Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.

BACKGROUND: Human polyomavirus (HPyV)6 and HPyV7 are shed chronically from human skin. HPyV7, but not HPyV6, has been linked to a pruritic skin eruption of immunosuppression. OBJECTIVE: We determined whether biopsy specimens showing a characteristic pattern of dyskeratosis and parakeratosis might be associated with polyomavirus infection. METHODS: We screened biopsy specimens showing "peacock plumage" histology by polymerase chain reaction for HPyVs. Cases positive for HPyV6 or HPyV7 were then analyzed by immunohistochemistry, electron microscopy, immunofluorescence, quantitative polymerase chain reaction, and complete sequencing, including unbiased, next-generation sequencing. RESULTS: We identified 3 additional cases of HPyV6 or HPyV7 skin infections. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 primarily infects keratinocytes. High viral loads in lesional skin compared with normal-appearing skin and the identification of intact virions by both electron microscopy and next-generation sequencing support a role for active viral infections in these skin diseases. LIMITATION: This was a small case series of archived materials. CONCLUSION: We have found that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a distinctive histologic pattern and describe this entity as "HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatoses."

Mucosal Alpha-Papillomavirus (HPV89) in a rare skin lesion.

BACKGROUND: Apocrine acrosyringeal keratosis is a rare skin lesion showing a unique benign keratotic lesion associated with syringocystoadenoma papilliferum. It is characterized by an exophytic proliferation of the epidermis with two distinct keratinocytic structures: a) columns of hyperkeratotic mass surrounded by acanthotic epidermis and b) papillated and/or cystic invaginations typical of syringocystoadenoma papilliferum. No causative agents were reported. FINDINGS: The present report describes a typical case of apocrine acrosyringeal keratosis localized in the right retro-auricular area of 57-year-old man in which the presence of HPV was evaluated. PCR analysis and direct sequencing revealed the presence of HPV 89. The presence of this low risk mucosal HPV in a skin localization was never reported as well as in association with this rare tumor. Furthermore rolling circle amplification, RT-PCR and in situ hybridization confirmed the presence of a transcriptionally active HPV 89. CONCLUSIONS: Taken together our results suggest that HPV89 plays a role in apocrine acrosyringeal keratosis with syringocystoadenoma papilliferum, in consideration of the documented biological activity of the virus. The association of low risk mucosal HPV infection with this skin lesion opens new perspectives in its clinical management. Further studies on samples from other patients are needed to confirm this association.

Kerinokeratosis Papulosa of Childhood.

BACKGROUND: Kerinokeratosis papulosa (KP) is considered an extremely rare genodermatosis presenting usually as waxy papules on the trunk in childhood. OBJECTIVE: To describe and analyze the clinical, histological and potential etiopathological aspects of KP. METHODS: The dermatoscopic features of a new case of KP of childhood are investigated. The presence of human papillomavirus (HPV) DNA in lesional skin was studied by polymerase chain reaction. Furthermore, all cases of KP of childhood reported so far were reviewed. RESULTS: As a diagnostic tool, we describe for the first time a dermatoscopic feature, namely a cribriform pattern of KP, in an 11-year-old boy. In addition, we detected HPV (type 57) in his KP lesions. CONCLUSIONS: Dermatoscopic examination might be a useful tool to distinguish KP from other skin lesions, e.g. common warts. The detection of HPV type 57 might hint to an etiological role of HPV for KP.

Seroprevalence of trichodysplasia spinulosa-associated polyomavirus in Japan.

