Cutaneous squamous cell carcinoma and human papillomavirus

The relationship between mucosal human papillomavirus (HPV) and cervical carcinoma or anogenital squamous cell carcinoma (SCC) is becoming increasingly evident, whereas a link between HPV and other cutaneous SCCs is less clear. Recent studies have reported links between epidermodysplasia-verruciformis-associated HPV and extragenital cutaneous SCC, particularly in immunosuppressed patients, although immunocompetent patients have also been affected. Mucosal HPV could also be linked to some types of Bowen disease and certain SCCs of the fingers, oropharyngeal mucosa, etc. We review the possible oncogenic mechanisms involving mucosal HPV and epidermodysplasia-verruciformis-associated HPV. Most SCCs could be explained by the combined action of HPV, immunosuppression, and the oncogenic and immunosuppressive effect of UV radiation. HPV might be associated with worse prognosis of SCC, with implications for clinical practice including greater risk of metastasis.     

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.     

Detection of mucosal human papilloma virus DNA in bowenoid papulosis, Bowen's disease and squamous cell carcinoma of the skin

Human papilloma virus (HPV) is known to be an etiologic agent for benign warts of the skin. Recently, HPV have been detected in malignant skin and mucosal diseases suggesting that HPV infection can induce malignant skin tumors. In the present study, we examined the presence of mucosal HPV DNA in normal tissue, Bowen's disease (BD), Bowenoid papulosis (BP) and squamous cell carcinoma (SCC) of the skin. We detected the HPV DNA with polymerase chain reactions, and identified the type by DNA sequencing. In the results, we detected HPV DNA in none of the 17 normal controls, two of the three BP (66.7%), one of the 21 BD (4.8%), and six of the 26 SCC of the skin samples (23.0%). The occurrence rates of HPV in BP and SCC were significantly elevated compared to that of normal controls (P < 0.01 and P < 0.01, respectively). In addition, the occurrence rate of HPV in BP was significantly elevated compared to that of BD (P < 0.05). The reproducibility was confirmed with a polymerase chain reaction (PCR) with another primer pair. Of the two cases of BP with positive HPV DNA, one case showed HPV 31 and the other case HPV 16. The case of BD with positive HPV DNA showed HPV 31. Of the six cases of SCC with positive HPV DNA, one case showed HPV 16, another case HPV 34, and the other four cases HPV 31. These results showed that mucosal HPV, including HPV 31 and 16, could be detected in SSC of the skin. Mucosal HPV, not only the epidermodysplasia verruciformis type, appear to induce malignant skin tumors.     

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.     

人乳头瘤病毒与皮肤Bowen病的相关性

目的 探讨人乳头瘤病毒(HPV)与皮肤Bowen病发病的相关性.方法 41例皮肤Bowen病患者皮损以及48例健康对照皮肤,采用多对引物,应用巢式PCR进行HPV DNA检测,同时应用半定量PCR进行病毒定量,对HPV DNA阳性标本进一步采用原位杂交方法分析组织内病毒的分布状况.结果 41例皮肤Bowen病患者皮损HPV DNA阳性检出率为12%(5例),其中黏膜型3例(2例HPV16,1例HPV33),病毒定量相当于101～103拷贝,原位杂交显示在多数肿瘤细胞核中有广泛阳性表达,而肿瘤邻近的正常组织无信号表达;皮肤型2例(HPV27和HPV76各1例),原位杂交均无阳性表达.此外,对照组中有1例检出HPV DNA,属于疣状表皮发育不良相关型HPV23,检出率为2.1%,与皮肤Bowen病皮损中HPV检出率比较,差异无统计学意义.2例患者皮肤型病毒定量较低,与正常对照组中检出的1例HPV23相似,均相当于10-2～10-3拷贝.结论 某些皮肤Bowen病的发病与黏膜型HPV密切相关.     

