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.     

Association of penile lichen sclerosus and oncogenic human papillomavirus infection

BACKGROUND: Data on the prevalence of human papillomavirus (HPV) infection in patients with penile lichen sclerosus (LS) are scant and controversial. AIM: To investigate the prevalence of HPV infections in patients with penile LS. METHODS: HPV infection was assessed by polymerase chain reaction (PCR) in paraffin-embedded penile biopsies obtained from the glans or inner foreskin of 46 adult patients with penile LS, and in brush cytology smears of penile healthy mucosa from an equal number of randomly selected control males matched for age. Statistical evaluation was performed using conditional logistic regression analysis. RESULTS: PCR disclosed the presence of HPV infection in 17.4% of LS patients (HPV 16, six cases; HPV 18, one case; HPV 45, one case). Amongst the controls, HPV infection occurred in 8.7% of patients (HPV 16, two cases; HPV 53, one case; HPV 70, one case). Statistical regression analysis confirmed that the rate of HPV infection was higher amongst patients with genital LS than amongst healthy controls [odds ratio (OR), 2.55; 95% confidence interval (CI), 0.73-8.89]. CONCLUSIONS: Infection with oncogenic "high-risk" HPV types in patients with genital LS may enhance the risk of penile cancer arising on LS.     

Human papillomavirus-associated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma.

BACKGROUND: Human papillomaviruses (HPVs) are sexually transmitted human carcinogens that may play a role in the oncogenesis of penile cancer. OBJECTIVES: To investigate the role of HPV infection and expression of the tumour suppressor protein p16INK4A in the pathogenesis of penile cancer. METHODS: By means of polymerase chain reaction amplification and reverse hybridization line probe assay to detect HPV infection, and immunohistochemical staining for p16INK4A and Ki67, we analysed 26 penile squamous cell carcinomas (SCCs) and 20 independent penile lichen sclerosus (LS) lesions from 46 patients. RESULTS: HPV DNA was found in 54% of penile SCCs and 33% of penile LS cases in single and multiple infections. High-risk HPV 16 was the predominant HPV type detected. No relationship between Ki67 expression and HPV infection was observed. Strong immunostaining for p16INK4A correlated with HPV 16/18 infection in both penile LS and penile SCC. In our penile SCC series the cancer margins were also associated with penile LS in 13 of 26 lesions, and HPV was detected in seven of the 13 SCC cases associated with LS and in six of the 11 SCC lesions not involving LS. CONCLUSIONS: Our study shows a high prevalence of HPV 16 and p16INK4A expression in penile lesions, consistent with an active role for HPV in interfering with the retinoblastoma pathway. High-risk HPV infection could be involved in the tumorigenic process in 50% of penile cancers, and the use of prophylactic HPV vaccines has the potential to prevent these cancers.     

High incidence of lichen sclerosus in patients with squamous cell carcinoma of the penis

BACKGROUND: There is a well-documented association between lichen sclerosus (LS) and vulval carcinoma in women; however, until recently, there have only been anecdotal reports of penile squamous cell carcinoma (SCC) occurring in men with LS. OBJECTIVE: The incidence of penile carcinoma occurring on a background of LS remains uncertain, and we wished to examine this possible association further. METHOD: To address this, all the cases (n = 20) of penile SCC held on our pathology database (4 years) were examined. Histology was reviewed, blind to the clinical picture, for evidence of LS, applying strict histological criteria. Subsequently, clinical notes were reviewed for history of LS before the SCC presented, and history of previous circumcision, treatments, node involvement, metastases and death. RESULTS: In eight cases, evidence of LS was found in the excision specimen. Seven of these had well-differentiated SCC. In the 12 cases with no evidence of LS, only three were well differentiated. With case note review, seven had a history of LS (four with histological LS), sometimes preceding the SCC by 10 years. These all had well-differentiated SCC. Ten of the 20 patients are dead, seven from metastatic disease. Four deaths occurred in the 'well-differentiated LS' group, but only one from penile SCC metastatic disease. CONCLUSIONS: There appears to be a definite association between SCC of the penis and the presence of LS, similar to that reported between LS and vulval SCC in women. Of the 20 patients with penile SCC studied, 11 had a clinical history and/or histological evidence of LS. However, clinical presentation of the LS or need for circumcision may precede the SCC by many years. As follow-up is impractical, counselling at the time of diagnosis is very important, and it is essential that medical practitioners are aware of this association so that the subsequent risk from SCC is reduced.     