BACKGROUND: Trichodysplasia spinulosa-associated polyomavirus (TSV) was identified in, and shown to be the probable cause of, trichodysplasia spinulosa, a rare skin disease. To date, serological analyses have revealed that TSV infection is common among adults in the general population of Europe and Australia. However, there have been no reports of TSV in Asia. OBJECTIVE: To study the prevalence of TSV infection in Japan. STUDY DESIGN: TSV-VP1 expressed in a recombinant baculovirus expression system in an insect cell line, Tn5, self-assembled into virus-like particles. Overall, 1000 serum samples were examined by enzyme-linked immunosorbent assays using virus-like particles of TSV as antigen. Participants ranged in age from 0 to 94 years. RESULTS: Overall, 629 of 1000 serum samples (62.9%) were positive for anti-TSV antibodies. The seropositive rate increased with age and the seroprevalence of TSV significantly increased from 17.1% (25/146) in children aged from 0 to 4 years to 78.7% (472/600) in adults aged over 20 years (odds ratio = 0.056, 95% confidence interval = 0.035-0.900, P = 0.000, Chi-squared test). TSV seropositivity was not different between sera obtained in 1980 and 2012, and was not associated with sex. Competitive assay demonstrated that TSV antibodies did not cross-react with BK virus or Merkel cell polyomavirus. CONCLUSIONS: These results provide evidence that TSV circulates widely in the Japanese population, with primary exposure occurring mainly at early childhood, similar to that previously reported in other countries.

The trichodysplasia spinulosa-associated polyomavirus: virological background and clinical implications.

Trichodysplasia spinulosa-associated polyomavirus (TSPyV) is a new species of the family Polyomaviridae that was discovered in 2010. TSPyV infects humans and is associated with the development of a rare disease called trichodysplasia spinulosa. Trichodysplasia spinulosa is a skin disease of severely immunocompromised hosts characterized by follicular distention and keratotic spine formation especially on the face. Electron microscopy, immunohistochemistry, and viral load measurements indicate an etiological role of active TSPyV infection in the development of this disease. This review will address virological and pathogenic properties of TSPyV, as well as epidemiologic, diagnostic, and therapeutic aspects of TSPyV infection.

Characterization of a novel papillomavirus species (ZcPV1) from two California sea lions (Zalophus californianus).

A seven-year old California sea lion (Zalophus californianus) presented with focally extensive, bilaterally symmetric, proliferative axillary skin lesions and preputial lesions. A second California sea lion in the same population presented with similar proliferative lesions on the underside of the tail. Histopathology revealed epidermal hyperplasia with severe hyperkeratosis, with proliferating keratinocytes forming broad, branching pegs that extended into the dermis. Pan-papillomaviral consensus PCR was used to obtain initial E1 sequence template and the complete genome was determined using a combination of rolling circle amplification and specific-primer PCR. Analysis revealed a novel papillomavirus, Zalophus californianus papillomavirus 1 (ZcPV1), with seven open reading frames encoding five early proteins (E6, E7, E1, E2 and E4) and two late proteins (L1 and L2). Phylogenetic analysis revealed that (ZcPV1) is most closely related to Equine papillomavirus 1 (EcPV1) in the genus Zetapapillomavirus, and Canine papillomaviruses 3 and 4 (CPV3, CPV4) in the genus Chipapillomavirus. The lesions regressed without intervention over a period of several months.

Virus-associated Trichodysplasia spinulosa.

This review discusses the evolution of an emerging dermatologic entity, virus-associated trichodysplasia spinulosa (TS), and its association with the novel human TS polyomavirus. We will describe how this distinct dermatologic diagnosis has arisen from the convergence of strikingly similar histopathologic findings observed across several case reports. The case of virus-associated TS exemplifies how a combination of astute clinicopathologic observation and a well-designed molecular genetic approach can provide insights into the pathogenesis of cutaneous disease.

Ulerythema ophryogenes, a rare and often misdiagnosed syndrome: analysis of an idiopathic case.

