverging detection rates are probably due to small sample sizes in the reviewed papers and different detection methods. Factors possibly underestimating the prevalence of HPV are a selective search for high-risk HPV, DNA destruction in fixed tissue, focally residing HPV, and possibly a clearing of HPV before the time of biopsy. Seventy-five percent of sexually active people acquire HPV during their lifetime, thus HPV alone is not a cause of LS. Genetic and immunological host factors and viral factors other than type are likely to contribute. Future studies should include patients with a short duration of symptoms, and biopsies should be multiple and fresh.

HPV status and favourable outcome in vulvar squamous cancer.

It is universally accepted that high-risk human papillomavirus (HR-HPV) is the cause of cervical dysplasia and cancer. More recently, it has been shown that HPV is also a marker of clinical outcome in oropharyngeal cancer. However, contemporary information is lacking on both the prevalence of HPV infection in vulvar cancer (VSCC), its precursor lesion, vulvar intraepithelial neoplasia (VIN) and the influence of HPV-status on the prognosis of this malignancy. We have conducted a detailed population-based study to examine rates of progression of VIN to VSCC, type-specific HPV prevalence in vulvar disease and the influence of HPV status on clinical outcome in VSCC. We observed that the age at which women are diagnosed with VSCC is falling and there is a significant time gap between first diagnosis of VIN and progression to invasive disease. HR-HPV infection was detected in 87% (97/112) cases of VIN and 52% cases (32/62) of VSCC. The presence of HR-HPV in squamous intraepithelial lesion was associated with lower rates of progression to invasive cancer (hazard ratio, 0.22, p = 0.001). In the adjusted analysis, HR-HPV was associated with improved progression-free survival of VSCC compared to those with HPV negative tumours (hazard ratio, 0.32, p = 0.02).

The presence of human papillomavirus and Epstein-Barr virus in male Chinese lichen sclerosus patients: a single center study.

This study aimed to investigate the presence of human papillomavirus and Epstein-Barr virus in male lichen sclerosus patients. We extracted DNA from formalin-fixed paraffin-embedded foreskin tissue blocks of 47 male LS patients and 30 healthy men and performed real-time PCR test to detect HPV and EBV. None of the 47 LS patients and 30 healthy men had detectable HPV infection. EBV was detected in 18 LS patients (38.3%) and four healthy men (13.3%), the difference is significant (P < 0.05). Tissue blocks with significant inflammatory reaction tend to have higher EBV load. HPV has no significant relationship with LS. Male LS patients have higher EBV infection rate, but the role of EBV in the pathogenesis of LS needs further investigate.

L1 gene sequence of a putative novel type human papillomavirus in an immunocompetent patient with glans lichen sclerosus.

The identification of a putative novel type human papillomaviruses (HPV) strain related to HPV-RTRX3 in a subject with penile skin warts and glans lichen sclerosus is reported. A beta-HPV-RTRX3-like strain was detected in a immunocompetent patient with glans lichen sclerosus. HPV screening was performed by PCR in L1 gene. The MY fragment showed 99% nt identity with HPV-RTRX3 and 64.5% nt identity with HPV-37. The remaining part of the L1 gene showed similarity with HPV 80, 15, 17, and 37. Based on the presence of penile lichen sclerosus and the HPV-RTRX3-like strain found in our patient, a potential correlation was hypothesized.

Differential gene hypermethylation in genital lichen sclerosus and cancer: a comparative study.

AIMS: Lichen sclerosus (LS) is a chronic inflammatory disease of the genital skin of unknown aetiology. The role of LS in penile squamous cell carcinogenesis is not well characterized. HPV has been implicated in both, as have epigenetic changes. The presence of HPV and hypermethylation of the MGMT, p16, RASSF1, RASSF2, TSLC1 and TSP1 genes were studied in penile LS; MGMT, RASSF2 and TSLC1 hypermethylation in penile cancer and TSLC1 hypermethylation in vulvar LS and cancer extends previous results reported by our group. METHODS AND RESULTS: Thirty-seven HPV genotypes and hypermethylation were evaluated by PCR/reverse-line-blot and methylation-specific PCR respectively, in 27 preputial LS, 24 penile SCC, 30 vulvar SCC, 21 vulvar LS and 22 normal skin cases. HPV66 was present in 3.7% of penile LS cases, and p16 and RASSF2 hypermethylation were more frequent in penile cancer than in penile LS. p16, RASSF1, RASSF2 and TSP1 hypermethylation were similar in penile and vulvar LS. CONCLUSIONS: Gene hypermethylation is a common event in penile LS, and occurs approximately as frequently as in vulvar LS. Certain genes can be hypermethylated as an early or late event in LS or cancer, respectively. This suggests a possible sequential role for these alterations in the transition from benign to malignant lesions.

Pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma.

Vulvar squamous cell carcinoma (VSCC) accounts for >90% of the malignant tumours of the vulva. Most VSCCs originate in intraepithelial lesions, named vulvar intraepithelial neoplasia (VIN), that precede the development of VSCC by a variable period of time. Strong evidence has accumulated showing that there are two different aetiopathogenic pathways for the development of VSCC and VIN, one associated with infection by human papillomavirus (HPV), and a second independent of HPV infection. These two different types of VSCC have different epidemiological, pathological and clinical characteristics, and should therefore be considered as two separate entities. Histologically, HPV-associated VSCCs are of the basaloid or warty type, and arise from VIN of the usual type. Inactivation of p53 and the retinoblastoma tumour suppressor gene product by the viral gene products E6 and E7 is involved in the process of malignant transformation. HPV-independent VSCCs are histologically keratinizing, are associated with differentiated VIN and lichen sclerosus, and frequently show mutations of p53. p16(INK4a) and p53 immunostaining can be useful for classifying VSCC into HPV-associated or HPV-independent. Although large, multicentre studies are needed to definitively assess the involvement of HPV in the prognosis of VSCC, most studies have not found clear differences in survival between HPV-associated and HPV-independent tumours.

Human papillomavirus, lichen sclerosus and penile cancer: a study in Belgium.

PURPOSE: The prevalence of penile cancer varies between 1.5 (industrialized countries) and 4.5 per 100,000 men (non-industrialized countries). Predominant histological subtype is squamous cell carcinoma (SCC). Human papillomavirus (HPV) is found in 40-46% of cases: penile cancer is considered to behave as vulvar cancer. Non HPV related risk factors are lack of circumcision, phimosis, chronic inflammation, and smoking. The role of lichen sclerosus (LS) is unclear. Clinical diagnosis is difficult and treatment often mutilating. Preventive measures can be taken since the risk factors are known: the use of the prophylactic HPV vaccines may contribute. We measured the prevalence of HPV and LS in penile cancer in Belgium. MATERIALS AND METHODS: We found 76 samples of penile lesions in the archives of the departments of Histology of four university hospitals in Belgium. Real-time PCR of type-specific HPV DNA was performed targeting 18 HPV types. PRINCIPAL RESULTS: Patients with penile intraepithelial neoplasia (PeIN) were 56.1 years of age: patients with invasive penile cancer (IPC) 68.5 (p=0.009). Fifty-five samples (55/76) were adequate for HPV targeting. Overall HPV DNA was 70.9%: 89.5% in samples of PeIN (n=19) and 61.1% in samples of IPC (n=36). Invasive penile cancer samples were less likely to be HPV infected (p=0.028). HPV 16 was most prevalent: 48.3%: 20% PeIN, and 28.3% IPC. HPV DNA of the types, included in the prophylactic vaccines, was found in 33% of PeIN and 31.7% of IPC samples. Thrice, low risk HPV (lrHPV) types 6 (1 IPC) and 11 (1 PeIN, 1 IPC) were solely present. There was no difference in the presence of LS between HPV positive and HPV negative samples (p=0.944). CONCLUSIONS: Prevalence of HPV DNA in penile lesions in Belgium is high. However, the prophylactic vaccines may contribute to primary prevention of only a subset of cases. The role of LS remains unclear.

Lichen sclerosus and squamous cell carcinoma.

Lichen sclerosus is a chronic inflammatory disease that can progress to malignancy. The literature indicates an association with anogenital squamous cell carcinoma and verrucous carcinoma. Two pathogenic pathways, differentiated vulvar and penile intraepithelial neoplasias, which have recently been described in relation to squamous cell carcinoma, are both highly associated with genital lichen sclerosus independently of human papilloma virus (HPV) infection. Furthermore, tumor-promoting molecular changes unrelated to HPV infection have been demonstrated and may explain the malignant potential of lichen sclerosus. The possible relationship between HPV and genital lichen sclerosus currently remains open to discussion, and the prognostic importance of the overlapping of these 2 diseases is still unclear. This review considers the relationship between lichen sclerosus and squamous cell and verrucous carcinomas, the possible oncogenic mechanisms involved, and their possible association with HPV infection.

