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.     

New types of human papillomaviruses and intracytoplasmic inclusion bodies: a classification of inclusion warts according to clinical features, histology and associated HPV types

Summary Two new types of intracytoplasmic inclusion bodies (ICBs) associated with distinct clinical features, and the presence of DNA of distinct types of human papillomaviruses (HPVs) are reported. One hundred and seven cutaneous warts containing ICBs were grouped into three categories according to distinct clinicopathological features: 67 were wart lesions with well-known granular (Gr)-ICB. 1 3 were punctate keratotic lesions with filamentous (Fl)-ICB and 31 were pigmented warts with homogeneous (Hg)-ICB. Molecular biological studies were performed in order to assess a specific association of each group of warts with distinct types of HPV.
HPV-1 DNA sequences were detected in all the lesions with a Gr-ICB. Punctate keratotic lesions with Fl-ICB were associated with HPV-63, which was newly cloned from such a lesion. One of the samples also contained HPV-1 DNA. Pigmentcd warts with Hg-ICBs contained one of the related HPVs, i.e. HPV-4. HPV-60 or a novel type of HPV, HPV-65. Based on these associations, a classification of inclusion warts is proposed.     

CONCURRENT HPV-16 INFECTION OF THE NIPPLE AND PERI ANAL AREA IN AN HIV-1+ PATIENT

Background. In patients with HIV-1 disease there has been an increasing association with human papilloma virus (HPV) infections in multiple locations as well as an increase in associated tumors. In addition, there has been increased recovery of HPV in individuals with decreasing T4 cell counts. Case Report. Recently we have seen an HIV-I+ patient with a cutaneous lesion on the nipple, as well as multiple perianal lesions in which HPV-16 was demonstrated by in-situ hybridization. Although these lesions contained the same subtype of HPV virus, they had very different clinical and histopathologic morphologies, and this represents the first reported association of HPV-16 in a nipple lesion. Discussion. Our patient illustrates that in HIV-I disease, HPV infections may present in more diffuse and atypical locations. In addition, the diffuse staining with the in-situ probe for HIV-16 within the lesions, tends to support the findings of others, that viral recovery increases with the immune suppression induced by HIV-I.     

Detection of human papillomavirus type 56 DNA, belonging to a mucous high-risk group, in hair follicles in the genital area of a woman no longer suffering from viral warts

BACKGROUND: Human papillomaviruses (HPVs) parasitize human epithelium, but it is not clear where they reside when they do not cause apparent infection. Hair follicles are important candidates as reservoirs. OBJECTIVES: A patient reported previously by us as having perianal warts caused mainly by HPV 56, demonstrated hair follicles in her genital area which bulged a little from the surface and appeared somewhat enlarged. We therefore examined whether DNA of HPV 56, a member of the mucous high-risk group, might be detectable in these structures. METHODS: We obtained plucked hairs and performed an examination by polymerase chain reaction and subsequent reverse-phase dot blot hybridization (PCR-RDBH) and in situ hybridization (ISH). RESULTS: Strong positive signals were obtained not only with PCR-RDBH but also with ISH. CONCLUSIONS: Hair follicles in the genital area might serve as reservoirs for HPVs belonging to the mucous high-risk group.     

Human papillomavirus-32-positive extragenital Bowenoid papulosis (BP) in a HIV patient with typical genital BP localization

OBJECTIVES: Bowenoid papulosis (BP) is characterized by multiple maculopapular lesions of the genitalia; extragenital localization is rarely found. Human papillomavirus (HPV) type 16 has been found in most cases of BP, but the other HPV genotypes associated with BP had been poorly characterized. GOAL: We describe an extragenital BP with concomitant genital involvement in an HIV-positive woman. STUDY: Several HPV gene-specific amplifications and sequencing were performed on DNA extracted from biopsy samples. RESULTS: The presence of HPV-16 DNA in anogenital and HPV-32 DNA in lip lesions was demonstrated in the absence of any other HPV type and with no coinfection. Semiquantitative polymerase chain reaction analysis revealed that HPV-16 and -32 DNA sequences are in the episomal state. CONCLUSIONS: This is the first report of BP associated with HPV-32 (the causative agent of a benign hyperplasia) and a rare case of BP associated with 2 HPV types in the same patient. The immune depression could have modified the normal benign progression of the extragenital lesions.     

Vulval intraepithelial neoplasia and periungual Bowen's disease concordant for mucosal (HPV-34) and epidermodysplasia verruciformis (HPV-21) human papillomavirus types

Human papillomavirus (HPV) infection is associated with genital malignancy and specific cutaneous malignancies. We report a case of an HPV-associated concurrent vulval intraepithelial neoplasia and periungual Bowen's disease in a young immunocompetent Afro-Caribbean woman with no known risk factors for either disease. HPV genotyping studies detected multiple alpha and beta papillomaviruses with concordance for HPV-34 [a high-risk (HR) mucosal type], and HPV-21 [an epidermodyslasia verruciformis (EV) type] in both vulval and finger tissue. Although the HR-mucosal viruses detected are likely to have a pathogenic role in vulval intraepithelial neoplasia, this is the first report of concordance for EV HPV types in both genital and nongenital skin premalignancies. This case, in the context of accumulating epidemiological and experimental data in cutaneous SCC, raises the question of whether EV HPV may contribute to vulval malignancy, and further study is merited.     

