Skin microtopography as a measure of photoaging and risk of squamous cell carcinoma of the skin in a US population.

BACKGROUND: Skin microtopography as a measure of photoaging is a noninvasive approach to measuring chronic ultraviolet radiation exposure and reflects the degree of dermal elastosis in populations of European descent in the subtropics. Less is known about the utility of this approach in populations at different latitudes, and whether it relates to skin cancer risk. METHODS: A population-based case-control study of 342 squamous cell carcinoma (SCC) cases and 331 age- and gender-matched controls were evaluated for histologic evidence of solar damage and severity of photoaging based on microtopography on a six-grade scale. Odds ratios (OR) for SCC associated with degree of photoaging were estimated using logistic regression analysis adjusted for potentially confounding factors. RESULTS: After adjustment for known risk factors, SCC was associated with increasing photoaging grade (OR = 1.7, 95% CI = 0.9-3.0 for severe photoaging; OR = 2.8, 95% CI = 1.6-5.0 for very severe photoaging). Associations remained among those with actinic keratosis (OR = 3.4, 95% CI = 0.9-12.4 for severe photoaging, OR = 5.7, 95% CI = 1.7-19.6 for very severe photoaging). LIMITATIONS: There was limited statistical power, particularly for subgroup analyses. CONCLUSION: Our findings provide further evidence of microtopography as an independent, objective indicator of risk of SCC.

Sex hormones and the risk of keratinocyte cancers among women in the United States: A population-based case-control study.

Men are at a higher risk of developing both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) than women, but there is emerging evidence that women may be experiencing greater increases in the incidence rates of these malignancies than men. One possible explanation is the expanding use of sex steroids among women, although only a few studies have examined this hypothesis. As part of a population-based, case-control study of women in New Hampshire, USA, we sought to evaluate the risk of SCC, BCC, and early-onset BCC in relation to exogenous and endogenous sex hormones. We found that oral contraceptive (OC) use was associated with an increased risk of SCC (OR = 1.4, 95% CI = 1.1-1.8) and BCC (OR = 1.4, 95% CI = 1.0-1.8), particularly high estrogen dose (>50 mg) OC use. Hormone replacement therapy (HRT) use also related to SCC, with an elevated OR largely for progestin use (OR = 1.4, 95% CI = 1.1-1.8). Additionally, both OC use and combination HRT use were associated with more aggressive BCC subtypes. In contrast, menstrual and reproductive history did not appear to influence keratinocyte cancer risk in our data. Our findings provide evidence that use of sex steroids may enhance risk of keratinocyte cancer.

The many masks of cutaneous Lyme disease.

Early cutaneous Lyme disease, erythema migrans, may show different histopathologic patterns. The intent of this case series is to raise awareness of these findings to prevent misdiagnosis and keep this entity in the differential. Erythema migrans develops after a tick bite and subsequent infection with the spirochete, Borrelia burgdorferi. It most commonly manifests as a solitary, annular lesion with a bull's-eye appearance. Classic histopathologic findings include superficial and deep perivascular and interstitial lymphocytic infiltrates mixed with plasma cells and eosinophils. We identified and reviewed eight cases of early erythema migrans. Each patient had confirmed B. burgdorferi IgM seropositivity and IgG seronegativity. Histopathologic evaluation of these biopsies reveals a diversity of patterns. Seven of eight cases show sparse to mild perivascular and interstitial mixed infiltrate of variable amount of lymphocytes, eosinophils, neutrophils and plasma cells, with only one case showing a dense inflammatory infiltrate. Epidermal changes such as spongiosis and interface change are seen in some cases. Additionally, perineural lymphocytic infiltrate is seen in one case, periadnexal infiltrate in four cases and pigment incontinence in one case. Based on variable histopathologic findings, it is important to consider erythema migrans in the differential diagnosis for prompt diagnosis and treatment.

Cutaneous alpha, beta and gamma human papillomaviruses in relation to squamous cell carcinoma of the skin: a population-based study.

