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.

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.

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.

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.

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.

Frequency of squamous cell carcinoma (SCC) invasion in transected SCC in situ referred for Mohs surgery: the Dartmouth-Hitchcock experience.

BACKGROUND: Squamous cell carcinoma (SCC) in situ may be transected in a superficial biopsy, which makes it difficult to distinguish between in situ and invasive carcinoma. This study investigated the frequency of invasive SCC in transected SCC in situ referred for Mohs surgery. METHODS: A retrospective chart review was performed to identify subjects with biopsy-proven, transected SCC in situ referred for Mohs surgery. The incidence of invasion, histologic variables, preoperative and intraoperative correlations, and clinical factors were determined and recorded. RESULTS: Of 51 cases identified, five (9.8%) were found to harbor invasive SCC, 15 (29.4%) showed SCC in situ, and 28 (54.9%) showed evidence of scarring, inflammation, or actinic keratosis at the prior biopsy site. Invasive lesions required significantly more stages of Mohs surgery to obtain tumor clearance but were similar with regard to patient age, symptoms, and family and personal histories of skin cancer. Preoperative lesion size and duration were greater in invasive cases, but these differences did not reach statistical significance. CONCLUSIONS: A small number of transected SCCs in situ, to which the caveat "invasion cannot be ruled out" can be applied, have an invasive component that is identified during Mohs surgery. Definitive treatment choices should depend on the physician's impression, the clinical characteristics of the lesion, tumor location, patient comorbidities, and patient desires.

History of allergy and atopic dermatitis in relation to squamous cell and Basal cell carcinoma of the skin.

BACKGROUND: Little is known about whether history of allergies and atopy is related to the occurrence of keratinocyte cancers. Thus, we evaluated the association between history of allergies and atopy and the incidence of squamous cell carcinoma (SCC) and early onset basal cell carcinoma (BCC). METHODS: As part of a population-based case-control study, interviews were conducted with 1,050 residents of New Hampshire (375 early onset BCC cases and 251 controls, 254 SCC cases and 432 controls). ORs of SCC and early onset BCC and history of allergy and atopic dermatitis were computed using logistic regression, while controlling for potential confounding factors. RESULTS: An overall inverse association was observed between a history of allergy and early onset BCC [OR, 0.61; 95% confidence interval (CI), 0.38-0.97] but not SCC (OR, 1.18; 95% CI, 0.78-1.79). Among women, we found reduced ORs of both early onset BCC and of SCC in relation to allergy history (early onset BCC OR, 0.53; 95% CI, 0.31-0.92 and SCC OR, 0.59; 95% CI, 0.29-1.19). Among men, we observed no clear association with early onset BCC (OR, 0.87; 95% CI, 0.39-1.99) and an increased risk of SCC (OR, 1.58; 95% CI, 0.93-2.69). CONCLUSION: Our findings suggest that allergies and atopy may influence risk of early onset BCC and SCC, and that effects may be gender specific. IMPACT: A deeper understanding of the immune mechanisms underlying allergies and atopy may provide new routes of preventing keratinocyte cancers.

Early-onset basal cell carcinoma and indoor tanning: a population-based study.

OBJECTIVE: Indoor tanning with UV radiation-emitting lamps is common among adolescents and young adults. Rising incidence rates of basal cell carcinoma (BCC) have been reported for the United States and elsewhere, particularly among those diagnosed at younger ages. Recent epidemiologic studies have raised concerns that indoor tanning may be contributing to early occurrence of BCC, and younger people may be especially vulnerable to cancer risk associated with this exposure. Therefore, we sought to address these issues in a population-based case-control study from New Hampshire. METHODS: Data on indoor tanning were obtained on 657 cases of BCC and 452 controls ≤50 years of age. RESULTS: Early-onset BCC was related to indoor tanning, with an adjusted odds ratio (OR) of 1.6 (95% confidence interval, 1.3-2.1). The strongest association was observed for first exposure as an adolescent or young adult, with a 10% increase in the OR with each age younger at first exposure (OR per year of age ≤23 = 1.1; 95% confidence interval, 1.0-1.2). Associations were present for each type of device examined (ie, sunlamps, tanning beds, and tanning booths). CONCLUSIONS: Our findings suggest early exposure to indoor tanning increases the risk of early development of BCC. They also underscore the importance of counseling adolescents and young adults about the risks of indoor tanning and for discouraging parents from consenting minors to this practice.