Keratosis pilaris (KP) is a follicular hyperkeratosis disorder which is frequently detected in the adult population (44%), mostly in female adolescents (80%). It is a genetic autodominant dermatosis with variable penetrance, but no specific gene association has been determined, even though association to the presence of chromosome 18p deletion has been reported in some cases. We report the case of a 51-year-old Caucasian woman affected by keratosis pilaris gradually progressing with age and with a story of multiple abortions. Standard karyotype and CGH array analyses did not reveal any genetic abnormality. Virological analyses detected the presence of HPV 36 DNA inside the dorsum biopsy, leading to hypothesize its involvement in the evolution of the lesion. Clinical history and patient examination led the diagnosis of an idiopathic case of Ulerythema ophryogenes. The analysis of more cases could be useful to verify the involvement of cutaneous HPV in the progression of the clinical manifestation of the KP variants.

Esophageal verrucous carcinoma arising from hyperkeratotic plaques associated with human papilloma virus type 51.

Esophageal verrucous carcinoma is a rare variant of esophageal squamous cell carcinoma. We report a case of esophageal verrucous carcinoma associated with human papilloma virus (HPV) type 51. The patient had long-standing dysphagia and odynophagia, and white esophageal plaques showing hyperkeratosis on biopsy. At repeat endoscopy, the esophagus was covered with verrucous white plaques and areas of nodular mucosa with white fronds, with a distal 10-cm smooth mass protruding into the lumen. Biopsies demonstrated an atypical squamoproliferative lesion but no frank malignancy. HPV type 51 DNA was detected in endoscopic biopsy specimens by polymerase chain reaction. Because the size of the lesion favored an underlying verrucous carcinoma, our patient underwent minimally invasive esophagectomy with gastric pull-up and cervical anastomosis. The pathologic diagnosis was a well-differentiated esophageal verrucous carcinoma. One year after esophagectomy, the patient feels well and is free of disease. Although HPV DNA was not detected in the cancer tissue obtained at surgery, our case suggests an association between HPV type 51 and esophageal verrucous carcinoma. The clinical evolution in this case highlights the importance of endoscopic surveillance in patients with exuberant esophageal hyperkeratosis, and of definitive surgical resection when malignancy is suspected even if frank malignancy is not demonstrated on superficial biopsies.

Human papillomavirus type 7-associated condyloma.

Human papillomavirus type 7 (HPV-7) was originally identified in common warts of butchers. It has remained unclear, however, whether HPV-7 also induces other distinct types of cutaneous lesions. We observed similar keratoses on the groins of 2 patients. The lesions presented as multiple, smooth and small with little change in color from that of the adjacent skin and were diagnosed as condylomas. Their histological features were acanthosis, papillomatosis and parakeratosis with hyperkeratotic perinuclear vacuolation in the granular layer. By Southern blot analysis, HPV-7 DNA was identified in both condylomas. We conclude that HPV-7 infection causes condyloma. In addition, we discuss the long-held dogma regarding the association of HPV-7 with butcher's warts and highlight the potential need for clinicians to know causal HPV types in cutaneous lesions given the increased use of prophylactic HPV vaccines.

Four novel human betapapillomaviruses of species 2 preferentially found in actinic keratosis.

Recent studies have suggested an association between human papillomaviruses (HPVs), particularly species 2 members of the genus Betapapillomavirus, and squamous cell carcinoma (SCC) of the skin. As most of these viruses are uncharacterized, molecular characterization and epidemiology are needed to advance our understanding of their significance in carcinogenesis. This study determined the complete genomes of four betapapillomaviruses of species 2 from skin lesions designated HPV-107, -110 and -111 and FA75[KI88-03], an isolate of an unpublished HPV type, and analysed their prevalence and viral loads in biopsies from SCC, actinic keratosis (AK), basal cell carcinoma, seborrhoeic keratosis and the healthy skin of 263 immunocompetent patients by HPV type-specific real-time PCR assays. Seventeen patients (6.5 %) harboured at least one of the four HPV types in their lesion, whereas seven patients (2.7 %) harboured one or more of the HPV types in healthy skin. Overall, the four viruses were more common in AK than in healthy skin (odds ratio 5.0, 95 % confidence interval 1.4-17.5), but the prevalence and viral loads were low. This characterization of HPV-107, -110 and -111 and FA75[KI88-03] expands the heterogeneity of members of species 2 of the genus Betapapillomavirus. However, as these types were found in only a few samples and in low amounts, a possible role in carcinogenesis remains elusive.