Treatment of lichen sclerosus with carbon dioxide laser vaporization

We have treated 10 patients (five women and five men) with lichen sclerosus (LS), verified by histopathological studies from skin biopsies, with CO₂ laser vaporization. All men studied had LS of the penile skin, of the women, three had extragenital lesions and two LS of the perineal skin. The mean follow-up time was 32 months (range 3-79 months). One man had both penile and urethral LS. All penile lesions of the five men were clinically cured by laser treatment: however, urethral lesions of one patient recurred despite three separate treatments. The two women with perineal LS improved after laser treatment. However, LS recurred on the treated area in one and on the margins of the treated area in another. Two women with LS on the skin of the breast became asymptomatic after treatment. One woman had several lesions on the skin of the trunk that improved after treatment but were not cured completely. The present study suggests that carbon dioxide vaporization may be an effective treatment of skin lesions in LS.     

Penile cancer among patients with genital lichen sclerosus

BACKGROUND: Genital lichen sclerosus (LS) has sporadically been reported to be associated with penile squamous cell carcinoma (SCC). OBJECTIVE: The purpose of this study was to assess the risk of malignant degeneration in a series of male patients affected by genital LS. METHODS: All cases of histologically proven epithelial malignancy associated with penile LS recorded in our pathology files over a 10-year period (1987-1997) were reviewed. Assessment for presence of human papillomavirus (HPV) was performed from paraffin-embedded tissues using polymerase chain reaction (PCR). RESULTS: Five of 86 white and uncircumcised men with genital LS (mean age at diagnosis, 53 years; range, 22-83 years) showed malignant or premalignant histopathologic features: 3 had SCC, one had erythroplasia of Queyrat (unifocal SCC in situ), and one verrucous carcinoma. The average lag time from onset of LS was 17 years (range, 10-23 years). Histologically, transition from LS to frank neoplastic foci was evident in all cases of SCC. In these SCC cases, areas of epithelial dysplasia were well evident at the tumor periphery. In the remaining cases, the histologic findings were consistent with erythroplasia of Queyrat and verrucous carcinoma. PCR detected HPV 16 infection in 4 of the 5 cases; one SCC patient was negative for HPV. CONCLUSION: Malignant changes were associated with 5.8% of the cases of penile LS in our series. Therefore patients with genital LS are at considerable risk of the development of penile SCC, as well as other epithelial and in situ carcinomas, namely verrucous carcinoma and erythroplasia of Queyrat. HPV infection probably plays a major role because 4 of 5 patients were positive for HPV. Histologically, epithelial dysplasia may represent a precancerous stage before the development of neoplasia in atrophic nonproliferative LS lesions, as its presence at the tumor periphery in our SCC biopsy samples seemed to suggest.     

Penile lichen sclerosus: Correlation between histopathologic features and risk of cancer

The relationship between penile lichen sclerosus (LS) and cancer development has not been clearly assessed so far. In order to define these histological features of LS that may indicate or precede a malignant degeneration, 104 biopsy specimens from 86 patients with LS of the glans (90.5%) and from 9 patients with a penile malignancy (7 squamous cell carcinomas, 1 in situ carcinoma, and 1 verrucous carcinoma) arising on LS (9.5%) were reviewed. Three different histopathologic LS patterns were identified: pattern 1 with a prominent lichenoid inflammatory infiltrate in the dermis (9%), pattern 2 characterized by a band-like infiltrate separated from the epidermis by a band of dermal sclerosis (44%), and pattern 3 showing prominent sclerosis with minimal or absent inflammatory infiltrate (9%). These patterns have previously been described in vulvar LS, and have been considered typical of early, mature, and late LS, respectively. In our study, we also found a fourth pattern in 38% of cases, with overlapping features between the first and third pattern, occasionally showing areas of epidermal thickening, with loss of the normal keratinocyte cytoarchitectural differentiation, mitoses and apoptotic cells. In our opinion, the histological features observed in this last pattern may be interpreted as areas of disease reactivation within a chronic stage. Furthermore, 7 out of 9 cases of penile cancer from our series (78%) were associated with this pattern, suggesting that it may correlate with a malignant degeneration.     

