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Abstract
Objectives High-risk human papillomavirus (HPV) types have been linked with genital carcinomas. However, the exact relation between HPV and erythroplasia of Queyrat (EQ), for example, in-situ carcinoma of the glans and prepuce, is still unclear. Thw aim of this study was to detect the presence of lesional HPV-DNA in patients with EQ.
Methods Paraffin-embedded biopsies were obtained from the glans or inner foreskin of 11 adult uncircumcised patients (mean age 67.7 years; range 57–79) with EQ. An equal number of randomly selected uncircumcised healthy control patients underwent a single brush cytology smear of the penile mucosa. Biopsy specimens and brushings were then assayed by a highly sensitive two-step nested PCR technique based on MY11/MY09 consensus primers and general GP5+/GP6+ PCR primers, followed by cycle sequencing. Statistical evaluation was performed using conditional logistic regression analysis.
Results None of the EQ or control samples proved to be positive for the presence of HPV-DNA.
Conclusions The findings do not support the hypothesis that there is a considerable risk of EQ development in patients with HPV infection. The prevalence of HPV infection in patients with EQ has rarely been investigated and available data are relatively scant and controversial. Therefore, the relation between HPV infection and the risk of progression of EQ into squamous cell carcinoma remains a matter of debate, and further investigations are needed in order to confirm the role of HPV in delineating this risk.
- anogenital cancer
- erythroplasia of Queyrat
- human papillomavirus
- in-situ carcinoma
- PCR
- penile carcinoma
- skin disease
- virology
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- anogenital cancer
- erythroplasia of Queyrat
- human papillomavirus
- in-situ carcinoma
- PCR
- penile carcinoma
- skin disease
- virology
Erythroplasia of Queyrat (EQ) is a carcinoma in situ that mainly occurs on the glans penis, the prepuce, or the urethral meatus of elderly men. The causes of EQ are unknown.1 Clinically, it appears as a sharply demarcated, velvety bright reddish plaque or plaques on the glans or on the foreskin. Patients may show erythema, scaling, crusting and difficulty in foreskin retraction. Many have pruritus or pain locally, while a few report bleeding. EQ usually progresses slowly. Transformation into invasive squamous cell carcinoma (SCC) has been reported in up to 33% of cases. Ulceration suggests that EQ may have transformed to invasive SCC, with a risk of penile submucosal involvement, regional lymph node metastases, or distant metastatic disease.2
Histological examination of EQ shows findings similar to those of Bowen disease (BD), an in-situ carcinoma characterised by a lack of maturation of the surface epithelium and partial or total replacement of mature keratinocytes with disorderly, dysplastic and sometimes dyskeratotic cells that display nuclear atypia. Marked epidermal acanthosis and parakeratosis and an inflammatory lymphohistiocytic infiltrate in the dermis are common findings. Compared with BD, EQ more often shows epithelial hypoplasia, with fewer multinucleated cells and fewer dyskeratotic cells but an increase in the number of plasma cells in the chronic inflammatory infiltrate.2
A 1% annual incidence of genital human papillomavirus (HPV) infection has been estimated among sexually active people.3 In the past few decades there has been an increasing trend of new diagnoses both in the USA and in Europe, reflecting not only an increasing incidence resulting from changes in sexual behaviour, but also greater ascertainment of cases through more testing and improved diagnostic methods.4 In men, depending on the population studied, sampling method and anatomical site, the prevalence of HPV-DNA positivity ranges widely, often reaching the highest prevalence rates among selected high-risk people.5
In the present study, we investigated the presence of lesional HPV-DNA in a series of patients with EQ.
Methods
Paraffin-embedded biopsies were obtained from the glans or inner foreskin of 11 adult uncircumcised patients (mean age 67.7 years; range 57–79 years) who were histologically consistent for EQ and were selected for HPV evaluation by PCR.
A control group consisting of an equal number of randomly selected uncircumcised men matched for age and attending our dermatology clinic for non-genital complaints was also enrolled in the study. Patients with a positive history of anogenital warts or any other HPV-related disorder were excluded from both the control group and the EQ group. Also excluded were those patients whose sexual partners had a past history of anogenital HPV infection and/or cervical intraepithelial neoplasia or invasive neoplasia. Control patients agreed to undergo a careful clinical inspection (no instrumentation) to confirm no evidence of excludable disorders.