Human papillomaviruses of the mucosal type are present in some cases of extragenital Bowen's disease

BACKGROUND: Bowen's disease in the genital area is generally considered to be caused by mucosal high-risk human papillomaviruses (HPVs). However, the detection rate and spectrum of HPVs in extragenital Bowen's disease are various and it is not clear to what extent HPV is involved in its pathogenesis. OBJECTIVES: To assess the degree of association of HPV in extragenital cases by examining detection rates, types, quantities and localization of HPV. METHODS: A polymerase chain reaction (PCR) approach that we had previously established, which can give sensitive detection of a broad range of HPVs from cutaneous [including epidermodysplasia verruciformis-related HPVs (EV-HPVs)] to mucosal HPVs, was applied to samples from 41 patients with extragenital Bowen's disease and normal skin samples from 48 individuals. Semiquantitative L1-PCR and tyramide-based in situ hybridization (ISH) were also employed for positive cases. RESULTS: HPVs belonging to the mucosal high-risk group were detected in three patients with Bowen's disease (7%; two HPV 16 and one HPV 33), with 10(1)-10(3) copy equivalents per diploid amount of cellular DNA. They were distributed among most nuclei of tumour cells but in none of the cells of adjacent normal skin. HPVs belonging to the cutaneous group were detected in two patients (5%; HPV 27 and HPV 76) at 10(-2)-10(-3) copy equivalents, the same level as in a normal skin specimen positive for type 23 EV-HPV. No positive signals were observed by ISH. CONCLUSIONS: HPVs belonging to the mucosal high-risk group may participate in the development of extragenital Bowen's disease.     

p53 immunoreactivity in non-melanoma skin cancer from immunosuppressed and immunocompetent individuals: a comparative study of 246 tumours

p53 immunoreactivity was examined in 132 cutaneous non-melanoma tumours from renal transplant recipients and in 114 histologically matched specimens from immunocompetent individuals. Skin lesions examined included 52 viral warts, 50 clysplastic keratoses, 51 intraepidermal carcinomas (IEC), 50 invasive squamous cell carcinomas (SCC) and 43 basal cell carcinomas (BCC). Overall, 51% (51/101) pre-malignant skin lesions and 45% (42/93) non-melanoma skin cancers (NMSC) showed p53 immunoreactivity, with extensive (> 50% cells positive) p53 staining in 27% (27/101) of pre-malignant and 20% (19/93) of malignant lesions. 17% (9/52) viral warts showed p53 immunoreactivity, but this was limited to focal or basal p53 staining. p53 immunoreactivity in all tumours was less in transplant than in non-transplant patients and this reached statistical significance for SCCs (p = 0.03).     

Human papillomavirus infection in Bowen disease: Negative p53 expression,not p16INK4a overexpression,is correlated with human papillomavirus‐associated Bowen disease

Genital Bowen disease (BD) has been linked to the high‐risk types of human papillomavirus (HPV) infection. Recently, it has been recognized that HPV also can be associated with extragenital BD. HPV oncoproteins E6 and E7 interfere with the function of p53 and pRb, respectively, leading carcinogenesis. p16^INK4a overexpression induced by inactivation of pRb is recognized as a surrogate marker for HPV‐associated cervical cancer. In this study, we examined the presence of HPV DNA in 142 BD lesions by polymerase chain reaction (PCR), and determined the type of HPV by PCR restriction fragment length polymorphism or direct DNA sequencing. HPV DNA was detected in 66.7% of genital BD and 8.3% of extragenital BD. The types of HPV detected were HPV types 6, 16, 33, 52, 56, 58 and 59. We also investigated the expression of p16^INK4a, pRb and p53 by immunohistochemistry. Positive expression was detected in 88.6% for p16^INK4a, 25.2% for pRb, and 63.8% for p53. There was no significant difference in p16^INK4a and pRb expression between HPV‐positive and ‐negative BD. However, a strong correlation of HPV positivity with p53 negativity was found. A total of 66.7% of HPV‐positive BD showed no p53 expression, whereas the corresponding rate was 32.8% of HPV‐negative BD. This study demonstrated that HPV can participate in the development of BD, not only in the genital lesion, but also in extragenital lesion. p16^INK4a overexpression is not a marker for HPV infection in BD. Instead, negative p53 expression is correlated with HPV‐associated BD.     

人乳头瘤病毒及癌基因在人生殖器癌发生中的作用

我们对生殖器疣与癌中人乳头瘤病毒型别别分布及癌基因表达进行了研究。结果：（１）９８例生殖哭疣中ＨＰＶ６，１１的检出率为９５％，４３例生殖器癌中ＨＰＶ１６检出率为８８．３％；（２）Ｃ－Ｈａ－ｒａｓ及Ｃｍｙｓ癌基因在阴茎癌及宫颈癌中表达较生殖器疣中均显著增强（Ｐ＜０．００１）；（３）ＨＰＶ６感染病例ｒａｓ，ｍｙｃ基因表达率分别为１６．７％、６．７％，ＨＰＶ１１分别为１０％、２０％、ＨＰＶ１６分别为７０     