[Lichen sclerosus and squamous cell carcinoma]. / Liquen escleroso y carcinoma escamoso.

Lichen sclerosus is a chronic inflammatory disease that can progress to malignancy. The literature indicates an association with anogenital squamous cell carcinoma and verrucous carcinoma. Two pathogenic pathways, differentiated vulvar and penile intraepithelial neoplasias, which have recently been described in relation to squamous cell carcinoma, are both highly associated with genital lichen sclerosus independently of human papilloma virus (HPV) infection. Furthermore, tumor-promoting molecular changes unrelated to HPV infection have been demonstrated and may explain the malignant potential of lichen sclerosus. The possible relationship between HPV and genital lichen sclerosus currently remains open to discussion, and the prognostic importance of the overlapping of these 2 diseases is still unclear. This review considers the relationship between lichen sclerosus and squamous cell and verrucous carcinomas, the possible oncogenic mechanisms involved, and their possible association with HPV infection.

Penile carcinogenesis in a low-incidence area: a clinicopathologic and molecular analysis of 115 invasive carcinomas with special emphasis on chronic inflammatory skin diseases.

BACKGROUND: Human papillomavirus (HPV) infections account worldwide for 50% of penile cancers. The role of lichen sclerosus and lichen planus in penile carcinogenesis needs further investigation. MATERIALS AND METHODS: Archival formalin-fixed high-grade penile intraepithelial neoplasias, differentiated penile intraepithelial neoplasias, and invasive carcinomas from a single pathology institution in a low-incidence area for penile cancer were analyzed for 28 HPV low-risk and HPV high-risk genotypes, p16 overexpression, presence of peritumoral lichen sclerosus, lichen planus, precursor lesions, and monoclonal rearrangement of the T-cell receptor γ locus. RESULTS: A total of 29 penile intraepithelial neoplasias (100%) and 69 of 115 (60%) invasive cancers contained HPV high-risk genotypes with a single HPV high-risk genotype (80% HPV16, 6% HPV33, 2% HPV45 and HPV18, 1% HPV73). Multiple HPV high-risk genotypes were identified in 4% with and in 5% without HPV16/18. p16 overexpression correlated in all but 1 case of HPV high-risk 45 cancer. No p16 overexpression and HPV genotype was found in 6 differentiated penile intraepithelial neoplasias and 46 of 115 (40%) invasive cancers, 30% of which were pT2/pT3 cancers. For 35 cancers, peritumoral tissue was available for analysis. Advanced lichen sclerosus was identified in 26, lichen planus in 9, and differentiated penile intraepithelial neoplasia in 18 carcinomas. Dense T-cell-dominant lymphocytic infiltrates were identified in 22 of 46 carcinomas and in 3 of 6 differentiated penile intraepithelial neoplasias, with 6 of 13 analyzed carcinomas/penile intraepithelial neoplasias showing a monoclonal rearrangement of the T-cell receptor γ locus. CONCLUSIONS: The prevalence of HPV high-risk in penile cancers from a low-incidence area was slightly higher than the global distribution. HPV-negative carcinomas were associated with advanced lichen sclerosus and lichen planus, differentiated penile intraepithelial neoplasia, and accumulation of T lymphocytes with monoclonal rearrangement of the T-cell receptor γ locus.

Specific serologic response to genital human papillomavirus types in patients with vulvar precancerous and cancerous lesions.

