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.     

DNA analysis indicates patient-specific human papillomavirus type 16 strains in Bowen's disease on fingers and in archival samples from genital dysplasia

Human papillomavirus (HPV) type 16 is casually involved in the pathogenesis of anogenital cancer and has also been demonstrated in some patients with Bowen's disease (BD) on the fingers. From two women with HPV 16 in BD on the fingers, and in archival samples from genital dysplasia, collected as long as 26 years ago, the non-coding region of the virus was amplified by the polymerase chain reaction and sequenced. The HPV 16 DNA sequences found in the finger lesions and in the genital archival samples showed no diversities within single patients. Compared with an HPV 16R reference sequence, one patient showed a unique T nucleotide at position 78, whereas the other patient exhibited T and A nucleotides at positions 7193 and 7521, respectively. In one of the patients, the same strain of HPV 16 was found in a digital tumour 26 years after its clearance from the genital tract. DNA sequence analysis indicated patient-specific HPV 16 strains. Auto-inoculation from the genital tract was favoured as a plausible explanation of why HPV 16 caused BD on the fingers.     

A broad spectrum of human papillomavirus types is present in the skin of Australian patients with non-melanoma skin cancers and solar keratosis

BACKGROUND: Human papillomavirus (HPV) may play a role in the pathogenesis of non-melanoma skin cancer (NMSC) in epidermodysplasia verruciformis (EV) patients, but in the general population no specific HPV types have been associated with these lesions. Objectives To examine the spectrum of HPV types present in the skin and tumours of Australian patients with NMSC or solar keratosis (SK). METHODS: Biopsies from tumours, and cotton swab samples of perilesional skin and buttock skin from each of 59 Australian patients with basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or SK were tested for HPV DNA by polymerase chain reaction (PCR) using HPV consensus (FAP) primers and by type-specific primers for HPV 38 and candidate HPV 92. The identification of HPV type from consensus PCR was performed by sequencing and comparison with GenBank. RESULTS: In total, 49 of 59 (83%) patients harboured HPV DNA, which was detected in 28 of 64 (44%) biopsies, 48 of 64 (75%; P < 0.001) perilesional swabs and 36 of 59 (61%; P = 0.04) buttock swabs. Forty-five different HPV types/putative types were detected: 15 were previously characterized HPV types, 17 were earlier described putative types and 13 were new putative types. In addition, six subtypes and four variants of HPV sequences were identified. HPV types within the B1 group (EV HPV types) were found in 26 of 64 (40%) lesions, 44 of 64 (69%) perilesional swabs and 35 of 59 (59%) buttock swabs. HPV 38 was detected in 23 of 59 (39%) patients, and was found in seven of 16 (43%) SKs, but was less common in SCCs [three of 23 (13%); P = 0.037] and BCCs [four of 25 (16%); P = 0.056]. Candidate HPV 92 was found in seven of 59 (12%) patients. CONCLUSIONS: A broad spectrum of HPV types, the majority from the B1 group, was found in skin of Australian patients with skin tumours. HPV 38 was found significantly more often in SK than in SCC. However, the role of cutaneous HPV infection in the pathogenesis of NMSC remains elusive.     

Genital HPV infection not a local but a regional infection: experience from a female teenage group.

OBJECTIVES--To investigate the prevalence of human papillomavirus (HPV) infections in a group of female teenagers, and to analyse to what extent HPV DNA was also detectable, in urethra and cervix samples among the patients with macroscopic genital warts compared with those without. DESIGN--The patients were interviewed about their sexual habits and history of venereal diseases. They underwent a gynaecological health control examination, including macroscopic inspection for genital warts and collection of a cytological vaginal smear (Pap smear). Cell samples were also taken from endocervix and urethra and from vulva lesions, when found. These samples were tested for HPV DNA of the types 6, 11, 16, 18 and 33 using the polymerase chain reaction (PCR) technique. SETTING--An adolescence out-patient clinic in Malmö, Sweden. SUBJECTS--Forty-nine female teenagers consulting for gynaecological complaints, some of them for genital warts. RESULTS--Twenty patients had present and four had a history of genital warts (group A). The other 25 patients had no visible lesions (group B). In the first group (A) 18 of the 24 patients were positive for HPV DNA in one or more of the three locations studied. More patients were positive in urethra (17) than in cervix (15). In group B four of the 25 patients were positive for HPV DNA in urethra, three of these also in cervix. In the two groups 11 and four patients, respectively, showed pathological Pap smears. CONCLUSIONS--The finding of HPV DNA in urethra, both from women with and without visible genital warts, indicates that there is a high probability that the infection is also present in cervix, suggesting that the genital HPV infections are multifocal. Thus, patients with genital warts are most likely to have cervical HPV infections and will more often have pathological Pap smears than patients without warts.     

