Evaluation of the role of genital human papillomavirus in the pathogenesis of ungual squamous cell carcinoma.

Human papillomaviruses (HPV), and particularly HPV 16, have been associated with ungual squamous cell carcinoma (USCC). But their role in tumor development remains unclear. In genital carcinoma, where the oncogenic role of HPV is well established, integration of HPV DNA into the host cell genome seems to be important for malignant transformation. To clarify the issue, we have studied the physical state of HPV 16 in 3 cases of in situ USCC by the polymerase chain reaction and by in situ hybridization. HPV DNA was integrated into the human genome in 2 cases and episomal in 1 case. This particular physical state of HPV 16 in USCC, similar to those encountered in anogenital SCC, confirms the probable role of this kind of virus in the pathogenesis of USCC.     

The role of human papillomavirus in the development of pyogenic granulomas

Background Pyogenic granulomas (lobular capillary hemangiomas) and condyloma acuminata share similar locations and risk factors. Human papillomavirus (HPV) types 6 and 11 are commonly associated with condyloma acuminata, but their association with pyogenic granulomas has not been evaluated. The purpose of this study was to determine whether pyogenic granulomas contain evidence of infection with condyloma producing HPVs. Methods Polymerase chain reaction assays for the E6 and E7 gene sequences of HPV types 6 and 11 and another assay for the E7 region of HPV types 16, 31, 33, 35, 42, and 58 were used to evaluate decxyribonucleic acid (DNA) extracted from archival pyogenic granuloma biopsies taken from cutaneous and oral epithelium. Results Neither cutaneous nor oral pyogenic granulomas contain amplifiable E6 or E7 sequences from any of these viruses. Conclusions Pyogenic granulomas are not caused by HPV 6, 11, 16, 31, 33, 35, 42, or 58. This study does not exclude the possibility that other viruses may be responsible for these tumors.     

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.     

Oral verrucous carcinoma and human papillomavirus infection

BACKGROUND: Verrucous carcinoma of the oral cavity is a clinical variant of squamous cell carcinoma. Infection with human papillomavirus (HPV) seems to be a significant risk factor in carcinogenesis, as illustrated in our case report. PATIENTS AND METHODS: A 72 year-old woman with a history of actinic cheilitis consulted for a bulky tumour of the lips and palate. Clinical examination revealed a highly infiltrated labial tumour vegetating and budding, with a thick edge. A bulky tumour and firm masses were seen on the hard and soft palates. Biopsy samples from both sites indicated well-differentiated veruccous epidermoid carcinoma with chorionic infiltration. The immunohistochemical study showed intestinal tumour containing HPV-16 virus. The central facial scan showed involvement of the nasal fossae, soft palate and lips with lysis of the upper maxilla arcade and the osseous palate. The patient died a few days before the start of preoperative chemotherapy following severe deterioration of her general state. DISCUSSION: Verrucous carcinoma is an authentic well-differentiated low-grade cancer. It appears as a wart-like exophytic lesion and progresses over several years. Diagnosis is based on histological examination. Management and treatment are not codified but surgery remains the treatment of choice and relapse is common in the case of locoregional involvement.     

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.     

The role of the human papillomavirus (HPV) vaccine in developing countries

Cervical cancer is a preventable health problem, yet is the second most common cancer of women worldwide. More than 80% of cases occur in developing countries, and this is expected to increase to 90% by the year 2020. The five‐year survival rate of patients in developing countries is less than 50%, compared to 66% in developed nations. A worldwide HPV vaccine program would significantly reduce the spread of HPV 16 and 18 and lower the incidence of cervical cancer. Mathematical models have determined that vaccinating 66% of the population will decrease the incidence of cervical cancer by 80% over the next 40–60 years. For every five‐year delay in a cervical cancer prevention/detection program, there will be an additional 1.5–2.0 million deaths. The introduction of a vaccination program will be a challenge due to high costs, unknown durability of the vaccine, and the potential for new oncogenic strains to emerge. A global effort will be required to eliminate cervical cancer from developing counties.     

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.     