OBJECTIVE: Antibodies to human papillomavirus are indicative for previous human papillomavirus exposure. Human papillomavirus antibody reactivities to vulvar precancerous lesions were reported poorly, and the role of human papillomavirus in some of these lesions is still unclear. STUDY DESIGN: In a direct enzyme-linked immunosorbent assay, serum samples from 126 healthy control subjects, 97 women with lichen sclerosus with or without squamous hyperplasia, 78 women with vulvar intraepithelial neoplasia, and 16 women with verrucous carcinoma were examined for immunoglobulin G and A antibodies to L1 virus-like particles of genital human papillomavirus types 6, 11, 16, 18, and 31, cutaneous human papillomavirus type 8, bovine papilloma virus, and cottontail rabbit papilloma virus. RESULTS: In lichen sclerosus/squamous hyperplasia with atypia immunoglobulin G and A, antibody positivity rates to high-risk human papillomavirus virus-like particle types 16, 18, and 31 were significantly higher than in the control group and the lichen sclerosus/squamous hyperplasia group without atypia. In patients with vulvar intraepithelial neoplasia I, increased immunoglobulin G antibody prevalences with both high-risk and low-risk human papillomavirus-virus-like particles were detected; whereas in patients with vulvar intraepithelial neoplasia II/III, this was observed only with the human papillomavirus types 16, 18, and 31. When only reactivities with 2 genital human papillomavirus types were compared, percentages of positives to only 1 of these 2 types ranged between 43% and 82%, with regard to all respective positives. CONCLUSION: Our data support the role of high-risk human papillomavirus types, mainly human papillomavirus-16, in the pathogenesis of different vulvar lesions with atypia. Serologically, there are no indications that lichen sclerosus/squamous hyperplasia without atypia is associated with human papillomavirus, but high-risk human papillomavirus in lichen sclerosus/squamous hyperplasia with atypia could play a role in carcinogenesis. High antibody specificity was clearly demonstrated among 5 genital, 1 cutaneous human, and 2 animal papillomavirus types.

Analysis of clonality and HPV infection in benign, hyperplastic, premalignant, and malignant lesions of the vulvar mucosa.

To elucidate the pathogenesis of vulvar carcinomas, we studied clonality and human papillomavirus (HPV) infection in vulvar epithelial diseases. Monoclonal composition was demonstrated in all 9 invasive tumors (squamous cell carcinoma [SCC], 6; basal cell carcinoma, 1; malignant melanoma, 2), 15 of 20 cases of vulvar intraepithelial neoplasia (VIN), 7 of 9 cases of Paget disease, 2 of 6 cases of lichen sclerosus (LS), and 2 of 3 cases of squamous cell hyperplasia (SCH); high-risk type HPV was revealed in 5 of 6 SCCs and 17 of 20 VINs. These observations might imply that a subset of cases of LS and SCH result from a neoplastic proliferation, similar to VINs but not related to infection with high-risk type HPV. In 1 case of SCC with concurrent VIN 3 in an adjacent lesion, both lesions showed the same pattern of X chromosome inactivation and the presence of HPV-16 in episomal and integrated forms, suggesting that monoclonal expansion triggered by high-risk type HPV integration is an early event for carcinogenesis of HPV-associated SCC.

Development of multifocal squamous cell carcinoma in lichen sclerosus et atrophicus of the penis associated to HCV hepatitis.

We describe the case of a 59-year-old uncircumcised man, with a history of meatal stenosis and balanitis xerotica obliterans (lichen sclerosus et atrophicus) and human C virus hepatitis, who developed an infiltrating squamous cell carcinoma of the penis. The relationship among these conditions is discussed.

Lichen sclerosus is frequently present in penile squamous cell carcinomas but is not always associated with oncogenic human papillomavirus.

BACKGROUND: Penile squamous cell carcinoma (SCC) may occur on pre-existing lesions of lichen sclerosus (LS). However, the prevalence of histological changes of LS in penile SCC is not well established. Moreover, mucosal oncogenic human papillomaviruses (HPVs) are sometimes detected in penile SCC, but have not been systematically sought in LS-associated penile SCC. OBJECTIVES: To establish the prevalence of LS histological changes and of mucosal oncogenic HPV in a series of patients with penile SCC. METHODS: Consecutive cases of histologically proven penile SCC from a single university hospital over a 14-year period were retrospectively selected and reviewed. Histological signs of LS were systematically sought. HPV was detected by polymerase chain reaction (PCR) amplification of DNA from paraffin-embedded skin samples using general primers GP5+/GP6+ (allowing detection of mucosal HPV) and oncogenic type 16-, 18-, 31- and 33-specific primers. RESULTS: Eighteen cases of penile SCC were found. The mean +/- SD age of patients at diagnosis was 67.3 (14.5 years). In eight of 18 (44%) cases, SCC was associated with histological features of LS. Seventeen skin biopsy specimens of SCC (nine without and eight with LS histology) were subjected to PCR amplification for HPV. Mucosal HPV was detected in six of them (35%). Five of nine SCCs without histological features of LS were positive for mucosal HPV: three with HPV type 16 and two with only general primers. In contrast, all eight SCCs associated with LS were negative for oncogenic HPV types, although one was positive with general primers. CONCLUSIONS: Penile SCC seems to be frequently associated with LS histological changes. As with vulval SCC, we found that non-LS-associated penile SCC tended to be frequently associated with oncogenic HPV infection, whereas LS-associated penile SCC was not. Larger series are needed to confirm this association.

