Molecular mechanisms of human papilloma virus related skin cancers: A review.

The human papillomavirus (HPV) belongs to the Papillomaviridae family of viruses which includes small, double-stranded DNA viral agents. Approximately 90% of HPV infections occur asymptomatically and resolve spontaneously. However, infection with high-risk viral strains can lead to the development of preneoplastic lesions, with an increased propensity to become cancerous. The location of these malignancies includes the oral cavity, cervix, vagina, anus, and vulva, among others. The role of HPV in carcinogenesis has already been demonstrated for the aforementioned neoplasia. However, regarding skin malignancies, the mechanisms that pinpoint the role played by HPV in their initiation and progression still elude our sight. Until now, the only fully understood mechanism of viral cutaneous oncogenesis is that of human herpes virus 8 infection in Kaposi sarcoma. In the case of HPV infection, however, most data focus on the role that beta strains exhibit in the oncogenesis of cutaneous squamous cell carcinoma (cSCC), along with ultraviolet radiation (UVR) and other environmental or genetic factors. However, recent epidemiological investigations have highlighted that HPV could also trigger the onset of other non-melanocytic, for example, basal cell carcinoma (BCC), and/or melanocytic skin cancers, for example, melanoma. Herein, we provide an overview of the role played by HPV in benign and malignant skin lesions with a particular focus on the main epidemiological, pathophysiological, and molecular aspects delineating the involvement of HPV in skin cancers.

Cutaneous Human Papillomaviruses and the Risk of Keratinocyte Carcinomas.

Cutaneous human papillomavirus (cuHPV) infections may be novel targets for skin cancer prevention and treatment, but critical information regarding the development of virus-positive skin cancers following cuHPV infection has been lacking. In this study, baseline cuHPV infection was measured by serology and viral DNA detection in eyebrow hairs (EBH) and forearm skin swabs (SSW) among 1,008 individuals undergoing routine skin cancer screening exams and followed for incidence of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC). Baseline ß-HPV detection, particularly in SSW, significantly predicted cuSCC (HR = 4.32; 95% confidence interval, 1.00-18.66), whereas serologic evidence of past ß-HPV infection was not associated with cuSCC. Less than 5% of baseline ß-HPV types detected in SSW were present in subsequent cuSCC tumors, and cuHPV detected in SSW with higher mean fluorescence intensity values were more likely to be present in cuSCC compared with those with lower levels (P < 0.001). ß-HPV-positive cuSCC occurred more often in areas of highly sun-damaged skin than did ß-HPV-negative cuSCC. Overall, no clear patterns were observed between baseline ß-HPV detection and subsequent development of BCC, or between baseline γ-HPV detection and either cuSCC or BCC. Collectively, these results demonstrate that ß-HPV detection in SSW is a significant predictor of cuSCC risk, although evidence suggests only a small subset of cuSCC is etiologically linked to ß-HPV infection. SIGNIFICANCE: ß-HPV positivity may be a useful biomarker for identifying individuals who could benefit from increased screening or novel cutaneous squamous cell carcinoma prevention strategies.

Association between Human Polyomaviruses and Keratinocyte Carcinomas: A Prospective Cohort Study.

BACKGROUND: A positive association between Merkel cell polyomavirus (MCPyV) infection and cutaneous squamous cell carcinoma (cuSCC) has been observed in at least one previous case-control study. To evaluate this association in a prospective context, we investigated infections with human polyomaviruses (HPyV), including MCPyV, as predictors of keratinocyte carcinomas, including cuSCC and basal cell carcinoma (BCC), among a cohort of immunocompetent individuals enrolled in the Viruses in Skin Cancer (VIRUSCAN) Study. METHODS: Associations between markers of baseline HPyV infection (serum antibodies and viral DNA in eyebrow hairs and skin swabs) and incident keratinocyte carcinomas were modeled using Cox proportional hazards regression. Proportions of baseline HPyV infections that were concordant with a subsequent tumor positive for the same HPyV type were assessed. RESULTS: No significant associations were observed between baseline markers of MCPyV or other HPyV infections and cuSCC or BCC. Less than 4.5% of baseline MCPyV infections were also detected in subsequently developed keratinocyte carcinoma tumors. CONCLUSIONS: HPyV infection was not a predictor of keratinocyte carcinoma risk in this prospective cohort. IMPACT: Cancer-associated infections represent attractive targets for cancer prevention; however, HPyV infections have limited potential as novel targets for cuSCC prevention.

