Tobacco smoking is associated with cutaneous squamous cell carcinoma but not with basal cell carcinoma or melanoma in adult subjects at risk of skin cancer: A cross-sectional study.

INTRODUCTION: The relationship between tobacco smoking and cutaneous photodamage or malignancies is still unclear. In addition to smoking, both ultraviolet radiation and immunosuppression have an impact on carcinogenesis. The purpose was to study the association of smoking with cutaneous photoaging, actinic keratosis (AK), skin cancers, and pigment cell nevi in adult subjects at risk of any type of skin cancer. METHODS: In this cross-sectional study at Kuopio University Hospital, Finland, between May 2017 and October 2020, 488 subjects (aged 21-79 years, 246 males and 242 females, 94 with immunosuppression) were examined for a variety of skin lesions, photoaging severity, nevi, tobacco pack-years (TPY), as well as for possible confounding factors. RESULTS: In logistic regression analyses, no marked association was found between TPY and total skin photoaging, facial photoaging, AK, or nevi, especially when other confounding factors, such as age, were considered. In addition, TPY was not associated with melanoma, basal cell carcinoma, or any type of skin cancer. However, ever smokers produced an elevated crude odds ratio (OR=1.99; 95% CI: 1.02-3.88, p=0.043) for squamous cell carcinoma (SCC) compared to non-smokers. In further analysis, TPY of ≤10 produced an elevated multivariable adjusted odds ratio (AOR=4.90; 95% CI: 1.31-18.26, p=0.018) for SCC, but TPY >10 did not (AOR=1.14; 95% CI: 0.22-6.05, p=0.876). CONCLUSIONS: Smoking was associated, though not dose-dependently, with an increased likelihood of SCC, but it was not associated with basal cell carcinoma or melanoma. However, the impact of smoking on cutaneous photoaging severity, AK, and nevi, appears to be weak.

Spectrum of malignant and premalignant skin lesions in 505 adult subjects at risk of skin cancers.

Patients at risk of skin cancers can develop varying types of cutaneous malignancies. However, some subjects may develop only one type of lesion. In this cross-sectional study, the spectrum of premalignant (PM) and malignant skin lesions and their risk factors were studied. Therefore, 505 adult subjects (aged 21-79 years, 256 males and 249 females, 96 with immunosuppression) at risk of any type of skin cancer were examined for cutaneous malignancies, nevi, actinic keratoses, photodamage, and possible risk factors. First, 12 different groups were identified with a varying set of PM and/or malignant skin lesions. Next, 5 larger groups were formed from them: basal cell carcinoma (BCC) only, malignant melanoma (MM) only, squamous cell carcinoma (SCC) and/or PM, BCC + SCC and/or PM, and MM + keratinocyte carcinoma (KC) and/or PM. The groups with BCC or MM only were younger and showed less photodamage than the mixed groups, while SCC/PM showed similarity with them. In logistic regression analyses, the platelet-to-lymphocyte ratio was associated with an increased risk of concomitant KC (OR 1.028, p = 0.023) or SCC/PM (OR 1.009, p = 0.047) in subjects with MM or BCC, respectively. Actinic keratoses produced ORs 0.246-0.252 (p = 0.008-0.020) for BCC in subjects with SCC/PM. Interestingly, atypical mole syndrome decreased the risk of SCC/PM in subjects with BCC (OR 0.092, p = 0.001). Advanced age was a significant risk factor for an additional type of lesion in all 3 comparisons (ORs 1.088-1.388, p = 0.001). In conclusion, even though there are numerous patients with only one lesion type, advancing age may determine the final lesion multiplicity.

Expression of mast cell tryptase and immunoglobulin E is increased in cutaneous photodamage: implications for carcinogenesis.

Purpose: Mast cells, their serine proteinase tryptase, and immunoglobulin E (IgE) can be involved in cutaneous carcinogenesis.Materials and methods: To study the association of tryptase+ and IgE+ cells with photodamage and skin cancers 385 adult patients (201 males, 184 females, 75 with immunosuppression) at risk of any type of skin cancer were examined. Skin biopsies were taken from the sun-protected medial arm and from the photodamaged dorsal forearm skin followed by immunohistochemical staining for tryptase and IgE.Results: The results show that tryptase+ and IgE+ cells are significantly higher in number in the photodamaged than sun-protected skin, both in immunocompetent and -compromised subjects, and there is a strong correlation between tryptase+ and IgE+ cells. The numbers of forearm tryptase+ and especially IgE+ cells associated significantly with the forearm photodamage severity. In the logistic regression analysis, the forearm to upper arm ratio of IgE+ cells produced a univariate odds ratio of 1.521 (p = .010) and a multivariate one of 3.875 (p = .047) for the history of squamous cell carcinoma. The serum level of total IgE correlated significantly to the IgE to tryptase ratio in both skin sites.Conclusions: Therefore, IgE+ mast cells participate in photodamage and carcinogenesis, though it is unclear whether they are tumor-protective or -causative.

Corticotropin-releasing hormone receptor-1 is increased in mast cells in psoriasis and actinic keratosis, but not markedly in keratinocyte skin carcinomas.

