Natural History of Incident and Persistent Cutaneous Human Papillomavirus and Human Polyomavirus Infections.

BACKGROUND: Cutaneous human papillomaviruses (cuHPV) and polyomaviruses (HPyV) have been implicated in skin cancers; however, interpretation of findings across studies is complicated by limited understanding of the natural history of these infections across normal tissue types. METHODS: In total, 675 eyebrow hair (EBH) and skin swab (SSW) samples were collected from 71 skin cancer screening patients every 6 months over 2 years and measured for presence of ß-HPV, γ-HPV, and HPyV. Incidence, persistence, and clearance of cuHPV/HPyV were estimated, and risk factors associated with infection were examined. RESULTS: Prevalence, incidence, and persistence of ß-HPV, γ-HPV, and HPyV were consistently higher in SSW than in EBH, with types 5, 24, 49, 76 and Merkel cell polyomavirus (MCPyV) having incidence rates greater than 20 per 1000 person-months. Prevalent γ-HPV EBH infections persisted more often in women (P = .024), incident ß-HPV EBH infections persisted less often among individuals with history of blistering sunburn (P = .019), and prevalent MCPyV SSW infections persisted more often in those with a history of skin cancer (P = .033). CONCLUSIONS: Incidence and persistence of cuHPV/HPyV were observed in SSW and EBH; however, none of the risk factors examined were commonly associated with cuHPV/HPyV infections across normal tissue types.

Cutaneous viral infections associated with ultraviolet radiation exposure.

The complex interplay between ultraviolet radiation (UVR) and cutaneous viral infections in the context of cancer etiology is challenging to unravel, given the limited information on the independent association between UVR and cutaneous viral infections. Using multiple biomarkers of infection with 24 types of cutaneous human papillomavirus (HPV) and 4 types of polyomaviruses (HPyV), we investigated cross-sectional associations with recent UVR exposure, using skin pigmentation measured by spectrophotometer. Age- and sex-adjusted associations between UVR and viral seropositivity, viral DNA present in eyebrow hairs (EBH) and skin swabs (SSW) were estimated using logistic regression. Beta-HPV seropositivity was associated with viral DNA positivity in EBH (OR = 1.40, 95% CI = 1.05-1.88) and SSW (OR = 1.86, 95% CI = 1.25-2.74). Similar associations were observed for Merkel cell polyomavirus. Participants in the highest tertile of UVR exposure were more likely to be seropositive for beta-HPV (OR = 1.81, 95% CI = 1.16-2.38), and have beta-HPV DNA in EBH (OR = 1.57, 95% CI = 1.06-2.33) and SSW (OR = 2.22, 95% CI = 1.25-3.96), compared to participants with the lowest tertile of UVR exposure. UVR exposure was positively associated with three different markers of beta-HPV infection. Therefore, future studies of HPV associated KC development should address more directly the role of HPV and UVR exposure as potential co-carcinogens.

Cutaneous Viral Infections Across 2 Anatomic Sites Among a Cohort of Patients Undergoing Skin Cancer Screening.

BACKGROUND: Findings from previous studies of cutaneous human papillomavirus (cuHPV) infection and keratinocyte carcinomas have varied due to several factors, including use of different sample types for cuHPV DNA detection. Elucidating the relationship between cuHPV infection in eyebrow hairs (EBHs) and skin swabs (SSWs) is critical for advancing the design of future studies. METHODS: DNA corresponding to 46 ß-HPV and 52 γ-HPV types was measured in EBHs and SSWs obtained from 370 individuals undergoing routine skin cancer screening examinations. RESULTS: Prevalence of ß-HPV/γ-HPV was 92%/84% and 73%/43% in SSWs and EBHs, respectively, with 71%/39% of patients testing positive for ß-HPV/γ-HPV in both sample types. Number of cuHPV types detected and degree of infection were correlated across SSWs and EBHs. When the EBH was positive for a given ß-HPV/γ-HPV type, the SSW was positive for that same type 81%/72% of the time. CONCLUSIONS: Testing SSWs captures more cuHPV infection than EBHs, with EBH infections usually representing a subset of SSW infections. The importance of optimizing sensitivity of cuHPV infection detection using SSWs vs specificity using EBHs (or a combination of the 2) will be ascertained in an ongoing cohort study investigating cuHPV associations with subsequent keratinocyte carcinomas.