RNA Expression Profiling of Lymphoepithelioma-Like Carcinoma of the Bladder Reveals a Basal-Like Molecular Subtype.

Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare subtype of urothelial carcinoma consisting of undifferentiated epithelial cells within a dense inflammatory cell infiltrate. We set out to molecularly characterize LELC-B through RNA expression profiling as well as immunohistochemistry (IHC) to understand its underlying biology. Sixteen cases of LELC-B were identified at Johns Hopkins University. RNA sequencing was performed on 14 cases. IHC staining for programmed cell death ligand 1 (PD-L1) and mismatch repair proteins MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, and PMS1 homolog, mismatch repair system component 2 (PMS2) was performed. Transcriptomic profiling of LELC-B showed that they are enriched in a basal-like phenotype, with 12 of 14 LELC-B cases correlating to the basal centroid of the bladder cancer analysis of subtypes by gene expression 47 (BASE47) predictive analysis of microarrays (PAM) classifier. Gene signature analysis confirmed the lymphocyte infiltration profile consistent with the histomorphology. LELC-B lacked features to explain the robust lymphocytic infiltrate, such as loss of mismatch repair protein expression or expression of Epstein-Barr virus transcripts. Nonetheless, PD-L1 IHC was positive in 93% of LELC cases. Our study demonstrates that LELC-B tumors are enriched in a basal-like molecular subtype and share a high level of immune infiltration and PD-L1 expression, similar to basal tumors. The basal-like phenotype is consistent with the known sensitivity of LELC-B to chemotherapy and suggests that immune checkpoint therapy should be explored in this rare disease.

Identification of Felis catus papillomavirus 3 in skin neoplasms from four cats.

Bowenoid in situ carcinomas (BISCs) are papillomavirus (PV)-induced skin neoplasms that are thought to be caused by Felis catus papillomavirus (FcaPV) 2. As BISCs are typically multiple and can become extensive, they can be difficult to treat. Herein we describe 4 cats that developed skin neoplasms that contained FcaPV-3 DNA. One cat developed multiple basal cell carcinomas (BCCs), 1 a BISC with unusual extension into hair follicles, and 2 developed a single typical-appearing BISC. All neoplasms contained prominent PV-induced cell changes and intense p16CDKN2a protein immunostaining. Results from these 4 cats provide evidence that FcaPV-3 could cause a proportion of feline skin cancers, albeit less frequently than FcaPV-2. Excision of the typical BISCs and the BCCs appeared curative. Although the cat with the unusual BISC was euthanized because of the large size of the lesion, evidence from these 4 cats suggests that skin neoplasms that contain FcaPV-3 DNA may have a less aggressive clinical behavior than those associated with FcaPV-2. A consistent feature of the neoplasms in all 4 cats was the presence of prominent basophilic intracytoplasmic inclusion bodies; these inclusions have not been reported in lesions caused by FcaPV-2, to our knowledge, and their detection may allow differentiation between the different PV types and could therefore be a useful prognostic feature.

Association of Multiple Primary Skin Cancers With Human Immunodeficiency Virus Infection, CD4 Count, and Viral Load.

Importance: Persons with human immunodeficiency virus (HIV) have a 2.8-fold higher risk than HIV-uninfected persons of nonmelanoma skin cancer (NMSC), defined as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Individuals with a prior NMSC history are at increased risk for subsequent NMSC, but the magnitude of risk and its relation to HIV disease-related factors, including CD4 count and viral load (VL), are unknown. Objective: To better understand how laboratory markers currently used to evaluate HIV disease progression may be associated with subsequent NMSC risk. Design, Setting, and Participants: This cohort study analyzed 455 HIV-infected and 1945 HIV-uninfected patients, all of them members of the Kaiser Permanente Northern California (KPNC) health care plan, diagnosed with at least 1 NMSC from 1996-2008 to determine risk of subsequent NMSCs in relation to CD4 count and VL. All participants were white, non-Hispanic persons 18 years or older who had had at least 1 NMSC during the 1996-2008 period. Participants entered the cohort at their first NMSC diagnosis and were observed through 2008. Incidence rates were calculated and adjusted hazard ratios were estimated using extended Cox regression models with recent CD4 count and VL analyzed as time-changing covariates. Main Outcomes and Measures: Measured CD4 count, VL, and subsequent NMSC (BCC and SCC). Results: The cohort comprised 455 HIV-infected participants (13 [3%] women) and 1952 HIV-uninfected participants (154 [8%] women). Median duration of observation was 4.6 years, and 16.5% (n = 390) either died (n = 35) or lost KPNC membership status (n = 355) without having a subsequent primary NMSC. Compared with HIV-uninfected persons, HIV-infected individuals were slightly younger (mean age, 52.5 vs 55.5 years), more likely men (97% vs 92%), more likely to have smoked (57% vs 45%), and less likely to be overweight/obese (50% vs 61%). The small observed differences by HIV status in matching characteristics (ie, age and sex) resulted from the restriction of the original cohort to those with at least 1 NMSC. Compared with uninfected individuals, those with HIV infection with a recent biomarker of more severe immune deficiency (CD4 count <200 cells/mL) had a 44% increased risk of subsequent NMSC overall and a 222% increase risk of SCC in particular, suggesting that subsequent SCC risk is associated with immune dysfunction. Conclusions and Relevance: HIV-infected persons compared with HIV-uninfected persons were are at higher risk for subsequent new SCC but not BCC, with a dose-response relationship between risk and lower CD4 counts and higher VLs. Subsequent new primary SCCs had a strong association with lower CD4 and higher VL among HIV-infected persons, suggesting that immune dysfunction might contribute to increased SCC risk. Clinical implications include targeted monitoring for SCC among HIV-infected individuals, particularly those with low CD4 counts or high VLs.