Human papillomavirus (HPV) infection is common worldwide and, in immunodeficient populations, may contribute to the pathogenesis of keratinocyte cancers, particularly squamous cell carcinomas (SCC). However, their role in SCC in the general population is less clear. We conducted a comprehensive analysis to investigate the independent effects of seropositivity for cutaneous alpha, beta and gamma HPV types on risk of SCC, and a meta-analysis of the available literature. In a population-based case-control study from New Hampshire, USA (n = 1,408), histologically confirmed SCC cases and controls were tested for L1 antibodies to alpha, beta and gamma cutaneous HPV types 2-5, 7-10, 15, 17, 20, 23, 24, 27b, 36, 38, 48-50, 57, 65, 75-77, 88, 92, 95, 96, 101, 103 and 107 using multiplex serology. An increasing risk of SCC with number of beta HPVs to which an individual tested positive was observed even among those seronegative for gamma types (p for trend = 0.016) with an odds ratio of 1.95 (95% confidence interval (CI) = 1.07-3.56) for four or more beta types positive. In a meta-analysis of six case-control studies, increased SCC risks in relation to beta HPV seropositivity were found across studies (meta odds ratio = 1.45, CI = 1.27-1.66). While the prevalence of gamma HPVs assayed was somewhat higher among SCC cases than controls, the association was only weakly evident among those seronegative for beta HPVs. Overall, the association between cutaneous HPVs and skin cancers appears to be specific to SCC and to genus beta HPVs in a general US population.

Combined blue nevus-smooth muscle hamartoma: a series of 12 cases.

BACKGROUND: One of the most common types of combined melanocytic nevus is that of a blue nevus with ordinary melanocytic nevus. Blue nevi have also been described in association with non-melanocytic cell types, such as those of neural or mesenchymal derivation. Although there are rare descriptions in the literature of blue nevi with myomatous structures, the specific association of combined blue nevi with smooth muscle hyperplasia has not been reported METHODS: We review the clinicopathological features of 12 cases of combined blue nevi with smooth muscle hyperplasia. RESULTS: The majority of these lesions occurred on the back of middle-aged patients and were clinically interpreted as melanocytic nevi or melanoma. Histopathologic examination revealed a combined population of 'common' and blue nevus melanocytes with accompanying smooth muscle hyperplasia. In addition to a lentiginous proliferation of melanocytes at the dermal-epidermal junction with variable basilar hyperpigmentation, there were varying degrees of epidermal acanthosis and follicular induction (three cases). CONCLUSION: We present an unusual hamartoma with features of combined blue nevus and smooth muscle hyperplasia, which has not been previously described.

The role of TP53 and MDM2 polymorphisms in TP53 mutagenesis and risk of non-melanoma skin cancer.

P53 is a key regulatory molecule in the cellular response to ultraviolet radiation, and TP53 mutation is the most common alteration in non-melanoma skin cancer. The MDM2 oncogene negatively regulates p53 protein levels, and both genes have functional polymorphisms that may modify skin cancer risk. Furthermore, prior research suggests that TP53 mutations preferentially occur on the arginine allele to selectively inactivate the p63 pathway. We tested these hypotheses of susceptibility and preferential mutation in non-melanoma skin cancer. The TP53 Arg72Pro and MDM2 309 polymorphisms were genotyped in a population-based case-control study of non-melanoma skin cancer, and TP53 alteration (mutation and immunohistochemistry staining) was evaluated in case tumors. In 902 cases of basal cell carcinoma (BCC), 676 cases of squamous cell carcinoma (SCC) and 812 controls, no association was found between the TP53 polymorphism and risk of non-melanoma skin cancer [odds ratio (OR)(BCC) 0.98, 95% confidence interval (CI) 0.80-1.20; OR(SCC) 0.93, 95% CI 0.75-1.16]. However, carriers of the MDM2 SNP309 G allele did have an elevated risk of non-melanoma skin cancer (OR(BCC) 1.15, 95% CI 0.93-1.42; OR(SCC) 1.29, 95% CI 1.02-1.63). We observed an association between TP53 alterations in the tumors and constitutive TP53 genotype (P < 0.01), with alterations preferentially occurring on the proline allele. Collectively, these data highlight the significant effects of genotype on gene-specific mutation events in carcinogenesis.

Analgesic and nonsteroidal anti-inflammatory use in relation to nonmelanoma skin cancer: a population-based case-control study.