Genital verrucous carcinoma is associated with lichen sclerosus: a retrospective study and review of the literature

Background The association of lichen sclerosus (LS) with genital squamous cell carcinoma is well recognized. However, the relationship between LS and verrucous carcinoma remains unclear. Objective To evaluate the associations of genital and perianal verrucous carcinomas with LS. Methods We conducted a retrospective study on patients with a genital or perianal verrucous carcinoma and reviewed their histopathology specimens and clinical notes. We also conducted a literature review. Results We identified a total of 13 patients (including 6 women and 7 men) with a genital or perianal verrucous carcinoma. All 5 women with vulval verrucous carcinoma had coexisting LS (5/5), and 1 man with penile verrucous carcinoma had coexisting LS (1/3). In contrast, no coexisting LS was found in all 5 cases of perianal verrucous carcinoma (0/5). Half of the cases of verrucous carcinoma with coexisting LS had recurrences (3/6), while no recurrences were found in those without coexisting LS (0/7). Conclusions Our study and review of the literature demonstrate that vulval verrucous carcinoma is strongly associated with LS. In contrast, perianal verrucous carcinoma is not associated with LS. When genital verrucous carcinoma is diagnosed, it is important to consider LS as a potential concomitant diagnosis and offer appropriate treatments and close follow‐up to detect recurrence of verrucous carcinoma.     

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.     

Balanitis xerotica obliterans: a review of diagnosis and management

Balanitis xerotica obliterans (BXO), or penile lichen sclerosus, is a progressive sclerosing inflammatory dermatosis of the glans penis and foreskin. It is associated with significant morbidity and may result in impaired urinary and sexual function. It was initially described by Stuhmer in 1928, named after its pathological features, and is considered the male equivalent of vulvar lichen sclerosis (LS).^3,40 The etiology of BXO is uncertain; however, autoimmune disease, local trauma, and genetic and infective causes have been proposed. BXO occurs most commonly on the prepuce and glans penis. It is considered to have premalignant potential to transform into squamous neoplasia. This postulation rests on retrospective studies and parallels drawn with vulvar LS and squamous cell carcinoma (SCC) development. Histologically, BXO and vulvar LS are considered the same disease.⁴¹ There is a paucity of evidence-based guidelines to assist with appropriate follow-up for patients with BXO.     

Incidence of preputial lichen sclerosus in adults: histologic study of circumcision specimens

BACKGROUND: Narrowing of the prepuce in men is poorly documented, and the causes are often unknown, except in the case of clinical infections or skin diseases such as lichen sclerosus (LS). OBJECTIVE: We conducted a histologic study of circumcision specimens with phimosis or paraphimosis. METHODS: This prospective study included 43 men with contraction referred for circumcision. RESULTS: LS was present in 32% of cases, but only 12% of these cases of LS had not been diagnosed before circumcision. In 31% of cases the histologic findings were normal. Subacute nonspecific inflammatory changes were diagnosed in 37% of all cases, and secondary narrowing of the prepuce in 62% of cases. It is probable that this histologic modification of the preputial mucosa is involved in narrowing of the prepuce. CONCLUSION: Phimosis in young adults is usually not associated with LS (only 14%). In contrast, most older patients had secondary phimosis caused by progressive LS (40%) or subacute nonspecific inflammatory changes (40%). Although all cases of phimosis in men should be treated by complete circumcision to prevent penile cancer, paraphimosis associated with preputial dyspareunia, with the exception of cases associated with LS, can be treated by corrective surgery.     

Inactivation of the CDKN2A and the p53 tumour suppressor genes in external genital carcinomas and their precursors