All eligible control subjects underwent a single brush cytology smear of the penile mucosa for HPV testing. A (saline-wetted) cotton tip swab was rubbed on the glans, coronal sulcus and inner foreskin. Biopsy specimens and brushings were then assayed by a highly sensitive two-step nested PCR technique based on MY11/MY09 consensus primers and general GP5+/GP6+ PCR primers, followed by cycle sequencing.6 This technique is able to detect 0.05–5 HPV-DNA copies, has a sensivity of 10 fg to 1 pg, and covers all known HPV types.7 SiHa and HeLa HPV-infected cell lines derived from human cervical carcinomas were used as positive controls for HPV analysis.8 9 Statistical evaluation was performed using conditional logistic regression analysis.
Results
None of the EQ or control samples proved to be positive for the presence of HPV-DNA, whereas SiHa and HeLa cell lines were all found to be positive (SiHa: HPV 16, one to 10 copies per cell; HeLa: HPV 18 10–50 copies per cell).8 9
Discussion
Main findings
Our retrospective analysis on a series of patients with EQ aiming to determine the frequency of associated HPV infection failed to detect the presence of HPV-DNA in all cases. Therefore, the findings of this study do not support the hypothesis that there is a considerable risk of EQ development in patients with HPV infection.2 10
Relation with existing literature
The prevalence of HPV infection in patients with EQ has rarely been investigated and available data are relatively scant and controversial.
EQ (which is usually diagnosed in men), BD (more frequently diagnosed in women) and bowenoid papulosis are a group of disorders known also as penile intraepithelial neoplasia (PIN). These three clinical variants of PIN share identical histological features of in-situ SCC. The malignant potential, however, may vary according to the disorder considered.2 Various pathogenic factors have been implicated in the pathogenesis of PIN: chronic irritation, poor hygiene, traumas and HPV infection.11
HPV infection may be latent, subclinical or clinically evident. The oncogenic potential of HPV has now been unequivocally proved, and this finding has raised considerable concerns due to the worldwide distribution of HPV infection. High-risk HPV types 16, 18, 31, 33, 39, 42, 51–54 have been linked with genital carcinomas. HPV 16 and 18 are more likely to be present in subclinical infections that may eventually become evident later in life. Although other routes of HPV transmission do exist, genital warts are predominantly transmitted by sexual contact.5 HPV 16 is a high-risk oncogenic virus associated with the development of genital SCC, although HPV-negative tumours have also been found. It is reported in approximately 70% of the cases of genital BD (in-situ SCC of genital skin).10 Nevertheless, it is rarely found in EQ, for example, in-situ carcinoma of the penile mucosa.
The exact relation between HPV and EQ is unknown.10 It has been suggested that HPV infection may enhance the risk of SCC development.2 However, a higher incidence of HPV infections in patients with EQ has not been demonstrated unequivocally. Previous studies analysed only a limited number of patients.1 2 In one study, 12 paraffin-embedded biopsies from eight patients affected by EQ were tested for the presence of HPV-DNA. Surprisingly, all patients were infected with the carcinogenic epidermodysplasia verruciformis-associated cutaneous HPV type 8. Seven of eight patients were coinfected with HPV 16. Control biopsies from patients affected by inflammatory penile disorders were negative.1 No positive controls were used. In another study, the relationship between HPV infection and external genital in-situ SCC was investigated by PCR using consensus primers.12 HPV-DNA was positive in 22 (55%) out of 40 cases of bowenoid papulosis, in all of five cases (100%) of BD and in two (33.3%) out of six cases of EQ. In all positive cases HPV 16 was detected.
Limitations of the study
EQ is a rare disorder, and its rarity hampers the collection of a wide case series able to provide reliable statistical data. In fact, the largest case series we found in the literature deals with a number of biopsy samples similar to ours, that is a relatively limited number of cases (12 vs 11).1 In addition, that study disclosed controversial findings, such as the presence of unusual HPV types, such as HPV 8, whose significance is difficult to assess due to the small sample size and that in our study we were unable to confirm. In the absence of stringent confirmation of the presence of HPV in penile in-situ carcinomas, a crucial role of HPV infection still remains debatable, and a causative role of other still unknown factors must be taken into account.
Meaning/future directions for research
The totally discordant data in our study are inconsistent with those of Wieland et al1 and may be related to the private life and sexual behaviour of individual patients.5 This issue is often difficult to explore thoroughly and should be better assessed in prospective research. The relationship between HPV infection and the risk of progression of EQ into SCC remains uncertain, and further investigations into the role of HPV and possibly other infectious agents are warranted.
Key messages
This retrospective analysis failed to detect the presence of HPV-DNA in a series of patients with EQ.
These findings do not support the hypothesis that there is a considerable risk of EQ development in patients with HPV infection.
Further investigations taking into consideration sexual habits are needed in order to confirm the role of HPV in delineating this risk.
References
Footnotes
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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