BACKGROUND: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are potentially chemopreventive. OBJECTIVE: We examined the relation between NSAID use and nonmelanoma skin cancer in a population-based case-control study. METHODS: NSAID and analgesic use was analyzed in 1484 participants: 535 with squamous cell carcinoma (SCC), 487 with basal cell carcinoma (BCC), and 462 control subjects. RESULTS: Use of NSAIDs, particularly aspirin, was associated with a reduced odds ratio (OR) of SCC, especially tumors positive for p53 (OR 0.29; 95% confidence interval 0.11-0.79) or with PTCH loss of heterozygosity (OR 0.35; 95% confidence interval 0.13-0.96). Although not considered a NSAID, decreased ORs of both basal cell carcinoma and SCC were observed in relation to use of paracetamol (acetaminophen). Risk of BCC was unrelated to NSAID use. LIMITATIONS: Self-reported drug use was a limitation. CONCLUSIONS: This study supports the hypothesis that NSAIDs, aspirin in particular, may reduce risk of SCC and may affect specific molecular subtypes of SCC.

Acute lymphocytic leukemia presenting as an isolated scalp nodule in an infant.

We describe the presentation and management of a patient referred for a presumed benign scalp lesion in infancy. The subcutaneous nodule was ultimately diagnosed as the first manifestation of acute lymphoblastic leukemia. We review leukemia cutis with special emphasis on the differential diagnosis of scalp nodules in infancy that may be encountered by the plastic surgeon.

A role for ultraviolet radiation immunosuppression in non-melanoma skin cancer as evidenced by gene-environment interactions.

The genotoxic effects of ultraviolet (UV) radiation are well-known causes of skin cancers; however, UV radiation also suppresses the immune system, decreasing the body's surveillance for tumor cells. In experimental systems, UV radiation immunosuppression is at least partially mediated through urocanic acid (UCA), an UV radiation-absorbing molecule in the stratum corneum. We tested the hypothesis that genetic variation in the histidase gene (HAL), which catalyzes the formation of UCA in the skin, modifies risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in a population-based study (914 BCC, 702 SCC and 848 controls). We observed no evidence of a main gene effect for the HAL I439V polymorphism (rs7297245) and BCC or SCC. However, we found a HAL genotype-sunburn interaction in association with BCC (P for interaction = 0.040) and SCC (P for interaction = 0.018). A HAL genotype-SCC association was observed primarily among women (odds ratio = 1.5, 95% confidence interval 1.1-2.2), and among women, we found an interaction between HAL genotype and oral contraceptive use on SCC risk (P = 0.040). The variant HAL allele likewise appeared to modify the SCC risk associated with glucocorticoid steroid usage (P for interaction = 0.0004). In conclusion, our findings are a first step in determining the genetic underpinnings of UV immune suppression and have identified important new genetic interactions contributing to the etiology of skin cancer.

An enlarging tender nodule on the finger of a 4-year-old boy: an unusual presentation of infantile myofibromatosis.

Infantile myofibromatosis is a benign neoplasm most commonly seen in the neonatal period through infancy. We report a case of a 4-year-old boy who had a nodule on his left index finger. Biopsy specimen showed features of infantile myofibromatosis (solitary type). Unusual features of this case included location and the concept of an infantile myofibromatosis/infantile hemangiopericytoma continuum.

Tea consumption and basal cell and squamous cell skin cancer: results of a case-control study.

BACKGROUND: Tea constituents, including polyphenols, are hypothesized to have chemopreventive properties, and inhibit the induction of skin cancers in animal models. OBJECTIVE: To explore the association between regular tea consumption (>or=1 cup/d for >or=1 month) and the incidence of squamous cell (SCC) and basal cell (BCC) carcinomas. METHODS: A population-based case-control study of 770 individuals with BCC, 696 with SCC, and 715 age- and sex-matched control subjects. RESULTS: After adjustment for age, sex, and lifetime history of painful sunburns, ever having consumed tea regularly was associated with a significantly lower risk of SCC (odds ratio [OR] = 0.70; 95% confidence interval [CI] 0.53-0.92), especially among long-term drinkers (>or=47 years consumption: SCC, OR = 0.49; 95% CI 0.29-0.83; P for trend = .008) and among those consuming >or=2 cups/d (OR = 0.65; 95% CI 0.44-0.96; P for trend = 0.013). After adjustment for age and sex, ever having consumed tea regularly was weakly associated with BCC risk (OR = 0.79; 95% CI 0.63-0.98). LIMITATIONS: Our case-control study was susceptible to recall bias and to confounding by unknown cancer risk factors associated with tea consumption. CONCLUSIONS: Our findings support the existence of an inverse association between tea consumption and skin carcinogenesis.

Lentigo maligna (melanoma in situ) treated with imiquimod cream 5%: 12 case reports.