Papillomaviruses in dogs and cats.

Papillomaviruses (PVs) cause disease in both dogs and cats. In dogs, PVs are thought to cause oral papillomatosis, cutaneous papillomas and canine viral pigmented plaques, whereas PVs have been rarely associated with the development of oral and cutaneous squamous cell carcinomas in this species. In cats, PVs are currently thought to cause oral papillomas, feline viral plaques, Bowenoid in situ carcinomas and feline sarcoids. Furthermore, there is increasing evidence that PVs may also be a cause of cutaneous squamous cell carcinomas and basal cell carcinomas in cats. These diseases are discussed in this review. Additionally, there is a brief overview of PV biology, including how these viruses cause disease. Diagnostic techniques and possible methods to prevent PV infection are also discussed.

Viruses in case series of tumors: Consistent presence in different cancers in the same subject.

Studies investigating presence of viruses in cancer often analyze case series of cancers, resulting in detection of many viruses that are not etiologically linked to the tumors where they are found. The incidence of virus-associated cancers is greatly increased in immunocompromised individuals. Non-melanoma skin cancer (NMSC) is also greatly increased and a variety of viruses have been detected in NMSC. As immunosuppressed patients often develop multiple independent NMSCs, we reasoned that viruses consistently present in independent tumors might be more likely to be involved in tumorigenesis. We sequenced 8 different NMSCs from 1 patient in comparison to 8 different NMSCs from 8 different patients. Among the latter, 12 different virus sequences were detected, but none in more than 1 tumor each. In contrast, the patient with multiple NMSCs had human papillomavirus type 15 and type 38 present in 6 out of 8 NMSCs.

Association of Human Papillomavirus Vaccine With the Development of Keratinocyte Carcinomas.

Importance: Keratinocyte carcinomas (KCs), consisting of squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), are the most common human malignant neoplasms. Several risk factors have been implicated in KC development. For some SCCs, particularly those in immunocompromised patients, human papillomavirus (HPV) may be an important factor. Objective: To determine whether quadrivalent HPV vaccination would affect the development of KCs in immunocompetent patients with a history of multiple KCs. Design, Setting, and Participants: Two patients with a history of multiple KCs-a man in his 70s (patient 1) and a woman in her 80s (patient 2)-were treated in a private dermatology practice. Each patient received 3 doses of the quadrivalent HPV vaccine at 0, 2, and 6 months in 2013, and both patients underwent full-body skin examinations at least every 3 months. Biopsy-proven skin cancers were recorded for 16 months (for patient 1) or 13 months (for patient 2) after the first dose of vaccine and then compared with the number of biopsy-proven skin cancers recorded over a similar period before the first dose of vaccine. The period of observation was from October 18, 2011, to June 21, 2014. Main Outcomes and Measures: The numbers of new SCCs and BCCs after the first dose of the quadrivalent HPV vaccine. Results: Patient 1 had a mean of 12 new SCCs and 2.25 new BCCs per year before vaccination. After vaccination, he developed 4.44 SCCs and 0 BCCs per year, a 62.5% reduction in SCCs and a 100% reduction in BCCs. Patient 2 had a mean of 5.5 new SCCs and 0.92 new BCCs per year before vaccination. After vaccination, she developed 1.84 SCCs and 0 BCCs per year, a 66.5% reduction in SCCs and a 100% reduction in BCCs. The quadrivalent HPV vaccine was well tolerated by both patients and had no adverse effects. Conclusions and Relevance: A reduction of SCCs and BCCs was observed in 2 patients after administration of the quadrivalent HPV vaccine. These findings highlight the possibility that cutaneous SCC development, and perhaps BCC development, may be driven in part by HPV in immunocompetent patients. Human papillomavirus vaccination may represent an efficacious, cost-effective, readily available, and well-tolerated strategy for preventing KCs.