Diversity of human papillomavirus types in periungual squamous cell carcinoma

Background There is accumulating evidence that infections with certain high‐risk α‐human papillomaviruses (HPVs) are involved in the pathogenesis of digital squamous cell carcinomas (SCCs) and their precursor lesions (SCCs in situ). Objectives This study was initiated to search for α‐ and β‐HPV infections in a collective of SCC and SCC in situ located on the hands. Methods HPV typing for 36 high‐risk and low‐risk α‐HPV types and 25 β‐HPV types was performed in SCCs located at different sites of the hands. Additionally, immunohistochemical staining for p16^INK4a and Ki67 was performed in 15 samples. Results In total, 25 SCCs/SCCs in situ (six periungual lesions, eight lesions from the proximal or lateral part of the finger, and 11 lesions from the dorsal part of the hand) were analysed for the presence of α‐ and β‐HPV types. Only one lesion (an SCC in situ positive for HPV11 and HPV31) of the dorsal hand and none of the proximal or lateral part finger lesions were α‐HPV positive. In contrast, all six periungual lesions were α‐HPV positive, and the majority (83%) of them carried HPV types other than HPV16 (HPV26, HPV33, HPV51, HPV56 and HPV73). β‐HPV types were found in only two biopsies. p16^INK4a and Ki67 expression was significantly higher in HPV‐positive lesions as compared with HPV‐negative tumours, and both markers significantly correlated with each other. Conclusions In contrast to other locations of the hands, periungual SCCs are frequently associated with α‐HPV infections. Several high‐risk HPV types other than HPV16 can induce periungual SCCs. Given the high recurrence rate and high proliferative activity of HPV‐associated periungual SCCs, aggressive treatment and close follow‐up of these tumours is mandatory.     

Human papillomavirus DNA detection in primary anogenital warts and cervical low-grade intraepithelial neoplasias in adults by in situ hybridization.

In this study, 58 consecutive patients with primary anogenital warts were selected from patients attending a genitourinary clinic. Patients were grouped on the basis of clinical lesion site, i.e. patients with genital warts only, patients with perianal or anal canal warts only, and patients with concurrent perianal and genital warts. Of these patients, 38% of the men (12/31) and 33.3% of the women (9/27) had other anogenital infections, such as nonspecific urethritis (NSU) or nonspecific genital infection, which were the most common. Of the patients who had perianal warts, 37% of the men (7/19) and 25% of the women (4/16) also had warts in the anal canal. Of the women who had anogenital warts, 63% (17/27) had concurrent subclinical low-grade cervical intraepithelial neoplasia (CIN) lesions. Human papilloma virus (HPV) DNA (either 6 or 11, 16 or 18, or 31 or 33 or 35) was detected in 53.3% (40/75) of the anogenital wart biopsy samples, and in 35.2% (6/17) of the low-grade CIN lesions. HPV types 6 or 11 were the most common types in anogenital warts (45.3%); and in CIN lesions HPV types 6 or 11 and 16 or 18 were found with equal frequency (17.6% each). There were no significant differences in HPV types between patients with genital warts and patients with perianal and anal canal warts. Anogenital infection with HPV is multicentric; external anogenital warts and subclinical CIN lesions often exist concurrently. The low prevalence of HPV DNA detected in anogenital warts and CIN biopsy samples may be due to insensitivity of the in situ hybridization technique used in this study.     

Laser in der Therapie der Warzen

Human papilloma viruses (HPV) lead to common warts in 5% of the population and genital warts in 1% of sexually-active individuals. Although about 50% of HPV infections regress spontaneously, the course is uncertain. Expectant waiting often leads to progression and dissemination. Plantar warts may cause pain on walking, while palmar and genital warts may impair social contacts. There are many treatments for warts, including a variety of laser systems. The CO(2) laser is the best ablative approach, producing cure rates of up to 75% for therapy-resistant common warts in cohort and case-control studies. Side effects such as bleeding, pain and reduced function over weeks must be weighed against the likelihood of success. Considering non-ablative approaches, pulsed dye lasers can be used for a selective, non-bloody destruction of extragenital and genital warts and may become the treatment of choice. In prospective randomized studies, they produced cure rates of up to 82% for therapy-resistant warts with few side effects.     