Case-control study of genus-beta human papillomaviruses in plucked eyebrow hairs and cutaneous squamous cell carcinoma.

Cutaneous human papillomaviruses (HPV) have been reported in cutaneous squamous cell carcinoma (SCC). We conducted a clinic-based case-control study to investigate the association between genus-beta HPV DNA in eyebrow hairs (EBH) and SCC. EBH from 168 SCC cases and 290 controls were genotyped for genus-beta HPV DNA. SCC tumors from a subset of cases (n = 142) were also genotyped. Viral load was determined in a subset of specimens positive for a single HPV type. Associations with SCC were estimated by odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and sex using logistic regression. Statistical tests were two-sided. EBH DNA prevalence was greater in cases (87%) than controls (73%) (p < 0.05), and the association with SCC increased with the number of HPV types present, (≥ 4 types vs. HPV-negative: OR = 2.02, 95% CI = 1.07-3.80; p(trend) = 0.02). Type-specific associations were observed between SCC and DNA in EBH for HPV23 (OR = 1.90, 95% CI = 1.10-3.30) and HPV38 (OR = 1.84, 95% CI = 1.04-3.24). Additionally, when compared with the controls, the DNA prevalence in EBH was significantly higher among cases for 11 of the 25 genus-beta types tested, when accounting for DNA for the same HPV type in the tumor (ORs = 3.44-76.50). Compared to controls, the mean viral DNA load in EBH among the selected cases was greater for HPV5, HPV8 and HPV24, but lower for HPV38. SCC cases were more likely than controls to have HPV DNA+ EBH for single and multiple HPV types, providing additional support for the potential role of genus-beta HPV infections in SCC development.

Sunlight exposure and cutaneous human papillomavirus seroreactivity in basal cell and squamous cell carcinomas of the skin.

BACKGROUND: Ultraviolet radiation exposure may interact synergistically with cutaneous human papillomavirus (HPV) infection in the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin. METHODS: To investigate differences in the risk of sunlight-associated BCC and SCC by cutaneous genus-specific HPV serostatus, a case-control study was conducted among 204 BCC and 156 SCC cases who were recruited from a university dermatology clinic and 297 controls who had no history of cancer and screened negative for current skin cancer. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between measures of sunlight exposure and BCC/SCC, stratified by genus-specific HPV serostatus, with adjustment for age and sex. RESULTS: Sunburn due to cutaneous sensitivity to sunlight exposure (P = .006) and poor tanning ability (P = .003) were associated with a higher seroprevalence for genus beta HPV types. Poor or no tanning ability was more strongly associated with SCC among individuals who were seropositive for antibodies to cutaneous HPV types in genera alpha (OR, 15.60; 95% CI, 5.40-45.1; P = .01 for interaction) and beta (OR, 6.86; 95% CI, 3.68-12.80; P = .001 for interaction), compared with individuals who were seronegative for these HPV types. CONCLUSIONS: Seropositivity for HPV types in genera alpha or beta increased the risk of SCC associated with poor tanning ability.

Case-control study of smoking and non-melanoma skin cancer.

OBJECTIVE: To investigate the association between cigarette smoking and basal and squamous cell carcinomas (BCC and SCC) of the skin, a clinic-based case-control study was conducted in Tampa, FL. METHODS: Patients with histologically confirmed BCC/SCC were recruited from a university dermatology clinic (n = 215 BCC, 165 SCC). Controls were comprised of individuals with no history of skin cancer who screened negative for skin cancer upon physical examination at the affiliated cancer screening or primary care clinics (n = 315). Information on smoking and other risk factors was obtained from self-administered questionnaires. RESULTS: After adjustment for age, sex, and other skin cancer-risk factors, ever smoking was not associated with BCC (odds ratio (OR) = 1.26, 95% confidence interval (CI) = 0.83-1.92), but was statistically significantly associated with SCC (OR = 1.97, 95% CI = 1.19-3.26), with significant trends observed for SCC associated with increasing cigarettes per day (p = 0.01) and pack-years smoked (p = 0.01). Among men, smoking ≥20 pack-years was associated with non-significant increased risks of BCC (OR = 1.90, 95% CI = 0.88-4.12) and SCC (OR = 1.97, 95% CI = 0.84-4.66), whereas among women, no association was observed with BCC (OR = 0.98, 95% CI = 0.39-2.46) while a statistically significant three-fold risk was observed with SCC (OR = 3.00, 95% CI = 1.02-8.80). CONCLUSION: Cigarette smoking is more strongly associated with SCC than BCC, particularly among women.

Patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skin--a case-control study.

BACKGROUND: Non-melanoma skin cancer (NMSC), comprised of basal (BCC) and squamous (SCC) cell carcinomas, is the most common cancer in Caucasians. Ultraviolet radiation (UVR) exposure is the most important environmental risk factor for NMSC. However, the precise relationship between UVR and the risk of NMSC is complex, and the relationship may differ by skin cancer type. METHODS: A case-control study was conducted among Florida residents to investigate measures of patterns (intermittent vs. continuous) and timing (childhood vs. adulthood) of sunlight exposure in BCC and SCC. Participants included 218 BCC and 169 SCC cases recruited from a university dermatology clinic and 316 controls with no history of skin or other cancers. RESULTS: A history of blistering sunburn (a measure of intermittent sunlight exposure) was associated with both BCC (OR = 1.96, 95% CI = 1.27-3.03) and SCC (OR = 2.02, 95% CI = 1.22-3.33). Additionally, having a job in the sun for ≥ 3 months for 10 years or longer (a measure of continuous sunlight exposure) was also associated with both BCC and SCC in our study population. With the exception of younger age at first blistering sunburn, measures of younger age at sunlight exposure tended to be associated with SCC, but not BCC risk. CONCLUSIONS: Results from the current study suggest that sunlight exposure is associated with both BCC and SCC risk regardless of the pattern in which the exposure was received (i.e. intermittent vs. continuous). The data also suggest that sunlight exposure at a younger age may be more important for SCC but not BCC, however additional studies are needed to further characterize sunlight exposure-response relationships in different types of NMSC.

Circulating Immunosuppressive Regulatory T Cells Predict Risk of Incident Cutaneous Squamous Cell Carcinoma.

Ultraviolet radiation exposure (UVR) is a risk factor for cutaneous squamous cell carcinoma (cuSCC) and has been shown to be positively associated with circulating immunosuppressive regulatory T cells ("Tregs"). However, the risk of cuSCC in association with circulating Tregs has not been studied. The aim of this study was to determine whether circulating Treg levels are associated with cuSCC development, particularly in the context of high UVR. Blood and spectrophotometer-based UVR measurements were obtained on 327 immunocompetent individuals undergoing routine skin cancer screenings at baseline and followed for up to 4 years for incident cuSCC development within a prospective cohort study. Proportions of phenotypically distinct Tregs, especially CCR4hi and CLA+ cells which are associated with activation and homing, respectively, were measured by flow cytometry. Tregs in cuSCC tumors were assessed using immunohistochemistry and graded for solar elastosis, a measure of cumulative UVR damage. Of several Treg phenotypes examined, higher levels of circulating CCR4hi Tregs at baseline were significantly associated with increased risk of subsequent cuSCC; those with higher levels of both CCR4hi and UVR were four times more likely to develop cuSCC compared to those with lower levels of both (Hazard Ratio = 4.11, 95% CI = 1.22-13.90). Within cuSCC tumors, CCR4hi Tregs were positively associated with solar elastosis. Results show that a higher proportion of CCR4hi peripheral Tregs predicts incident cuSCC up to 4 years, especially among highly UV-exposed individuals. Research of the underpinning biology of Tregs in UVR-associated skin damage may possibly reveal novel opportunities for screening, prevention, and treatment.

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.

Viruses in Skin Cancer (VIRUSCAN): Study Design and Baseline Characteristics of a Prospective Clinic-Based Cohort Study.