[Human papilloma virus infection in basal cell carcinoma of the skin: a systematic review and meta-analysis study].

Human papillomaviruses (HPVs) are a large and ubiquitous group of viruses that some of them have been suggested as a co-factor in the development of non-melanoma skin cancers. The aim of this meta-analysis study was to evaluate HPVs' prevalence in basal cell carcinoma (BCC) of the skin and the risk of them in the BCC patients compared with the healthy controls. Five databases were searched from January 1980 to February 2017. A random-effects meta-analysis was done with the event rate (ER) for the prevalence of HPVs and odds ratio (OR) for estimation of the incidence of HPVs. Out of 1087 studies, 45 studies were included in the review. The pooled analysis demonstrated that the incidence of γ-HPV was effective in the BCC patients compared with the healthy controls [OR = 1.97; 95% CI: 1.52-2.55; p < 0.00001], but not for α-HPV, ß-HPV and epidermodysplasia verruciformis (EV)-HPV (p > 0.05). The pooled ER of incidence of ß1-HPV in the BCC patients was z3.3% and for ß2-HPV in BCC patients was 44.2%. In conclusion, this meta-analysis showed that probably the risk of γ-HPV was more on BCC patients and also the rate of γ-HPV was higher than α-, ß- and EV-HPVs in the BCC patients.

Detection of DNA sequences from a novel papillomavirus in a feline basal cell carcinoma.

BACKGROUND: Basal cell carcinomas (BCCs) are uncommon feline skin neoplasms of uncertain cause. CASE: A 14-year-old Abyssinian cat developed a soft dermal nodule on the dorsal thorax. This mass grew slowly over a six month period before being surgically excised. METHODS AND RESULTS: Histology revealed a BCC. Additionally, changes suggestive of an early Bowenoid in situ carcinoma (BISC) were present in the overlying epidermis. Both the BCC and the BISC contained papillomavirus-induced cell changes and prominent basophilic intracytoplasmic bodies. PCR using consensus primers and primers specific for Felis catus papillomavirus types 2 and 3 (FcaPV-2 and -3) was used to amplify papillomaviral DNA. The same papillomaviral DNA sequence was present in the BCC and the BISC. This sequence was most similar to FcaPV-3, but with just 70.5% similarity, was from a novel papillomavirus type. No recurrence or further masses developed. CONCLUSIONS: This case is unusual due to the presence of a large dermal BCC associated with minimal BISC changes in the overlying epidermis. Additionally, papillomavirus-induced cell changes have not been described previously in a BCC. Furthermore, both the BCC and the BISC contained sequences from a novel papillomavirus type. These observations suggest that the development of some BCCs could be influenced by papillomavirus infection. The novel papillomavirus type detected is the third papillomavirus type to be associated with skin cancer in cats.

Phylogenetic and structural analysis of merkel cell polyomavirus VP1 in Brazilian samples.

Our understanding of the phylogenetic and structural characteristics of the Merkel Cell Polyomavirus (MCPyV) is increasing but still scarce, especially in samples originating from South America. In order to investigate the properties of MCPyV circulating in the continent in more detail, MCPyV Viral Protein 1 (VP1) sequences from five basal cell carcinoma (BCC) and four saliva samples from Brazilian individuals were evaluated from the phylogenetic and structural standpoint, along with all complete MCPyV VP1 sequences available at Genbank database so far. The VP1 phylogenetic analysis confirmed the previously reported pattern of geographic distribution of MCPyV genotypes and the complexity of the South-American clade. The nine Brazilian samples were equally distributed in the South-American (3 saliva samples); North American/European (2 BCC and 1 saliva sample); and in the African clades (3 BCC). The classification of mutations according to the functional regions of VP1 protein revealed a differentiated pattern for South-American sequences, with higher number of mutations on the neutralizing epitope loops and lower on the region of C-terminus, responsible for capsid formation, when compared to other continents. In conclusion, the phylogenetic analysis showed that the distribution of Brazilian VP1 sequences agrees with the ethnic composition of the country, indicating that VP1 can be successfully used for MCPyV phylogenetic studies. Finally, the structural analysis suggests that some mutations could have impact on the protein folding, membrane binding or antibody escape, and therefore they should be further studied.