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.     

Elevated amount of human papillomavirus 31 DNA in a squamous cell carcinoma developed from bowenoid papulosis

A 50-year-old woman presented with asymptomatic, multiple black macules on the genitalia for 6 months. She presented multiple, round to irregularly shaped, black macules on her labia major and perineum. A keratotic reddish nodule was found on one of the macules. The results of laboratory investigations showed pancytopenia and a decreased CD4/CD8 ratio. A lymphocyte stimulation test showed a decreased response. The histological examination of a biopsy specimen led us to the diagnosis of bowenoid papulosis (BP) for the macules and squamous cell carcinoma (SCC) for the nodule. The macules and nodule were removed successfully. An elevated amount of HPV DNA was demonstrated in SCC compared with that of BP. The HPV DNA in SCC and BP was shown to be HPV-31. These observations indicated that the elevated amount of HPV-31 DNA could have led to the emergence of SCC from BP under the condition of decreased cellular immunity.     

Detection of human papillomavirus type 58 in polydactylous Bowen's disease on the fingers and toes of a woman - concurrent occurrence of invasive vulval and cervical carcinomas

The group related to human papillomavirus (HPV) type 16 (HPV-16, -31, -33, -35, -52, -58 and -67) is dominantly identified in cervical intraepithelial neoplasia and cervical carcinomas. HPV-16 has also been frequently detected in Bowen's disease on the hands and feet. We describe herein a case of polydactylous Bowen's disease on the fingers and toes of a woman who had had radical vulvectomy and hysterectomy for concomitant invasive vulval and cervical carcinomas. All the lesions, except for the lesions on the periungual side of her left index, middle and ring fingers, harbored HPV-58 DNA with more than 100 entire viral genome copies per cell detected by Southern blot hybridization. The histological localization of the viral DNA was confirmed in all the lesions by in situ hybridization. We could also retrospectively demonstrate HPV-58 DNA in her invasive vulval and cervical carcinoma tissues.     

Human papillomavirus status in extragenital nonmelanoma skin cancers

About 5% of all cancers worldwide can be attributed to human papillomaviruses (HPVs); namely, six sites are strongly associated with HPV infections: cervix, penis, vulva, vagina, anus, and oropharynx. Nonmelanoma skin cancers (NMSC), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) are the most common malignancies in Caucasians. In fact, there is an intense connection between sunlight exposure, fair skin, HPV, and development of NMSC. We have conducted a pilot study that included tissue samples from 26 carcinoma patients, of which there were 13 BCC and 13 SCC. HPV detection and typing was done with DNA amplification and sequencing, respectively. In total, 23.1% of SCC samples (3/13) and 7.7% of BCC samples (1/13) were positive for HPV DNA. The importance of understanding all aspects of NMSC carcinogenesis may be to reveal novel therapeutic options or preventive measures for HPV containing NMSC patients.     

Characterization of two HPV-3 related papillomaviruses from common warts that are distinct clinically from flat warts or epidermodysplasia verruciformis

We have recently identified two unusual human papillomavirus (HPV) isolates while engaged in an ongoing study of wart disease in meat handlers and veterinarians. The papillomas from which these two viruses were isolated clinically resembled verruca vulgaris rather than either flat warts or epidermodysplasia verruciformis (EV). These two previously uncharacterized HPVs were molecularly cloned and characterized with respect to known HPVs. The genomes of the two viruses exhibited dramatically different restriction endonuclease cleavage patterns but were found to have significant sequence homology to each other, as well as to HPV-3 and a new virus isolated from a patient with EV. Neither of the two new HPV isolates exhibit detectable sequence homology under stringent conditions of hybridization or share similar restriction endonuclease cleavage patterns with previously characterized HPV types 1,2,4,5,6b, or a previously isolated HPV from meat handlers.     

Bowenoid papulosis and carcinoma in situ of the cervix uteri in sex partners. An example of the transmissibility of HPV-16 infection

The development of bowenoid papules in a 20-year-old man and a carcinoma in situ of the portio uteri of the 22-year-old female sexual partner is reported. In both lesions HPV-16 DNA could be detected by molecular biological means. This observation led us to the conclusion that HPV 16 had been transmitted sexually. The same seems to be true for HPV-11-induced condylomata acuminata, which appeared on the external genitalia of both patients after recuperation from the HPV-16-induced lesions and conisation treatment. The clinical significance of this observation and its consequences for dermatologists and gynecologists are discussed.     