BACKGROUND: Accumulating evidence suggests that cutaneous viral infections are risk factors for the development of keratinocyte carcinomas. The Viruses in Skin Cancer (VIRUSCAN) Study, a prospective cohort study, was established in 2014 to investigate the risk of keratinocyte carcinoma associated with cutaneous human papillomavirus and polyomavirus infection and the possible interaction with ultraviolet radiation exposure (UVR). METHODS/RESULTS: VIRUSCAN incorporates repeated measures of viral infection using multiple markers of infection and quantitative measures of UVR using a spectrophotometer. Participants were recruited between July 14, 2014 and August 31, 2017 at the University of South Florida Dermatology Clinic in Tampa, FL. After excluding 124 individuals with prevalent keratinocyte carcinomas at baseline, 1,179 participants (53.2% women, 46.8% men, all ages 60 years and older) were followed for up to 4 years with routine skin exams occurring every 6 to 12 months. Here, we present the VIRUSCAN Study design, methods, and baseline characteristics, including demographics, sun exposure behavior, quantitative UVR exposure measurements, and cutaneous viral prevalence, for the full study cohort. CONCLUSIONS: The VIRUSCAN Study will provide critical temporal evidence needed to assess the causality of the role cutaneous viral infections play in the development of keratinocyte carcinomas, as well as the potential interaction between cutaneous viral infections and UVR exposure. IMPACT: Study findings will be valuable in future development of novel keratinocyte carcinoma prevention strategies.

Immunohistochemical stains in Mohs surgery: a review.

BACKGROUND: During Mohs surgery, there are instances in which residual tumor cells may be difficult to detect, thereby increasing the risk of incomplete excision and tumor recurrence. It is possible to employ immunohistochemical techniques as an adjunct to routine hematoxylin and eosin staining to aid in ensuring negative margins. OBJECTIVE: To review the literature regarding the use of immunostains in Mohs surgery. RESULTS: Various immunostains have proved useful in detecting tumor cells in various malignancies, including melanoma, basal cell carcinoma, squamous cell carcinoma, dermatofibrosarcoma protuberans, extramammary Paget's disease, primary cutaneous mucinous carcinoma, granular cell tumor, and trichilemmal carcinoma. CONCLUSIONS: In this article, we review immunohistochemical stains that have been employed in Mohs micrographic surgery and evaluate their utility in enhancing detection of residual tumors with respect to tumor type, particularly in situations in which detection of residual tumor may be difficult.

Innovative 19-minute rapid cytokeratin immunostaining of nonmelanoma skin cancer in Mohs micrographic surgery.

BACKGROUND: Dense inflammation can obscure nonmelanoma skin cancer (NMSC) on frozen sections, prompting removal of additional layers to ensure negative margins. Cytokeratin (CK) immunostaining in Mohs micrographic surgery (MMS) has been examined and found to be useful but is limited by lengthy 1-hour processing. OBJECTIVE: Our objective was to develop an effective ultrarapid CK frozen section immunostain to be used during MMS in cases of NMSC with dense or perineural inflammation. METHODS: An ultrarapid immunostain with a mixture of AE1/AE3 monoclonal antibodies was performed in 21 MMS cases and compared with permanent sections prepared from the same material. RESULTS: The ultrarapid CK protocol stained all of the cells in each of the 21 examples of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in frozen tissue in a way equivalent to immunostains being applied to permanent sections. CONCLUSION: The 19-minute CK immunohistochemistry protocol in frozen tissue appears to be as effective at labeling tumor cells of SCC and BCC as methods requiring permanent sections. It is hopeful that this technique may prevent recurrences after MMS and limit the number of Mohs layers required to obtain free margins when inflammation is abundant. It also is effective in uncovering subtle perineural invasion.

Topical corticosteroids in dermatology.

Topical corticosteroids are the most commonly prescribed agents in the treatment of dermatologic conditions. They are used primarily as monotherapy or in combination with other agents for enhanced efficacy. Several stronger preparations are now available since their first introduction. They are also available in various vehicles altering the potency and giving the option of tailoring them for use based on specific anatomic locations, area of involvement, age of the patient, and most importantly, severity of the condition. Several local and systemic side effects have been associated with their inadvertent use. Allergic contact dermatitis to most of the preparations has also been noticed. Judicious use with reinforced patient education lowers such risk for side effects, and can be of great use in treating dermatologic conditions.

Primary mucosal melanoma.

Primary mucosal melanomas are rare, biologically aggressive neoplasms. The distribution of head and neck, female genital tract, anal/rectal, and urinary tract sites is 55.4%, 18.0%, 23.8%, and 2.8%, respectively. The median age at presentation is the seventh decade, and women are given the diagnosis more frequently than men. Unfortunately, most afflicted individuals harbor micrometastatic disease and experience a course characterized by multiple local recurrences before the clinical development of distant disease. Approximately a third of patients have nodal involvement at presentation, and the overall 5-year survival is only 25%. Despite aggressive surgical resection and a multitude of adjuvant treatments, the prognosis remains grave. Early detection, which is difficult because of the occult anatomic locations in which these tumors occur, allows the best hope for cure.