Detection of human papillomavirus DNA on the fingers of patients with genital warts

OBJECTIVE: To determine whether patients with genital warts carry human papillomavirus (HPV) DNA on their fingers. METHODS: 14 men and eight women with genital warts had cytobrush samples taken from genital lesions, finger tips, and tips of finger nails. Samples were examined for the presence of HPV DNA by the polymerase chain reaction. RESULTS: HPV DNA was detected in all female genital samples and in 13/14 male genital samples. HPV DNA was detected in the finger brush samples of three women and nine men. The same HPV type was identified in genital and hand samples in one woman and five men. CONCLUSION: This study has identified hand carriage of genital HPV types in patients with genital warts. Although sexual intercourse is considered the usual mode of transmitting genital HPV infection, our findings raise the possibility of transmission by finger-genital contact.     

Immunohistochemical staining of p16 in squamous cell carcinomas of the genital and extragenital area

Background and objectivesPositive immunostaining for the tumor suppressor protein p16 is associated with the presence of mucosal or αsubtypes of human papillomavirus (HPV) in cervical and genital squamous cell carcinoma (SCC). The aim of this study was to determine whether p16 immunostaining is also associated with mucosal HPV in extragenital SCC.Material and methodsParaffin sections of lesions located in the genital region (8 genital warts, 3 intraepidermal SCCs, and 7 invasive SCCs) and extragenital area (29 intraepidermal SCCs corresponding to Bowen disease and 10 invasive SCCs) were stained for p16 by immunohistochemistry. Mucosal HPV was detected by polymerase chain reaction (PCR).ResultsIn the genital area, p16 immunostaining was negative in genital warts and positive in all 3 intraepidermal SCCs and 2 invasive SCCs (29%). Mucosal HPV was detected in 6 genital warts and 2 intraepidermal SCCs (100% after exclusion of 3 lesions that could not be analyzed by PCR) and in the 2 invasive SCCs that were positive for p16. In the extragenital area, 19 intraepidermal SCCs (95%) and 2 invasive SCCs (20%) were immunopositive for p16. Mucosal HPV was detected in 4 intraepidermal SCCs (p16 immunopositive) and 1 invasive SCC (p16 immunonegative). In intraepidermal SCCs, p16 immunostaining facilitated the identification of dermal microinfiltration or invasion of normal skin appendages.ConclusionsAccording to our results, unlike in genital SCCs, p16 immunopositivity is independent of the presence of HPV in extragenital SCCs. Compared with intraepidermal SCCs, the absence of p16 protein in invasive SCCs in the extragenital area would indicate progression of the disease.     

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 papillomavirus-16 DNA in a cutaneous invasive cancer

A middle-aged man with a 20-year history of a warty lesion on his finger was diagnosed histologically as having an invasive carcinoma at that location. Molecular analysis of the lesion showed that human papillomavirus (HPV) DNA was present in this tumor. Under stringent hybridization conditions, only HPV-16 DNA, which is commonly associated with genital neoplasia or cutaneous bowenoid lesions, was detected. Two-dimensional gel electrophoresis revealed that various sections of the tumor contained mostly episomal viral DNA; but in one case, low levels of integrated HPV-16 DNA were detected as well.     

Human papillomavirus type 58 in Bowen's disease of the elbow

Human papillomavirus (HPV) can be detected in skin lesions of Bowen's disease, particularly on the fingers, and its genotype is associated with mucosal/genital types of HPV. We report herein an 85-year-old woman who had HPV-associated Bowen's disease on her elbow. HPV-58 DNA was detected in the lesion by polymerase chain reaction with restriction fragment length polymorphism and by Southern blot hybridization. In situ hybridization revealed numerous hybrid cells in the nuclei of the upper epidermis and stratum corneum of Bowen's disease. A high-risk type of mucosal HPV-58 DNA is associated with Bowen's disease in this case, suggesting that HPV-related Bowen's disease is not always restricted to genital or finger lesions.     