Preliminary study of analyzing mucosal human papillomaviruses in cutaneous warts by restriction fragment mass polymorphism

Cutaneous human papillomavirus (HPV) types 1, 2, 4, 7 and 57 are reportedly found in cutaneous warts. However, there are few reports that have investigated the prevalence of mucosal HPV types in cutaneous warts. The aim of this study is to investigate the prevalence of mucosal HPV types in patients with cutaneous warts and to determine any association between HPV types and patient characteristics. We analyzed 62 wart samples that were taken from patients who were diagnosed with cutaneous warts, and 30 normal skin samples were used as negative control. We recorded the following characteristics: sex, age, type of warts, duration of warts, number of warts and patient's immune status. A matrix‐assisted laser desorption ionization time‐of‐flight (MALDI‐TOF) mass spectrometry (MS)‐based restriction fragment mass polymorphism (RFMP) assay was used for HPV genotyping. Of the total 62 wart samples, 50 samples (81.6%) were positive for HPV genotypes. All of the negative controls (30 samples) using normal skin showed negative reaction. Mucosal HPV types (49 samples, 84.4%) were highly detected, and high‐ or probable high‐risk HPV types (39 samples, 67.2%) were more common than lower risk HPV types (10 samples, 17.2%). A statistically significant association was observed between sex, age, duration of warts and the risk of HPV types. To the best of our knowledge, this is the first study to use the RFMP assay to analyze cutaneous wart‐associated mucosal HPV types. The high prevalence of high‐risk and probable high‐risk HPV in this study is of great significance.     

Human papillomavirus type 26 infection causing multiple invasive squamous cell carcinomas of the fingernails in an AIDS patient under highly active antiretroviral therapy

Squamous cell carcinoma (SCC) of the nail unit is a rare disorder. An association with high-risk genital human papillomavirus (HPV) infection has been reported. We report a 28-year-old human immunodeficiency virus (HIV)-infected bisexual man who had multiple invasive SCC of the fingers, infected with the rare type HPV 26. Classification of HPV 26 as high- or intermediate-risk type has been uncertain, due to its rare presence in cervical cancer. Despite successful treatment with highly active antiretroviral therapy (HAART), the patient developed extensive hyperkeratotic nailbed proliferations of all fingers. Tumours were refractory to treatment and invaded into adjacent tissues. X-rays of the hands demonstrated bone invasion, necessitating amputation of distal phalanges of several fingers. Histologically, highly differentiated preinvasive and invasive verrucous SCCs were identified. Molecular DNA typing identified HPV 26 in the SCCs and in some premalignant lesions. By in situ hybridization HPV 26 DNA was detected in numerous tumour cells, indicating productive infection with high-level amplification of the viral genome. In the remaining proliferations, high-risk HPV type 58, cutaneous HPVs and a putative new HPV type were identified. HPV 26 infection appears to be causally involved in the development of SCC of the nail unit in this immunosuppressed patient. Timely evaluation of chronic verrucous nailbed tumours is recommended, especially in immunocompromised patients. Identification of HPV 26, besides known high-risk HPV types, may identify patients at risk for developing SCC of the nailbed and possibly at other locations.     

Genotype distribution of human papillomavirus in anogenital warts of male patients in Taiwan

BackgroundReports on the prevalence of different human papillomavirus (HPV) genotypes in male patients with anogenital HPV infection are limited.MethodsWe retrospectively analyzed the HPV genotypes of 100 consecutive patients seen in our department with anogenital HPV infection during 2003–2006. History was gathered from the medical records.ResultsThe most common HPV genotypes among Taiwanese male patients for check of anogenital warts (in descending order) were HPV 6 (46%), HPV 11 (28%), HPV 16 (6%), HPV 33 (5%), HPV 66 (5%), HPV 18 (4%), HPV 53 (4%), and HPV 72 (4%). Coinfections with two, three, and four genotypes of HPV were present in 16%, 7%, and 1% of the patients, respectively. HPV 16 or 18 was found in 10% of cases, with 60% (6/10) coexisting with HPV 6/11. The presence of either HPV 6, 11, 16, or 18 was 77%. HPV 16 was more common in anal compared to genital warts, with an odds ratio of 3.65.ConclusionThe most common genotype of anogenital HPV infection in Taiwanese males was HPV 6, followed by HPV 11. Coinfection with more than one genotype of HPV as well as concurrent low- and high-risk HPV infection was not uncommon.     

Human papillomavirus DNA in the urogenital tracts of men with gonorrhoea, penile warts or genital dermatoses.