Detection of human papillomavirus in verrucous carcinoma from HIV-seropositive patients

Anogenital squamous cell carcinoma has been noted with increased frequency in HIV-seropositive patients. Verrucous carcinoma is a variant of squamous cell carcinoma that tends to be locally invasive and non-metastasizing. Although human papilloma-virus (HPV) has been strongly implicated in other squamous neoplasms, it has been variably associated with verrucous carcinoma and has not been examined in these lesions in the HIV-positive population. The aim of this study was to examine the association of HPV with anal verrucous carcinoma in patients with the human immunodeficiency virus (HIV). HPV DNA in situ hybridization for HPV Types 6/11, 16/18, and 31/33/35 was performed on formalin-fixed, paraffin-embedded tissue from six cases of verrucous carcinoma and four cases of condyloma acuminatum in perianal specimens from HIV-seropositive patients. HPV DNA sequences were identified in five of six cases of verrucous carcinoma and in all cases of condyloma acuminatum. Of the five verrucous carcinomas that harbored detectable HPV DNA, four contained HPV 6/11 and two contained HPV 16/18. One contained both HPV 6/11 and HPV 16/18. All four cases of condyloma acuminatum were positive for HPV 6/11. One patient included in this series had three chronologically separate verrucous carcinomas. The initial lesion was negative for HPV DNA. Subsequent verrucous carcinomas were positive for HPV type 6/11 and type 16/18, respectively. The data presented support the concept that verrucous carcinoma in the HIV-seropositive population is associated with HPV, which may indeed play an important role in its pathogenesis.     

The human papillomavirus vaccine

Dialogues in Dermatology, a monthly audio program from the American Academy of Dermatology, contains discussions between dermatologists on timely topics. Commentaries from Dialogues Editor-in-Chief Warren R. Heymann, MD, are provided after each discussion as a topic summary and are provided here as a special service to readers of the Journal of the American Academy of Dermatology.     

The human papillomavirus vaccines

Genital human papillomavirus (HPV) infection is the most common sexually transmitted infection (STI) among sexually active couples. Its annual incidence is approximately 5.5 million. Overall, an estimated 75% of sexually active men and women have been exposed to HPV at some point in their lives. HPV-16 and -18 account for about 70% of cancers of the cervix, vagina and anus, and for about 30%-40% of cancers of the vulva, penis and orophaynx. Cancer of the cervix uteri is the second most cancer among women worldwide. Cancer of the penis is a rare cancer, accounting for less than 0.5% of cancers in men. Spontaneous clearance of HPV infection is accompanied by humoral and cellular immune response against virus-specific antigens. Two vaccines, prophylactic and therapeutic ones, are considered. Prophylactic vaccines use L1 and L2 capsid proteins to induce production of conformationally-specific antibodies. They block HPV infection. Lone L1 and L2 proteins self-assemble into a capsid that is identical to the complete virion. In this way, an antibody-mediated response is induced before the body actually comes into contact with the live virion. Therapeutic vaccines are being developed to protect HPV-positive persons against tumor development. For these vaccines, researchers are targeting the activity of the E6 and E7 oncoproteines.On June 8, 2006, the U.S. Food and Drug Administration (FDA) approved an HPV vaccine for clinical use. The HPV vaccine that has been approved is the quadrivalent vaccine that consists of recombinant viral-like particles (VLPs) of HPV 6, 11, 16, 18 mixed with an aluminum-containing adjuvant. It is manufactured by Merck & Co., Inc. and sold under the name of Gardasil?. The new vaccine is approved for use in females 9-26 years of age. The primary target population for vaccination should be females aged 11-12 years. However, vaccination can be given to girls as young as 9 years of age. Vaccination can receive women aged 13-26 years who have been sexually active. There are still no data on the vaccine efficacy in women older than 26, and currently no data to demonstrate the efficacy of vaccination in males; male subjects should not be vaccinated until such data become available. The vaccine is to be administered intramuscularly either into the deltoid muscle of the arm or the high anteriolateral area of the leg. Each patient receives three 0.5 mL doses given according to the following schedule: first dose is given at the elected date, second dose two months after the first dose, and third dose six months after the first dose. According to statements from Merck, the list price of the vaccine is 120 USD per dose. GlaxoSmithKline is now conducting a phase III trial of a bivalent (HPV 16, 18) vaccine, and it is going to be presented under the name of Cervarix. Similar results to those obtained with the quadrivalent HPV vaccine have been reported with the bivalent vaccine. It is expected to be released in June next year. Evaluation of the HPV vaccine efficiency in preventing dysplasia and cancer has been recommended as a globally accepted endpoint for population based studies.     