Lifelong severe verrucosis associated with human papillomavirus type 2: report of a case with a 38-year follow-up

We describe a 67-year-old woman with disseminated warts which she had had for more than 38 years. The lesions consisted of common and plane warts, wart-like plaques and red-brownish macules similar to those in pityriasis versicolor. Furthermore, during follow-up, several solar keratoses, plaques of Bowen's disease and invasive squamous cell carcinomas were excised. The patient also had T-cell immunodeficiency of unknown aetiology. Histopathology demonstrated that all the warts showed the cytopathological features of common warts, but not those of the warts in epidermodysplasia verruciformis (EV). We investigated the presence of human papillomavirus (HPV) DNA in the warts by blot hybridization and molecular cloning and found that the lesions harboured HPV 2, but not EV–HPVs or other HPVs. In addition, the histopathological distribution of the viral DNA was confirmed in paraffin sections of warts from the patient at different ages by in situ hybridization. However, these investigations yielded negative results in specimens of Bowen's disease and invasive squamous cell carcinoma. These results demonstrated that the patient had been infected with HPV 2 from childhood, but the negative results for detection of DNA of HPV 2 in carcinomas from the patient do not support an oncogenic potential for HPV 2. In conclusion, HPV 2, an aetiological agent of common warts in the general population, may induce a lifelong severe verrucosis in some immunosuppressed patients.     

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.     

Widespread cutaneous carcinomas associated with human papillomaviruses 5, 14 and 20 after introduction of methotrexate in two long-term PUVA-treated patients

BACKGROUND: PUVA treatment for patients with severe psoriasis has been demonstrated to be highly effective. However, an increased risk of nonmelanoma and melanoma skin cancers has been reported. It is generally accepted that the risk of squamous-cell carcinoma (SCC) is significantly increased in patients with long-term PUVA therapy. The role of methotrexate (MTX) and infection with oncogenic human papillomaviruses which may act as cocarcinogens is poorly documented. CASE REPORTS: Two cases of multiple SCCs associated with numerous PUVA keratoses and PUVA freckles after long-term PUVA therapy and subsequent treatment with MTX are presented. In 1 case, the tumor progressed to metastatic SCC. Tumors and scrapings of psoriatic skin lesions were analyzed for the presence of oncogenic human papillomavirus (HPV) genotypes. The genotype of HPV-5, -14 and -20 was detected in scrapings and skin tumors using PCR amplification. CONCLUSION: These observations support the concept that long-term PUVA treatment is carcinogenic and rise questions concerning an additional influence of MTX in the development and progression of skin cancer. The risk of metastatic SCC seems to be underestimated in high-dose PUVA-treated patients due to longer latency for developing metastases and the small number of studies with long-term follow-up. Treatment with MTX should be considered cautiously in patients previously exposed to high doses of PUVA. The presence of oncogenic HPVs in carcinomas and psoriatic skin lesions detected only with the highly sensitive nested PCR method is not necessarily a proof of their implication in skin carcinogenesis.     

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 heterogeneity in 36 renal transplant recipients

Immunosuppressed patients such as renal transplant recipients are prone to increased incidence of wart disease. We examined 48 tissue specimens from 36 renal transplant recipients using human papillomaviruses (HPVs) 1, 2, 3, 4, 5, and 6 in filter hybridization under stringent conditions. The results showed that 90% of the samples contained HPV DNA. Of these 43 positive samples, we found HPV-1 in 2%, HPV-2 in 56%, HPV-3 in 19%, HPV-4 in 47%, HPV-5 in 9%, and HPV-6 in 5%. In several cases, more than one type of HPV DNA was observed. In a few of these cases, the clinical appearance of the lesions differed from what might have been expected, such as those lesions containing HPV-3- or HPV-5-related DNAs.     

Prevalence status and association with human papilloma virus of anal squamous proliferative lesions in a patient sample in Taiwan

BACKGROUND AND OBJECTIVE: Anal squamous proliferative lesions, including condyloma, anal high-grade squamous intraepithelial lesion (AHSIL) and squamous cell carcinoma (SCC), are associated with human papilloma virus (HPV) infection. The objectives of the study were to investigate the HPV prevalence of anal squamous proliferative lesion in Taiwan. STUDY DESIGN: From 1991 to 2005, 41 cases with condyloma, 12 cases with AHSIL, and 13 cases with SCC were collected. DNA was extracted from the tissue sections of these patients, and the HPV genotype was identified using polymerase chain reaction and gene chip. The integration status of HPV16 DNA was also evaluated by quantitative real-time polymerase chain reaction. RESULTS: Anal condyloma mainly occurred in young males, but AHSIL and anal SCC developed in older patients. In the patients with human immunodeficiency virus (HIV) infection, AHSIL developed much earlier than patients without HIV infection (36 vs. 61 years). HPV DNA was detected in all 56 patients whose specimens contained adequate DNA. High-risk HPVs (type 16, 58, etc.) were mainly detected in the AHSIL and SCC. Multiple HPV infection was found in AHSIL (4 of 12) and condyloma (11 of 34) but was rare in invasive cancer (1 of 12). Seven of 8 patients with HPV16 infection had coexistent episomal and integrated forms. CONCLUSION: HPV58 is a unique high-risk HPV prevalent in Taiwan. The integration status of HPV seems not correlated with the severity of the dysplasia. In our study, emerging HIV-positive AHSIL in recent years indicates that we should devote more efforts to promote sexual safety among the people who engaged in anal intercourse.