Lentigo maligna (LM) is an in situ variant of melanoma. Although LM has the potential for invasion, it often has a greatly protracted radial growth phase and may remain indolent for years. The current standard of care is surgical excision, but this often results in substantial morbidity; thus, nonsurgical approaches continue to be investigated. Imiquimod cream 5% is an immunomodulatory agent that previously has been reported to successfully eradicate LM. We evaluated the treatment course of topical imiquimod in 12 patients with LM. Data from patients with biopsy-proven LM were collected retrospectively, reviewed, and summarized. Patients ranged in age from 54 to 83 years. Most patients chose imiquimod cream as their initial form of treatment; however, other patients had a history of LM recurrence after excision or had positive histologic margins at the time of excision. Initial application regimens varied from 2 to 7 times weekly. The average duration of treatment was 15.7 weeks but ranged from 7 to 44 weeks. Results of posttreatment biopsies of the most clinically suspicious areas in 6 patients showed histologic clearance; 2 patients demonstrated single atypical melanocytes and 4 patients demonstrated clinical clearance without histologic confirmation. These findings suggest that imiquimod cream 5% may be an effective alternative treatment for LM.

Rice Consumption and Squamous Cell Carcinoma of the Skin in a United States Population.

BACKGROUND: Rice contains arsenic, a known skin carcinogen. Rice intake has been associated with arsenic-related skin lesions in South Asia, but its association with skin cancers is as yet unknown. OBJECTIVES: We aimed to investigate whether rice intake contributes to urinary arsenic concentration and risk of squamous cell carcinoma (SCC) of the skin in a U.S. population. METHODS: Rice consumption was assessed using a food frequency questionnaire administered as part of a population-based case-control study of 487 SCC cases and 462 age- and gender-matched controls. Arsenic concentration in household tap water and urine samples were measured using inductively coupled mass spectrometry (ICP-MS) and high-resolution ICP-MS, respectively. Odds ratios (OR) for SCC associated with the frequency of rice consumption were estimated using logistic regression, with adjustment for age, gender, and caloric intake. RESULTS: Those who reported any rice consumption had higher urinary arsenic concentrations than those who did not consume rice, and the association was most pronounced among those with <1µg/L arsenic in their household water (19.2% increase in total urinary arsenic, 95% CI: 5.0, 35.3%). Any rice consumption was associated with a 1.5-fold (95% CI: 1.1, 2.0) higher odds of SCC compared with those who reported no rice consumption, and the relation appeared to be largely among those with <1µg/L water arsenic. CONCLUSION: Rice consumption may be related to the occurrence of SCC in the United States, especially among those with relatively low drinking water arsenic exposure. https://doi.org/10.1289/EHP1065.

Allelic loss at Drosophila patched gene is highly prevalent in Basal and squamous cell carcinomas of the skin.

The human homolog of the Drosophila Patched gene (PTCH), located at chromosome 9q22.3, is frequently altered in both nevoid basal cell carcinoma syndrome, and sporadic basal cell carcinomas (BCCs). However, alteration of the PTCH gene locus has been poorly studied in squamous cell carcinoma (SCC). We analyzed loss of heterozygosity (LOH) at five markers in and around the PTCH gene in 276 keratinocyte tumors from a population-based study in New Hampshire. We found a high prevalence of any 9q22.3 LOH in both BCC (75.5%) and SCC (60.8%), with BCC being significantly more likely to have LOH than SCC (P<0.009). The PTCH gene was specifically lost in 60% of BCC, and 50% of SCC tumors. Among SCC tumors, 9q22 LOH was significantly more likely to occur in those who tend to burn (P<0.05), and this association was strongest for tumors that occurred on sun-exposed areas of the body (P<0.04). Additionally, 9q22 LOH occurred more frequently in SCC tumors associated with a history of severe sunburns (P<0.08). Thus, in our large, population-based sample, 9q22 loss, including PTCH, was highly prevalent in both BCC and SCC. Overall, these data support the hypothesis that PTCH loss is a common, early lesion for SCC and BCC.

Multiple primary melanoma: two-year results from a population-based study.