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.     

Presence of human papilloma virus type 16 DNA sequences in human nonmelanoma skin cancers

The presence of human papillomaviruses (HPV) has been shown to be associated with the development and progression of invasive cancers of the genital tract, skin, and head and neck. In this study we analyzed 37 human nonmelanoma skin cancers (21 squamous cell carcinomas and 16 basal cell carcinomas) for the presence of HPV sequences. The polymerase chain reaction (PCR) was employed using primers designed to amplify DNA encoding the E6-E7 region of HPV types 6b/11, 16, and 18. HPV type 6b/11 and 18 sequences were absent from the DNA of all 37 tumors examined. However, HPV type 16 sequences were detected in four of 21 squamous cell carcinomas (SCC) (19%) and three of 16 basal cell carcinomas (BCC) (19%) as indicated on agarose gel electrophoresis by the presence of a single specific DNA band of predicted length. Furthermore, HPV type 16 sequences were absent in the DNA of normal skin from these seven skin cancer patients. The presence of HPV type 16 sequences in the seven skin tumors was confirmed by dot blot hybridization of PCR-amplified material to 32P-labeled HPV type 16, but not to HPV type 6/11 or 18-specific probes. These data indicate that HPV type 16, but not 6b/11 or 18, is associated with development of some human nonmelanoma skin cancers.     

Human papillomavirus–associated diseases

The human papillomavirus (HPV) may be associated with various oral, genital, and cutaneous conditions, both benign and malignant. The association between sexually transmitted α-HPV types is the strongest with cervical cancer because almost all such malignancies contain viral DNA, notably HPV types 16 and 18. The contribution of cancer causing HPV types in other anogenital, oral, and oropharyngeal malignancies, plus benign disorders, is lower and with a less significant public health concern. Cervical cytologic screening is a well-established preventive measure that allows early detection and successful treatment of precancerous cervical lesions. In cases of all other HPV-associated disorders, early detection of a precancerous lesion is either difficult or almost impossible. HPV vaccination remains the only preventive measure against most HPV-related diseases.     

Frequency and spectrum of HPV types detected in cutaneous squamous-cell carcinomas depend on the HPV detection system: a comparison of four PCR assays

BACKGROUND: The association of human papillomavirus (HPV) with cutaneous squamous-cell carcinomas (SCCs) has been described recently, but the frequency and spectrum of HPV types identified differed substantially in distinct studies. OBJECTIVE: Comparison of different PCR assays with respect to sensitivity and range of HPV types detected. METHOD: Cutaneous SCC were analyzed for HPV DNA using both consensus PCR assays with degenerate primers and PCR assays with nondegenerate primers derived from HPV types 5 and 8. RESULTS: HPV DNA was found in 50% of SCC specimens using degenerate primers. The rate of HPV-DNA-positive specimens increased to 69% when PCR assays with nondegenerate primers were applied in addition. The spectrum of HPV types detected with each of the PCR assays differed considerably. CONCLUSIONS: The frequency and spectrum of HPV types detected in cutaneous SCC strongly depends on the HPV detection system used and urges the need for standardization of HPV detection and typing in skin lesions in order to characterize HPV types predominating in distinct tumors.     

Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease

A woman with Hailey-Hailey disease, suffering from carcinoma of the vulva, was examined by histology and for the presence of human papillomavirus (HPV) DNA by polymerase chain reaction (PCR) and in situ hybridization. Our diagnosis by histological examination revealed the vulval carcinoma to be a squamous cell carcinoma (SCC), adjacent to lesions of Hailey-Hailey disease and severe dysplasia/carcinoma in situ [vulval intraepithelial neoplasia (VIN) III]. The PCR with consensus primers for the L1 region (L1-PCR) successfully amplified HPV DNA using total DNA extracted from formalin-fixed and paraffin-embedded tissue specimens. Restriction fragment length polymorphism analysis and sequencing of L1-PCR products revealed HPV types 16 and 39. HPV 16-specific primers for the E6 region identified HPV 16 DNA. In situ hybridization analysis with biotinylated HPV 16 and 39 DNA probes revealed the presence of the HPV 39 genome in the nuclei of the tumour cells in the SCC. These results indicate that HPV 16 and 39 are associated with lesions in vulval carcinoma. Regarding the patient's susceptibility to infection in the case of Hailey-Hailey disease, there is a possibility that HPV was inoculated into the lesions of Hailey-Hailey disease and induced those of VIN III and SCC.     