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.

A population-based case-control study of urinary arsenic species and squamous cell carcinoma in New Hampshire, USA.

BACKGROUND: Chronic high arsenic exposure is associated with squamous cell carcinoma (SCC) of the skin, and inorganic arsenic (iAs) metabolites may play an important role in this association. However, little is known about the carcinogenicity of arsenic at levels commonly observed in the United States. OBJECTIVE: We estimated associations between total urinary arsenic and arsenic species and SCC in a U.S. population. METHODS: We conducted a population-based case-control SCC study (470 cases, 447 controls) in a U.S. region with moderate arsenic exposure through private well water and diet. We measured urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), and summed these arsenic species (ΣAs). Because seafood contains arsenolipids and arsenosugars that metabolize into DMA through alternate pathways, participants who reported seafood consumption within 2 days before urine collection were excluded from the analyses. RESULTS: In adjusted logistic regression analyses (323 cases, 319 controls), the SCC odds ratio (OR) was 1.37 for each ln-transformed microgram per liter increase in ln-transformed ΣAs concentration [ln(ΣAs)] (95% CI: 1.04, 1.80). Urinary ln(MMA) and ln(DMA) also were positively associated with SCC (OR = 1.34; 95% CI: 1.04, 1.71 and OR = 1.34; 95% CI: 1.03, 1.74, respectively). A similar trend was observed for ln(iAs) (OR = 1.20; 95% CI: 0.97, 1.49). Percent iAs, MMA, and DMA were not associated with SCC. CONCLUSIONS: These results suggest that arsenic exposure at levels common in the United States relates to SCC and that arsenic metabolism ability does not modify the association.

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.

Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case-control study.

It is well-known that UV light exposure and a sun-sensitive phenotype are risk factors for the development of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). In this New Hampshire population-based case-control study, we collected data from 5,072 individuals, including histologically confirmed cases of BCC and SCC, and controls via a personal interview to investigate possible associations between photosensitizing medication use and NMSC. After adjustment for potentially confounding factors (e.g., lifetime number of painful sunburns), we found a modest increase in risk of SCC (odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4) and BCC (OR=1.2, 95% CI=0.9-1.5), in particular early-onset BCC, (≤ 50 years of age) (OR=1.5, 95% CI=1.1-2.1) associated with photosensitizing medication use. For SCC the association was strongest among those with tendency to sunburn rather than tan. We also specifically found associations with BCC, and especially early-onset BCC, and photosensitizing antimicrobials. In conclusion, certain commonly prescribed photosensitizing medications may enhance the risk of developing SCC, especially in individuals with a sun-sensitive phenotype, and may increase the risk of developing BCC and incidence of BCC at a younger age.

Genetic determinants of UV-susceptibility in non-melanoma skin cancer.

A milieu of cytokines and signaling molecules are involved in the induction of UV-induced immune suppression and thus the etiology of non-melanoma skin cancer (NMSC). Targeting the UV-induced immunosuppression pathway, and using a large population based study of NMSC, we have investigated the risk associated with functional variants in 10 genes (IL10, IL4, IL4R, TNF, TNFR2, HTR2A, HRH2, IL12B, PTGS2, and HAL). The most prominent single genetic effect was observed for IL10. There was increasing risk for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with increasing number of variant IL10 haplotypes (BCC: p(trend) = 0.0048; SCC: p(trend) = 0.031). Having two IL10 GC haplotypes was associated with increased odds ratios of BCC and SCC (OR(BCC) = 1.5, 95% CI 1.1-1.9; OR(SCC) = 1.4, 95% CI 1.0-1.9), and these associations were largely confined to women (OR(BCC) = 2.2, 95% CI 1.4-3.4; SCC: OR(SCC) = 1.8, 95% CI 1.1-3.0). To examine how combinations of these variants contribute to risk of BCC and SCC, we used multifactor dimensionality reduction (MDR) and classification and regression trees (CART). Results from both of these methods found that in men, a combination of skin type, burns, IL10, IL4R, and possibly TNFR2 were important in both BCC and SCC. In women, skin type, burns, and IL10 were the most critical risk factors in SCC, with risk of BCC involving these same factors plus genetic variants in HTR2A, IL12B and IL4R. These data suggest differential genetic susceptibility to UV-induced immune suppression and skin cancer risk by gender.

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.