P16INK4a Immunostaining but Lack of Human Papilloma Virus Type 16 in Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma: a Report from West Iran.

The tumor suppressor p16 is a biomarker for transforming human papilloma virus (HPV) infections that can lead to contradictory results in skin carcinomas. The aim of this study was to evaluate p16 expression and HPV-16 infection in the cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This case-control study was performed on paraffin blocks of BCCs and SCCs and normal skin (53, 36, and 44 cases, respectively), between 2006 to 2015. Initial sections for groups were stained with hematoxylin and eosin (H and E). Immunohistochemistry was performed for p16 expression and human papilloma virus type 16 (HPV-16) infection. Normal group was skin of mammoplasty specimens and normal skin tissue in the periphery of tumors. The mean age at diagnosis was 42.1, 61.7 and 71.4 years for normal, BCC and SCC groups, respectively. P16 positivity was more in SCC and BCC groups compared to normal group (P<0.05) and HPV was negative in all patients in three groups. Also, the mean age at diagnosis and P16-positivity were higher for the SCC group than the BCC group (P<0.005). In conclusion, in non-melanoma skin cancers (SCC and BCC), p16-positivity can be a prognostic factor but there is no correlation between HPV-16 and p16 in these tumors.

[Carcinogenic viruses in etiopathogenesis of skin cancers in patients after organ transplantation]. / Wirusy onkogenne w etiopatogenezie nowotworów skóry u chorych po przeszczepieniach narzadów.

The latest literature report specifies multifactoral etiology of skin cancer in population of patients after organs transplats. Carcirogenic viruses are one of etiopathogenesis components. Viruses of a vital meaning for skin oncogenesis are called Human papillomavirus - HPV, Human herpesvirus 8 - HHV8 i Merkel cell polyomavirus - MCV. Report on connections exisisting between viruses HPV and skin cancers in the population of patients after organs transplants confirms clinical connection between viruses papillas and cancers centres occuring in similar locations and more frequent appearance of attributes characteristic for HPV infection within the limits of changes in the type of Squamous cell carcinoma (SCC). What's more, coexisting of viruses papillas and SCC is more often noticed in the population of organ recipients than in the population of healthy people. It is not confirmed yet that any specific correlation between subtypes of HPV and greater frequency of morbidity in skin cancers really exist. However, in the population of organ recipients infections of different types of HPV are found within the limits of cancers centres in the case of SCC (63%) as well as in basal cell carcinoma-BCC (55%). DNA of HPV was also fund in healthy parts of organ recipients skin (92-94%). HHV8 is also an oncogenic viruse that influences the development of lymphoma. Infection of that virus may cause ocuuring of Kaposi's sarkoma, which is one of the most frequent types of cancer appearing in population of patients treating by long-term immunosuppression in particular geographical zones. MCV, which belongs to the group called Polyomaviriade, owes a particular meaning in etiopathogenesis of Merkel cell carcinoma - MCC. It is a rare cancer derived from neuroendocrine cells of the basic layers of epidermie. For over 30 years it was supposed that correlation between viruses and skin cancers in population of organ recipient exist. Knowledge of the total viruses influence on skin cancers allows to widen the spectrum of anti-cancers prevention in the future.

Epidemiological, Clinicopathological and Virological Features of Merkel Cell Carcinomas in Medical Center of University of Pécs, Hungary (2007-2012).

Merkel cell carcinoma (MCC) is a rare, highly aggressive skin tumour. In 2008, a Merkel cell polyomavirus (MC) was identified in MCCs as a potential etiological factor of MCC. The aims of this retrospective study were to investigate the epidemiological, clinicopathological and virological features of MCCs. Between 2007 and 2012, 11 patients had been diagnosed with MCC by histological methods in University of Pécs, Hungary. In eight MCC cases MC was tested by PCR (in primary skin lesions, lymph nodes/cutan metastases, MCC neighboring carcinomas). Clinicopathological characteristics (age, histological pattern, lymphovascular invasion, co-morbidities) of MC-positive and MC-negative cases were compared. MC was detected in three (37.5%) out of eight patients' primary tumour or metastasis. The average age was 73.8 (64.3 in MC-positive group). Except the youngest, 55 year-old patient (the primary tumour appeared on his leg), all tumours were found at the head and neck region. Immunosuppression (steroid therapy, chronic lymphoid leukaemia, chronic obstructive pulmonary disease) and/or old age were characteristic for all cases. Histological pattern was different in MC-positive and in MC-negative groups: MCCs with MC showed more homogeneous histological pattern, lack of lymphovascular invasion and were associated with better prognosis (mortality rate: 33% versus 80%). MCC associated with oncogenic virus is a newly recognized clinical entity. However, MC could not be detected in all histologically proven MCCs. The well-defined selection of patients/disease groups and better characterization of differences between MC-positive and negative cases is an important step towards the recognition of the etiology and pathogenesis of all MCCs.