OBJECTIVE--To assess the presence of human papillomavirus (HPV) DNA in urethral and urine specimens from men with and without sexually transmitted diseases. DESIGN--Prospective study. SETTING--Two London departments of genitourinary medicine PATIENTS--100 men with urethral gonorrhoea, 31 men with penile warts and 37 men with genital dermatoses. METHODS--Urethral and urine specimens were taken, HPV DNA extracted and then amplified using the polymerase chain reaction. HPV types 6, 11, 16, 18, 31 and 33 were identified using Southern blotting followed by hybridisation. RESULTS--HPV DNA was detected in 18-31% of urethral swab specimens and in 0-14% of urine specimens. Men with penile warts had HPV detected in urethral swabs more often than did men in the other two clinical groups. "High risk" HPV types were found in 71-83% of swab specimens and in 73-80% of urine specimens containing HPV DNA. CONCLUSIONS--HPV is present in the urogenital tracts of men with gonorrhoea, penile warts and with genital dermatoses. In men with urethral gonorrhoea, detection of HPV in urethral specimens is not related to the number of sexual partners, condom usage, racial origin or past history of genital warts. HPV DNA in the urethral swab and urine specimens may represent different aspects of the epidemiology of HPV in the male genital tract. The preponderance of HPV types 16 and 18 in all three groups of men may be relevant to the concept of the "high risk male".     

The value of laminin-322 staining in distinguishing between keratoacanthoma, keratoacanthoma with areas of squamous cell carcinoma, and crateriform squamous cell carcinoma

IntroductionKeratoacanthoma is a fast-growing crateriform skin tumor. Approximately 25% of such tumors undergo malignant transformation and develop areas of squamous cell carcinoma (SCC). The presence of laminin-322 has been associated with progression to invasive forms of SCC. The aim of this study was to determine whether or not immunohistochemical staining for laminin-322 would be of value in distinguishing between keratoacanthomas, keratoacanthomas with areas of squamous cell carcinoma, and SCCs.Material and methodsSeventy-four lesions were selected from the pathology archives of our hospital and divided into 4 groups: 20 keratoacanthomas without SCC, 20 keratoacanthomas with areas of squamous cell carcinoma, 20 invasive SCCs (8 with crateriform morphology) unrelated to keratoacanthoma, and 14 problem lesions (keratoacanthomas with areas suggestive of SCC). All 74 lesions were stained for laminin-322.ResultsLaminin-322 staining was strongly positive both in areas of SCC in keratoacanthomas with malignant transformation and in invasive SCCs (mostly at the invasive front of the SCC). However, in benign keratoacanthomas, it was only weakly positive and furthermore it was confined to isolated cells or small groups of cells. The 14 problem lesions were reexamined after laminin-322 staining and 8 were diagnosed as keratoacanthomas with incipient SCC and 6 as keratoacanthomas without SCC.ConclusionsLaminin-322 staining is different in keratoacanthomas and SCCs and would thus be a useful test for differentiating keratoacanthomas from both invasive SCCs and keratoacanthomas with areas of squamous cell carcinoma. It would also be of value in diagnosing keratoacanthomas with areas suggestive of SCC or with incipient SCC.     

Subclinical human papilloma virus infection in condylomata acuminata patients attending a VD clinic.

In 37 (77%) of 48 patients with external genital warts, application of 5% acetic acid revealed areas of acetowhite epithelium. The lesions were not clinically apparent before acetic acid was applied but were easily detected without the use of a colposcope. In a control group of 20 patients with chlamydial urethritis and no history of genital warts, none had acetowhite genital lesions. Histological examination of biopsy specimens from the flat acetowhite lesions showed HPV infection with koilocytosis in 29 (78%) and in 3 (8%) intra-epithelial neoplasia grade II-III. Using in situ hybridization with commercially available biotinylated DNA probes, HPV types 16/18 could be detected in 7 (24%) patients with koilocytosis and in 3 (100%) patients with dysplasia. Simultaneous infection with HPV types 6/11, 16/18, and 31/33/35 was found in 8 of the 13 HPV DNA-positive patients. It is concluded that subclinical HPV-induced acetowhite lesions are common among patients with genital warts and that these flat lesions may be associated with a high grade of dysplasia. Consequently, routine use of the acetic acid test on the genital epithelium is recommended in patients with condylomata acuminata in order to diagnose and treat all HPV-infected areas.