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.     

Detection of human papillomavirus DNA in squamous cell carcinomas of a patient with mycosis fungoides: report of a case

Human papillomaviruses (HPV) have been associated with squamous cell carcinomas (SCC) of the skin in both the immuno-competent and the immunocompromised individual. A paucity of literature, however, exists concerning die presence of HPV in SCCs from patients with mycosis fungoides (MF)-[cutaneous T-cell lymphoma (CTCL)]. We describe a case of multiple SCCs in which HPV DNA was detected over a 9-year period from a patient with MF. This patient with a long history of MF developed 7 small red scaly indurated lesions of sun and non-sun-exposed areas during a 9-year period (1981–1989). Histologic examination of all the lesions revealed that they were SCCs. The patient had no recorded history of arsenic exposure. To investigate the possible role of HPV as a co-carcinogen, we tested the 7 cases of SCC for HPV. Polymerase chain reaction (PCR) was performed on formalin-fixed tissue sections using HPV L1 consensus sequence primers. Four of the 7 SCCs were positive for HPV DNA. These results suggest a possible role for HPV as a co-carcinogen in the development of SCCs in this patient.     

Viral DNA detection and RAS mutations in actinic keratosis and nonmelanoma skin cancers

Background Actinic keratosis (AK) is a well‐established precancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). Basal cell carcinoma (BCC) is a locally aggressive slowly growing tumour that rarely metastasizes. A number of viruses have been proposed to play a role in the development of nonmelanoma skin cancers (NMSC), but the most plausible evidence to date suggests that cutaneous human papillomavirus (HPV) is the key instigating factor. Objectives To evaluate the prevalence of HPV, cytomegalovirus (CMV), herpes simplex virus (HSV) and Epstein–Barr virus (EBV) and investigate their relationship with the presence of RAS gene mutations in cutaneous lesions obtained from nonimmunosuppressed patients. Methods HPV, CMV, HSV and EBV detection was performed using polymerase chain reaction (PCR) in skin biopsies (26 AK, 12 SCC and 15 BCC samples) that were collected from immunocompetent patients. The RAS mutation incidence was also investigated in all cutaneous lesions by use of PCR/restriction fragment length polymorphism and direct DNA sequencing. Results Seventeen out of 53 (32%) skin lesions were found to be positive for HPV DNA. The highest incidences of HPV infection were five of 15 (33%) in BCC and four of 12 (33%) in SCC specimens. The HPV incidence was eight of 26 (31%) in AK and eight of 53 (15%) in normal skin tissue. Twelve out of 53 (23%) skin lesions were CMV‐positive. The highest incidence of CMV infection was six of 15 (40%), observed in BCC specimens. The CMV incidence was two of 26 (8%) in AK and four of 12 (33%) in SCC. No normal skin biopsy was found to be positive for CMV. All cutaneous samples were negative for HSV and EBV DNA, as assessed by our PCR‐based assays. Only three samples, one AK (4%), one BCC (6%) and one SCC (8%), were found to carry a G>T transversion at the second position of HRAS codon 12. Both HRAS mutant SCC and BCC biopsies were HPV‐ and CMV‐positive, as well. Conclusions HPV DNA is detected in NMSC, AK and normal skin biopsies. Our results also indicate that CMV is involved in NMSC at higher levels than in premalignant lesions, whereas the virus was not detected in normal skin biopsies. HSV and EBV do not appear to be involved in the pathogenesis of cutaneous lesions. Moreover, we suggest that the HRAS codon 12 mutation is not a very common event in AK or NMSC. Finally, both viral infection and HRAS activation appear to represent independent factors in the aetiology of NMSC, samples of which were obtained from immunocompetent patients.