OBJECTIVE: To assess the frequency of occurrence and risk factors for multiple primary melanoma. DESIGN: Population-based, case-control study. SETTING: New Hampshire. PARTICIPANTS: Three-hundred fifty-four New Hampshire residents with a confirmed first diagnosis of cutaneous melanoma. MAIN OUTCOME MEASURE: Diagnosis of a subsequent primary cutaneous melanoma. RESULTS: An additional melanoma occurred in 27 individuals (8%) within 2 years of their initial diagnosis, including 20 (6%) within the first postdiagnosis year. In 9 (33%) of these 27 cases, at least 1 subsequent melanoma was deeper than the first tumor. The 27 individuals with a subsequent melanoma diagnosis were classified as "cases" and were compared on the basis of risk factors to the 327 "controls" with a single melanoma diagnosis. The data indicate an inverse relation of risk of multiple primary melanomas with multiple blistering sunburns (P = .01 for the trend); the odds ratio (OR) was 0.32 (95% confidence interval [CI], 0.11-0.93) for 2 or more sunburns compared with none. The number of atypical moles was significantly related to increased risk (P = .004 for the trend). The presence of 3 or more atypical moles compared with none was associated with more than a 4-fold risk of multiple primary melanomas (OR, 4.29; 95% CI, 1.51-12.16). CONCLUSIONS: Additional melanomas occur more frequently than previously shown. Our study confirms that atypical moles are strongly associated with risk of multiple primary melanomas but provides little evidence that risk is influenced by pigmentary characteristics, hours of sun exposure, or benign moles. The inverse association with blistering sunburn may reflect the influence of an unmeasured covariate.

Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells.

Natural killer (NK)-cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10-5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors.

Human polyomaviruses and incidence of cutaneous squamous cell carcinoma in the New Hampshire skin cancer study.

Squamous cell carcinoma (SCC) of the skin is a malignancy arising from epithelial keratinocytes. Experimental and epidemiologic evidence raise the possibility that human polyomaviruses (PyV) may be associated with the occurrence of SCC. To investigate whether the risk for SCC was associated with PyV infection, seropositivity to 10 PyV types was assessed following diagnosis in a population-based case-control study conducted in the United States. A total of 253 SCC cases and 460 age group and gender-matched controls were included. Antibody response against each PyV was measured using a multiplex serology-based glutathione S-transferase capture assay of recombinantly expressed VP1 capsid proteins. Odds ratios (OR) for SCC associated with seropositivity to each PyV type were estimated using logistic regression, with adjustment for potentially confounding factors. SCC cases were seropositive for a greater number of PyVs than controls (P = 0.049). Those who were JC seropositive had increased odds of SCC when compared to those who were JC seronegative (OR = 1.37, 95% CI: 0.98-1.90), with an increasing trend in SCC risk with increasing quartiles of seroreactivity (P for trend = 0.04). There were no clear associations between SCC risk and serostatus for other PyV types. This study provides limited evidence that infection with certain PyVs may be related to the occurrence of SCC in the general population of the United States.

Prospective Study of Human Polyomaviruses and Risk of Cutaneous Squamous Cell Carcinoma in the United States.

BACKGROUND: Merkel cell polyomavirus (PyV) is causally related to Merkel cell carcinoma, a rare skin malignancy. Little is known about the serostability of other PyVs over time or associations with cutaneous squamous cell carcinoma (SCC). METHODS: As part of a U.S. nested case-control study, antibody response against the PyV VP1 capsid proteins of BK and John Cunningham virus (JC) was measured using multiplex serology on 113 SCC cases and 229 gender, age, and study center-matched controls who had a prior keratinocyte cancer. Repeated serum samples from controls and both pre and postdiagnosis samples from a subset of SCC cases were also tested. Odds ratios (OR) for SCC associated with seropositivity to each PyV type were estimated using conditional logistic regression. RESULTS: Among controls, BK and JC seroreactivity was stable over time, with intraclass correlation coefficients of 0.86 for BK and 0.94 for JC. Among cases, there was little evidence of seroconversion following SCC diagnosis. JC seropositivity prior to diagnosis was associated with an elevated risk of SCC (OR = 2.54; 95% CI, 1.23-5.25), and SCC risk increased with increasing quartiles of JC (Ptrend = 0.004) and BK (Ptrend = 0.02) seroreactivity. CONCLUSIONS: PyV antibody levels were stable over time and following an SCC diagnosis. A history of PyV infection may be involved in the occurrence of SCC in a population at high risk for this malignancy. IMPACT: A single measure of PyV seroreactivity appears a reliable indicator of long-term antibody status, and PyV exposure may be a risk factor for subsequent SCC. Cancer Epidemiol Biomarkers Prev; 25(5); 736-44. ©2016 AACR.