Cutaneous human papillomaviruses as recurrence factor in actinic keratoses.

Actinic keratoses (AK) are common, premalignant lesions cause mainly by UV DNA damage. Progression into squamous cell carcinoma may be influenced by other several factors such as chronic chemical exposure or viral infection. A carcinogenic role of Human Papillomaviruses (HPV) in early steps of skin tumour development was recently hypothesized; moreover the presence of HPV DNA seems to be higher in cancer precursor lesions. The aim of this work is to identify the presence of HPV DNA in biopsies from Actinic Keratoses (AK) and from normal skin samples collected from dermatological healthy subjects in Italy, in order to evaluate the severity and the clinical evolution of the HPV positive lesions. The DNA test revealed 37% HPV positivity in AK patients versus 0% in the control group; many different genotypes and variants were identified by direct sequencing of PCR product. The HPV positive AK were usually clinically indistinguishable from the HPV negative. All AK lesions were removed by laser treatment, but AK lesions recurred in all HPV positive patients after a period of 45-60 days whereas the same disappeared in the HPV negative ones. These data permit to hypothesize that the presence of HPV DNA could be an aggravating factor for AK lesion severity and recurrence.

Seroreactivity to cutaneous human papillomaviruses among patients with nonmelanoma skin cancer or benign skin lesions.

Cutaneous human papillomaviruses (HPV) are common in nonmelanoma skin cancers, benign skin lesions, and healthy skin. Increased seroprevalences for cutaneous HPV among nonmelanoma skin cancer patients have been described. To determine whether antibodies to cutaneous HPV are related to presence of the virus and/or to skin disease, we collected serum and biopsies from both lesions and healthy skin from 434 nonimmunosuppressed patients (72 squamous cell carcinomas, 160 basal cell carcinomas, 81 actinic keratoses, and 121 benign lesions). Biopsies were analyzed for HPV DNA by PCR, cloning, and sequencing. Serum antibodies to the major capsid protein L1 of HPV 1, 5, 6, 8, 9, 10, 15, 16, 20, 24, 32, 36, 38, and 57 as well as to the oncoproteins E6 and E7 of HPV 8 and 38 were detected using a multiplexed fluorescent bead-based assay. Type-specific seroprevalence among patients with the same type of HPV DNA (sensitivity of serology) varied from 0% to at most 28%. Presence of HPV DNA and antibodies to the same HPV type was not significantly correlated. However, seropositivity to any HPV type was significantly more common among patients positive for HPV DNA of any HPV type (odds ratio, 1.90; 95% confidence interval, 1.55-2.34). Seroprevalences were similar among the different patient groups but was, for most HPV types, somewhat higher among squamous cell carcinoma patients than among basal cell carcinoma patients (P < 0.01). In conclusion, additional studies are required to clarify the biological meaning of seropositivity as a marker of cutaneous HPV infection and skin disease.

Cutaneous human papillomavirus 88: remarkable differences in viral load.

A human papillomavirus (HPV) was cloned from a patient with multiple squamous cell carcinomas (SCCs) and identified as HPV88, recently categorized into a new species within the genus Gamma. The HPV88 viral load in an SCC of the index patient exceeded 1 million copies/cell. By contrast, a survey of 447 skin lesions (79 actinic keratoses, 73 seborrhoeic keratoses, 169 basal cell carcinomas and 126 SCCs) and 362 healthy skin biopsies found detectable HPV88 DNA in only 7 specimens. All these had very low viral loads (<1 copy/10(3) cells) implying extreme biological variability in viral load.