Potential human papillomavirus reactivation following topical corticosteroid therapy of genital lichen sclerosus and erosive lichen planus.

Using a highly sensitive polymerase chain reaction (PCR) technique, based on general GP5+/GP6+ PCR primers covering 34 different human papillomavirus (HPV) types, the presence of HPV DNA was studied in paraffin-embedded penile biopsies from 20 men treated topically with corticosteroids. Clobetasol propionate was applied for 2-16 (mean 7) weeks by 19 men (age 18-73; mean 40) with lichen sclerosus. High-risk HPV was detected prior to therapy in three patients (16%) who lacked clinical or histopathological signs of HPV infection. Following therapy high-risk HPV was detected in biopsies from four men (21%), of whom three also exhibited clinical and/or light microscopic signs of HPV infection. Low-risk HPV DNA was not detected in any of these samples. Four biopsies were collected during a 5-year period from a 51-year-old man who was treated repeatedly with topical mild-moderate potent corticosteroids at intervals of up to 10 weeks for penile erosive lichen planus, followed by nine clinical outbreaks of typical condylomas that consistently showed the presence of low-risk HPV DNA only. These observations indicate that long-lasting topical corticosteroid therapy occasionally may be associated with opportunistic reactivation of a latent high- and low-risk mucosotrophic HPV type infection. The importance of clinical follow-up is underlined.

Human papillomavirus-negative spindle cell carcinoma of the vulva associated with lichen sclerosus: case report and literature review.

Although spindle cell carcinoma (SC) is a common neoplasm in the oral cavity, upper respiratory tract, and other head and neck areas, its occurrence in the vulva is rare. We report a case of this rare condition with immunohistochemical, ultrastructural, and human papillomavirus (HPV) testing. The neoplastic cells were positive for vimentin, keratins (AE1-AE3, keratin 902, and keratin 903), and epithelial membrane antigen. Ultrastructurally, they showed primitive junctions and tonofilaments. HPV testing by polymerase chain reaction was negative. In addition, we review the clinicopathologic findings of the four well-documented cases of vulvar SC that have been reported previously in the English language literature.

Lymphohistiocytic and granulomatous phlebitis in penile lichen sclerosus.

Lichen sclerosus (LS) is a chronic inflammatory disease of unknown etiology that may affect the genital and/or extragenital skin of individuals of either sex at all ages. In boys, the prepuce is the most common site of involvement. The diagnostic criteria of LS include the presence of inflammatory infiltrates mainly composed of T lymphocytes. We report on two cases of LS of the prepuce because of the unusual feature of lymphocytic (CD45RO+ and CD20+), histiocytic (CD68+), and granulomatous phlebitis. This lesion was not present in a group of another 18 cases of childhood penile LS. We have not been able to find any references describing and illustrating inflammatory involvement of the dermal vein walls in LS. Unlike the data reported in the literature, the dermal inflammatory infiltrates of these two cases showed a similar proportion of B and T lymphocytes in addition to frequent CD68+ histiocytes.

Human papillomavirus is present in some cases of childhood penile lichen sclerosus: an in situ hybridization and SP-PCR study.

Lichen sclerosus (LS) is a skin disease that may affect both sexes at all ages and at any site. Its etiology remains unknown. The observation of focal koilocytotic-like changes in the stratum malpighii in prepuce samples of LS in children prompted us to investigate the presence of HPV-DNA. Twenty-three paraffin-embedded samples of LS lesions from children aged 4 to 14 years were studied using nested-PCR and in situ hybridization (ISH). Twelve out of 23 cases amplified HPV-DNA (8 cases corresponded to HPV-DNA type 6; 2 cases each to HPV-DNA types 16 and 18). ISH detected HPV sequences in the nuclei of koilocytotic and some parakeratotic cells in 13 cases (9/13 also HPV-DNA positive by PCR). Our results demonstrated the presence of HPV-DNA in roughly 70% of cases of LS of the prepuce in children. We highlight the observation of koilocytotic-like changes in the prepuce and its association with HPV. The possible pathogenetic significance between the virus and the lesion is not settled.