Corticotropin-releasing hormone receptor-1 (CRH-R1) is expressed in human mast cells, but its role in skin diseases is unknown. By using a sequential double-staining technique, the mast cell expression of CRH-R1 was investigated in biopsies from lesional and non-lesional skin samples of patients with actinic keratosis (AK), basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and psoriasis. Dermal tryptase+ mast cells expressed CRH-R1 immunoreactivity in the non-lesional skin in all patient groups. The CRH-R1 expression was significantly increased in the lesional skin of AK (p = 0.03) and psoriasis (p = 0.02), non-significantly in BCC (p = 0.129), but not increased in SCC. To investigate the regulation of CRH-R1, the LAD2 mast cell line was irradiated with UVB or stimulated with CRH or 1,25-dihydroxyvitamin D3 [1,25-(OH)2 D3 ]. Consequently, UVB at 90 mJ/cm2 (p = 0.041) and 120 mJ/cm2 (p = 0.039) decreased CRH-R1 expression. Instead, CRH at 100 and 1000 nM increased CRH-R1 immunostaining, but did not affect the proliferative response. The treatment with 10 and 100 nM 1,25-(OH)2 D3 led to a noticeable increase in CRH-R1 staining. After irradiating with UVB, the concentration of CRH increased in the conditioned medium, but not in sonicated LAD2 mast cells. In conclusion, the lack of sufficient levels of CRH-R1 in mast cells may be related to diminished antitumoural response in SCC and possibly in BCC.

Patients with a history of atopy have fewer cutaneous melanomas than those without atopy: a cross-sectional study in 496 patients at risk of skin cancers.

The connection between atopy and skin cancers may be related to the stimulation of protective immune response, for example, through autoreactive immunoglobulin-E (IgE), or to the predisposition to carcinogenesis through chronic inflammation. The aim of this study was to investigate whether a past or present atopic disorder is associated with cutaneous photodamage, pigment cell nevi and skin cancers. For this, adult subjects at risk of any type of skin cancer (aged 21-79 years, 250 males, 246 females, 94 with immunosuppression) were examined for past or present malignancies in skin and extracutaneous site (ECS), photodamage, nevi, past or present atopic disorder in skin or mucus membranes, and possible other cancer-related factors. No association between atopy and photodamage, keratinocyte carcinomas or nevus count was found. Instead, there were fewer subjects with melanoma in 171 atopic (14.6%) than in 325 nonatopic subjects (22.2%) ( P = 0.044), and the investigator-estimated risk class of skin cancers was lower in atopic than nonatopic subjects. In all subjects, the multivariate odds ratio (OR) for melanoma was 0.583 ( P = 0.046; 95% confidence interval, 0.343-0.990) in atopic subjects, but in immunocompetent subjects, the reduced risk was confined to mucus membrane atopy (OR, 0.417; P = 0.020). Also, there were fewer subjects with malignancy in ECS in atopic (8.8%) than nonatopic subjects (15.7%) ( P = 0.031). No association between serum total IgE and skin cancers, photodamage, nevi or malignancies in ECS was found. In conclusion, the atopy, especially mucus membrane atopy, is associated with lower percentages of subjects with a history of melanoma.

Regular use of vitamin D supplement is associated with fewer melanoma cases compared to non-use: a cross-sectional study in 498 adult subjects at risk of skin cancers.

There are conflicting results on the role of vitamin D system in cutaneous carcinogenesis. Therefore, it was investigated whether the use of oral vitamin D supplements associates with photoaging, actinic keratoses, pigment cell nevi, and skin cancers. In this cross-sectional study, 498 adults (aged 21-79 years, 253 males, 245 females, 96 with immunosuppression) subjects at risk of any type of skin cancer were examined, and possible confounding factors were evaluated. The subjects were divided into three groups based on their self-reported use of oral vitamin D supplements: non-use, occasional use, or regular use. The serum level of 25-hydroxyvitamin-D3 was analyzed in 260 subjects. In 402 immunocompetent subjects, vitamin D use did not associate with photoaging, actinic keratoses, nevi, basal, and squamous cell carcinoma. In contrast, there were lower percentages of subjects with a history of past or present melanoma (32/177, 18.1% versus 32/99, 32.3%, P = 0.021) or any type of skin cancer (110/177, 62.1% versus 74/99, 74.7%, P = 0.027) among regular users compared to non-users. In the logistic regression analysis, the odds ratio for melanoma was 0.447 ( P = 0.016, 95% confidence interval, 0.231-0.862) among regular users. Furthermore, the investigator-estimated risk class of skin cancers was significantly lower among regular users. Serum 25-hydroxyvitamin-D3 did not show marked associations with skin-related parameters. The results on 96 immunosuppressed subjects were somewhat similar, although the number of subjects was low. In conclusion, regular use of vitamin D associates with fewer melanoma cases, when compared to non-use, but the causality between them is obscure.

CD40 Ligand Is Increased in Mast Cells in Psoriasis and Actinic Keratosis but Less So in Epithelial Skin Carcinomas.

The expression of CD40 ligand (CD40L) in mast cells was investigated in biopsies from lesional and non-lesional skin samples of patients with psoriasis, actinic keratosis (AK), basal cell carcinoma, and squamous cell carcinoma using a sequential double-staining technique. The percentage of CD40L+ mast cells was higher in the lesional than in the non-lesional skin (p < .003). Interestingly, this percentage was lower in both carcinomas than in psoriasis and actinic keratosis (p < .025). Cells immunopositive for CD40 receptor were increased in all lesion types but especially so in carcinomas. The results suggest a dysregulated anti-tumoral immune response by mast cell CD40L in skin carcinomas.