Treatment of locally metastatic melanoma: a novel approach.

We report a case of an 83-year-old female with locally metastatic melanoma treated with imiquimod and tazarotene. The patient originally presented to our dermatology clinic with local metastases of malignant melanoma after having undergone multiple surgical procedures and adjuvant radiation therapy for disease recurrence. At this juncture, she refused further surgical management but was interested in topical therapy. A 4-week course of topical imiquimod therapy was initiated. As no clinical response was noted at the end of the treatment period, tazarotene cream was introduced. The patient experienced complete clinical clearance of the treated area after a 6-week course of combination imiquimod and tazarotene therapy. The rationale for using both medications will be discussed.

Aquagenic syringeal acrokeratoderma: report of a case with histologic findings.

Aquagenic syringeal acrokeratoderma is a rare acquired condition characterized by painful symmetric swelling and hypopigmentation of the palms and lateral fingers, which develops after brief exposure to water. Histopathologic examination suggests that an aberration in the eccrine sweat gland apparatus may be the underlying cause of this condition. The "hand-in-the-bucket sign," in which patients arrive in their physician's office with their hand in a bucket of water to more readily demonstrate their lesions, is such a common presentation that it almost can be regarded as pathognomonic. All 12 cases reported to date have been in young females. We report a case of aquagenic syringeal acrokeratoderma in a male with unique histologic findings.

IgG4-related skin disease may have distinct systemic manifestations: a systematic review.

IgG4-related disease (IgG4-RD) is an increasingly prevalent protean multisystem disorder characterized by single or multi-organ infiltration of IgG4-bearing plasma cells. Skin involvement has been recognized and is relevant to proper diagnosis. A systematic literature review of 50 cases involving the skin reveals that patients with IgG4-related skin disease show predominant involvement of the head and neck and have a distinct pattern of systemic involvement, also favoring the head and neck - lymphatics, orbit, salivary, and lacrimal glands - but generally lacking pancreaticobiliary involvement (16% of cases), which by contrast is a predominant manifestation in systemic IgG4-RD (60% with pancreaticobiliary involvement). We summarize clinical and pathologic descriptive data from this systematic review. We review differential diagnosis and propose a diagnostic scheme for stratifying probability of disease based upon comprehensive integration of clinical, histopathologic, and laboratory data. Plasmacyte infiltration and storiform fibrosis are prominent in IgG4-related skin disease, but obliterative venulitis is less common than in the prototypical IgG4-related disease manifestation of autoimmune pancreatitis. IgG4 tissue and serum values, with a mean (±95% CI) in the reviewed cases of 132.8 ± 32.6 IgG4-positive plasma cells per high-power field and 580 ± 183.8 mg/dl, respectively, are incorporated into the suggested criteria. The distinct set of manifestations identified by this systematic review and the proposed diagnostic considerations, while requiring further validation in prospective studies, highlight the need to consider that IgG4-related skin disease defines a unique systemic disease complex along the spectrum of IgG4-RD.

Optimum treatment strategies for actinic keratosis (intraepidermal squamous cell carcinoma).

Actinic keratoses are superficial squamous cell carcinomas. Treatment of these lesions is indicated to prevent the cells from invading the dermis and possibly metastasizing. If a lesion exhibits evidence of possible dermal invasion, such as marked erythema, ulceration, tenderness, bleeding, and especially induration, the physician should always consider performing a biopsy. Cryosurgical destruction, the most common treatment employed, has been shown to be 98.8% effective in eliminating the lesions. Adverse reactions such as scarring, textural changes, infection, and pigmentation alteration rarely occur. Physical destruction using electrodesiccation and curettage is particularly effective when the patient has hyperkeratotic lesions. When a patient has a multitude of actinic keratoses, the use of other treatments including fluorouracil, nonsteroidal anti-inflammatory preparations, immune response modifiers, and photodynamic therapy should be considered. However, none of these treatments has proven to be as effective overall as cryosurgical destruction. If a lesion does not respond to treatment, obtaining a biopsy of the lesion should be considered to be certain that the lesion is not an invasive squamous cell carcinoma.