Human papillomaviruses and non-melanoma skin cancer.

Human papillomaviruses (HPVs) infect the squamous epithelium and can induce benign and malignant lesions. To date, more than 200 different HPV types have been identified and classified into five genera, α, ß, γ, µ, and ν. While high-risk α mucosal HPVs have a well-established role in cervical carcinoma and a significant percentage of other anogenital tract and oral carcinomas, the biology of the cutaneous ß HPVs and their contribution to non-melanoma skin cancer (NMSC) has been less studied. Although the association of ß HPV infection with NMSC in patients with a rare, genetically determined condition, epidermodysplasia verruciformis has been well established, the role of ß HPV infection with NMSC in the normal population remains controversial. In stark contrast to α HPV-associated cancers, the presence of the ß HPV genome does not appear to be mandatory for the maintenance of the malignant phenotype. Moreover, the mechanism of action of the ß HPV E6 and E7 oncoproteins differs from the ß HPV oncoproteins.

Betapapillomavirus in multiple non-melanoma skin cancers of Netherton syndrome: Case report and published work review.

Netherton syndrome (NS) is a rare genetic disease presenting with ichthyosiform erythroderma, hair alterations and atopy. NS is due to SPINK5 gene mutations, which cause absent or decreased expression of the encoded protein lymphoepithelial Kazal-type-related inhibitor (LEKTI) in all stratified epithelia. We report a 43-year-old man affected with NS, who developed several squamous and basal cell carcinomas on the face, ears and scalp and papillomatous lesions of hips, groin and genitoanal area. Molecular analysis of the SPINK5 gene revealed homozygosity for the recurrent mutation c.238dupG. Human papillomavirus (HPV) DNA detection and genotyping on patient skin carcinomas and hyperplastic lesions found betapapillomavirus DNA in 10 of 12 (83%) carcinomas and in a hip papilloma, with multiple betapapillomavirus types being identified. Immunohistochemistry showed upregulated expression of p16(INK4a) protein in nine of 12 (75%) patient carcinomas, in line with findings reported in HPV-related cancers. LEKTI and filaggrin immunostaining was strongly decreased in patient skin. A published work search for NS cases with skin cancers and HPV infection identified 15 NS patients, five of them showing mucosal or cutaneous HPV infection. Overall, our results confirm the increased susceptibility to skin carcinomas of some NS patients and provide further evidence of an association between HPV and non-melanoma skin cancers in NS. The highly impaired skin barrier function, hallmark of NS, could facilitate HPV infection, in turn increasing the risk for cancer development.

Human papillomavirus and the incidence of nonmelanoma and melanoma skin cancer using cervical conization as a surrogate marker: a nationwide population-based Danish cohort study.

PURPOSE: Human papillomavirus' (HPV's) role in skin cancer is controversial. To examine whether an individual is prone to develop a chronic oncogenic infection, we conducted a nationwide population-based cohort study of the risk of skin cancer after another HPV-related neoplasia-that is, cervical high-grade dysplasia or carcinoma-using cervical conization as a surrogate marker. METHODS: Using Danish registries, we identified all women who underwent conization from 1978 to 2011 (n = 87,164) and followed them until first-time skin cancer diagnosis, death, emigration, or 31 December 2011, whichever came first. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma (MM) according to national incidence rates. RESULTS: The 1-year absolute risks were 0.0012%, 0.045%, and 0.029% for SCC, BCC, and MM, respectively. Conization was clearly associated with increased incidence of SCC (SIR = 1.37; 95% CI: 1.13-1.65), but not MM (SIR = 1.00; 95% CI: 0.91-1.11). BCC risk was slightly increased (SIR = 1.08; 95% CI: 1.02-1.13). CONCLUSIONS: The association between conization and cutaneous SCC provides evidence for conization as a marker of underlying general susceptibility to oncogenic HPV.