BACKGROUND: p53 has been extensively studied in external genital carcinoma (EGC), and is frequently inactivated, but little is known about the role of the CDKN2A tumour suppressor gene in the oncogenesis of EGC. OBJECTIVES: To investigate the role of CDKN2A and p53 in the pathogenesis of EGCs and their precursor lesions vulval intraepithelial neoplasia (VIN3), penile intraepithelial neoplasia and lichen sclerosus (LS). METHODS: By means of CDKN2A and p53 mutation screening (single-strand conformational polymorphism analysis and sequencing), methylation analysis of alternative CDKN2A promoters (methylation-specific polymerase chain reaction) and p53 immununochemistry, we analysed eight invasive EGCs (five from vulva and three from penis) and 25 precancerous lesions (two undifferentiated VIN3 and 23 vulval/penile lesions of LS) from 33 patients. RESULTS: p53 mutations (mainly transversions) and CDKN2A mutations (including one hot spot) were present in 75% and 50% of invasive tumours, respectively, but were absent in all precancerous lesions. Remarkably, all CDKN2A-mutated tumours also harboured a p53 mutation. CDKN2A or p53 mutations were observed more frequently in LS-derived EGCs than in human papillomavirus-derived EGCs (P = 0.053). A positive anti-p53 staining, but without p53 mutations, was also detected in 30% of LS lesions, suggesting a p53 stabilization in response to inflammation and carcinogenic insult. Methylation of p16(INK4a) and p14(ARF) promoters was not a frequent mechanism of CDKN2A inactivation. CONCLUSIONS: Our study shows a high prevalence of co-inactivating mutations of p53 and/or CDKN2A genes in EGC, that seem to occur preferentially in LS-derived tumours and late in oncogenesis.     

Childhood Lichen Sclerosus—A Challenge for Clinicians

Childhood lichen sclerosus (LS) is a rare and often misdiagnosed inflammatory dermatitis with an unpredictable course. The complications of LS are architectural changes of the vulva; malignant transformation is possible. The objective of our study was to define the background and the long‐term course of childhood LS. A registery study identified 44 children with LS treated at Tampere University Hospital, Tampere, Finland, from 1982 to 2010. A questionnaire was sent to the identified patients and 15 responded. The clinical depiction of LS varied significantly. LS was diagnosed in only 16% of the patients at the referring unit. Autoimmune disorders were observed in 6 of the 44 patients. High prevalences of Turner's syndrome (2/44) and kidney disease (2/44) were noted. The majority of the patients were treated with topical corticosteroids. Eight developed architectural changes of the vulva. The questionnaire revealed that three of six patients who were asymptomatic at the end of the registery study follow‐up experienced a recurrence of symptoms. None of them were undergoing follow‐up. Nine of the 15 patients reported reduced quality of life. Childhood LS is a heterogeneous disease with a remarkable effect on quality of life. The misdiagnosis of childhood LS is common. The association between LS and autoimmune diseases should be noted. The high prevalence of Turner's syndrome raises questions regarding the influence of low estrogen levels on the development of LS. The prognosis cannot be predicted, so long‐term follow‐up is recommended. New tools for diagnosis and surveillance are needed.     

Primary classic Kaposi''s sarcoma of the penis: report of a case and review

Kaposi's sarcoma is a vascular tumour of multifocal origin occurring primarily on the extremities. The case of a 45-year-old HIV negative and HHV-8 positive man with an asymptomatic reddish macular lesion on the inner layer of the prepuce is described. Although primary penile Kaposi's sarcoma is a relatively uncommon disorder in HIV negative men, dermatologists and venereologists should consider this possibility when treating non-specific penile lesions. A minimal penile lesion with non-distinctive clinical features may sometimes be the exclusive manifestation of Kaposi's sarcoma, making histologic evaluation necessary to establish the diagnosis.     

Extragenital bullous lichen sclerosus: A case report and literature review

Lichen sclerosus (LS) is a chronic dermatosis characterized by atrophic white papules or plaques, most commonly occurring on the anogenital skin. Blisters have been rarely described developing in the background of extragenital LS. A 74-year-old woman with a 4-year history of sclerotic patches on the trunk showed a flaccid bulla on the lower back for 3 months. The histopathological finding of the skin biopsy was consistent with the diagnosis of bullous LS. In this paper, we present this uncommon case, review the literature on extragenital bullous LS, discuss the pathogenesis, and provide some treatment options for the case.     

Subclinical penile human papillomavirus infection and dysplasia in consorts of women with cervical neoplasia.