The role of human papillomavirus in common skin conditions: current viewpoints and therapeutic options

A direct causal relationship between human papillomavirus (HPV) infection and cervical neoplasia is well-accepted, but the specific role of HPV in the pathogenesis of other cutaneous disorders is less clear. This article explores the role of HPV in 2 common disorders associated with considerable morbidity: external genital and perianal warts (EGWs) and actinic keratosis (AK). Because the potential role of HPV in the pathogenesis of EGW and AK may have implications that influence management, the available topical pharmacotherapy for each disorder also is reviewed. External genital and perianal warts represent a possible phenotypic expression of HPV infection and results from hyperkeratosis and hyperplasia of keratinocytes. The cell cycle disruption caused by low-risk anogenital HPV subtypes (eg, HPV-6, HPV-11) is similar to high-risk HPV subtypes, except low-risk HPV E6 and E7 proteins likely bind regulatory proteins with less affinity. Although UV light clearly has a primary causal role in the development of AK, new data suggest that HPV infection, particularly with 3-HPV subtypes, may serve as a cocarcinogen. By impairing normal DNA repair and apoptotic mechanisms, HPV may set the stage for later UV-induced transformation. It also has been suggested that HPV may increase the severity of AK lesions and contribute to their recurrence following therapy.     

Epidemiology of human papillomavirus infections.

Human papillomavirus infection represents the most common mucocutaneous viral infection, and 3% to 5% of all patients have clinically evident warts. Human papillomavirus infections of the genital tract are one of the most common sexually transmitted viral infections in the United States. Data from STD clinics and private physicians' offices reveal that genital warts, one manifestation of genital HPV infection, have been diagnosed more frequently in recent years. With the use of a variety of diagnostic techniques, asymptomatic HPV infection has been identified in men and women and is probably much more common than is clinically apparent infection.     

皮肤鳞状细胞癌中人乳头瘤病毒的检测

目的:检测皮肤鳞状细胞癌(SCC)皮损中的人乳头瘤病毒(HPV)并探讨其在SCC发病中的作用.方法:用原位杂交(ISH)、聚合酶链反应技术(PCR)检测SCC患者43例,健康者28例标本组织切片中的HPV6、11、16、18、31、33.结果:43例SCC中有2例肢端部位皮损呈HPV DNA阳性,检出类型为HPV16和HPV33.其中1例标本中HPV16和HPV33同时阳性.对照组全部为阴性.结论:HPV16等6种黏膜型HPV可能与肢端以外SCC的发生无相关性,而与肢端部位SCC可能有关联性.     

Detection of human papillomavirus type 16 in Bowen's carcinoma of the toe

Background Human papillomavirus (HPV) is known to cause cervical cancer. Because it has been detected in lesions of Bowenoid papulosis, Bowen’s disease, and Bowen’s carcinoma, HPV infection has been implicated in the pathogenesis of these diseases. Methods A 44‐year‐old man was diagnosed clinicopathologically with Bowen’s carcinoma of the right great toe. He developed multiple organ metastases and died. We examined HPV DNA in skin biopsy specimens from the primary and skin metastatic lesions by polymerase chain reaction (PCR) and in situ hybridization (ISH). The PCR assay was carried out using primer sets specifically designed for detecting the E6 and E7 genes of the HPV types associated with malignancy. Purified and cloned PCR products were subjected to DNA sequence analysis. The ISH studies used INFORM^® HPV III probes. Results We found HPV DNA in specimens from both the primary and the skin metastatic lesions. DNA sequencing detected HPV type 16. We compared the base sequences of viral DNA from the primary and metastatic lesions. Point mutations of the base sequences of the E6 and E7 genes were observed in viral DNA from metastases but not in that from primary lesions. The E6 gene had mutated from G to A in the 383rd base sequence, causing a Glu‐to‐Lys amino acid change. Results of ISH showed punctuate signals in the nuclei of tumor cells. Conclusions We suspect an association between HPV 16 infection and the development of this malignant occurrence.