Fifty men whose sexual partners were 50 women with histologically proved cervical intraepithelial neoplasia (CIN) grade III (severe dysplasia or carcinoma in situ) were studied. A further 25 men whose current regular sexual partners were 25 women with chlamydial cervicitis were recruited as controls. If either of the partners in either group had genital condylomata acuminata or a known history of similar lesions, the couple was excluded from the study. Abnormal penile epithelium, which was detected by colposcopy after application of 5% acetic acid to the penile skin, was reported in 25 men in the study group compared with three in the control group. Histologically proved subclinical penile infection with human papillomavirus (HPV) was present in 23 men in the study group compared with three in the control group (p less than 0.01). Of the 50 men in the study group, four had histologically proved severe penile dysplasia or carcinoma in situ with evidence of HPV infection, the disease being subclinical in each case and diagnosed on histology of a specimen obtained by colposcopically directed biopsy. HPV DNA was detected on filter hybridisation of penile scrapes from 15 of the 23 men in the study group with histologically proved penile HPV infection, HPV16 DNA being detected in 10 of them. HPV DNA was detected on DNA-DNA hybridisation of biopsy material in seven of 18 men with histologically proved penile HPV infection. Five of these biopsy specimens were positive for HPV16 DNA. Only one man in the control group had HPV DNA detected in a penile scrape. This patient had histologically proved subclinical penile HPV infection. Such lesions may represent an important male reservoir of HPV types implicated in genital squamous carcinogenesis in both sexes.     

Case for diagnosis. Atypical genital lesion

We present a case of a penile lesion with a clinical appearance similar to Mondor penile disease (thrombosis of the dorsal vein of the penis) or penile sclerosing lymphangitis. Laboratory evaluation, however, showed a solid lesion, with no vascular component to Doppler ultrasonography and no treponema to immunohistochemistry. Histological and serological tests were compatible with secondary syphilis. The authors reinforce the need for the inclusion of syphilis in the differential diagnosis of penile cord injuries.     

Penile cutaneous horn ten years after treatment of verrucous squamous cell carcinoma on penile glans: case report

Penile cutaneous horn is a clinical term that describes protruding hyperkeratosis, usually conical in shape, located on penile glans. Penile localization of this lesion, predominantly located on sun-exposed areas, is very rare. The association with malignancy on the penis makes proper identification of these lesions essential. We present a 45-year-old man with a cutaneous horn, 25 mm in size, located on the basis of penile glans. The patient had a history of phimosis, pseudoepitheliomatous balanoposthitis, surgical excision of penile verrucous squamous cell carcinoma (SCC) and postoperative radiotherapy of carcinoma in situ on the same localization, ten years before. Complete surgical removal of the horn with separate excision of the margins and base was done. Pathologic examination revealed squamous hyperplasia with suspicion of carcinoma in situ. Additional negative p16(INK4a) immunohistochemical analysis confirmed benign proliferative lesion. DNA polymerase chain reaction for human papilloma virus infection was negative. These findings suggested sparing surgical procedure in our patient, without indication for partial penile amputation, but with mandatory follow-up. Our case confirmed the association of pseudoepitheliomatous balanoposthitis with verrucous SCC, as well as the possible influence of radiotherapy on the development of penile cutaneous horn. Additionally, we showed the important role p16(INK4a) immunohistochemical analysis in the differential diagnosis of alterations adjacent to invasive SCC of the penis.     

Measurement of transepidermal water loss in localized scleroderma

Localized scleroderma (LS) is a disease characterized by fibrotic changes in the dermis. Connective tissue growth factor and transforming growth factor β2 are the main mediators of fibrogenesis; this, along with excessive connective tissue production, affects epidermal keratinocytes, and thereby contributes to the changed quality of skin barrier. The objective of this article was to study the objective measurement of the skin barrier quality in LS with transepidermal water loss (TEWL) meter. The measurements of TEWL were performed on LS plaques in all three stages of various body locations. Control measurements were made on the contralateral side of healthy skin. The difference between TEWL in LS area and the contralateral side of the healthy skin was evaluated. A higher average TEWL 7.86 g/m²/h (SD 5.29) was observed on LS plaques compared with the control measurements on healthy skin 6.39 g/m²/h (SD 2.77). TEWL average values decreased from the inflammatory stage, through the sclerotic and to the atrophic stage. The mean difference 1.301 g/m²/h (SD 5.16) was found between TEWL on LS plaques and on the contralateral healthy skin in 82 measurements, i.e., a higher TEWL was observed in LS. The difference was statistically significant with p = 0.0250. Although fibrogenesis in scleroderma is localized in dermis, the skin barrier changes can be detected.