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.

Increased expression of complement C3c, iC3b, and cells containing CD11b or CD14 in experimentally induced psoriatic lesion.

Psoriasis is a chronic inflammatory skin disease with a characteristic isomorphic reaction, i.e. the Köbner reaction, induced by slight epidermal trauma. In this study, the tape-stripping technique was used to induce the development of Köbner reaction in 18 subjects with psoriasis. Eight subjects developed a positive reaction. To study the early cellular changes, skin biopsies were taken at the baseline and subsequent time points of 2 h, 1 d, 3 d, and 7 d for the immunostaining of complement C3c, iC3b, and cells expressing complement receptor 3 (CD11b/CD18; a receptor of iC3b) or CD14. The results show that the positive Köbner reaction is associated with rapid (2 h-1 d) and sustained (3-7 d) increase in the expression of epidermal C3c and iC3b and dermal C3c. In addition, there was a positive correlation between CD11b+ and CD14+ cells in baseline and 2 h-1 d biopsies with a subsequent increase in CD11b+ and CD14+ cells in 3-7 d biopsies in the Köbner-positive group. In the Köbner-negative group, only a transient increase in epidermal iC3b at 2 h-1 d, as well as rapid (2 h-1 d) and sustained increase (3-7 d) in dermal iC3b and CD14+ cells, was observed. In experiments with cultured monolayer keratinocytes, a slight cell damage already at 30 mJ/cm2 ultraviolet B irradiation led to increased expression of C3c, but not iC3b. Therefore, there are marked differences between Köbner groups in respect to the expression of C3c, iC3b, and cells expressing CD11b or CD14. Of note is the rapid and sustained increase in epidermal C3c and iC3b in the positive Köbner reaction.

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.

FoxP3-Positive Cells and Their Contacts with Mast Cells Are Highly Increased in Basal Cell Carcinoma.

INTRODUCTION: The cells of the immune system are thought to contribute to the development of skin cancers, such as basal cell carcinoma (BCC). One possible mechanism may be the interaction between mast cells and regulatory T cells (Tregs), resulting in immunosuppression. METHODS: Fresh-frozen biopsies from the lesional and nonlesional skin of 16 patients with BCC were processed for the enzymehistochemical staining of mast cell tryptase, immunohistochemical staining of FoxP3 (a marker of Tregs) as well as for the double-staining method to label tryptase+ cells and FoxP3+ cells on the same cryosection. The cell numbers and apparent morphological contacts (AMCs) between these cell types were counted. RESULTS: There was a high increase in the number of tryptase+ cells, FoxP3+ cells, and AMCs between them in the lesional compared to corresponding nonlesional skin (p < 0.0001) in all cases. CONCLUSION: A morphological basis is theoretically present in BCC, suggesting an immune evasive microenvironment.

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.

The prognostic and predictive role of tumor-infiltrating lymphocytes (FoxP3 + and CD8 +) and tumor-associated macrophages in early HER2 + breast cancer.

PURPOSE: In HER2-positive (HER2 +) breast cancer, tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may influence the efficacy of the HER2-antibody trastuzumab and the patient's outcome. In this HER2 + patient cohort, our aim was to study the numbers of FoxP3 + regulatory TILs and CD8 + cytotoxic TILs, their correlations with CD68 + and CD163 + TAMs, and the prognostic and predictive value of the studied factors. METHODS: We evaluated 139 non-metastatic HER2 + breast cancer patients operated between 2001 and 2008. The FoxP3+TIL count (FoxP3+TILs) was assessed using the hotspot method, and the CD8 + TIL count (CD8+mTILs) utilizing a digital image analysis from invasive margin areas. The ratios between CD8+mTILs and FoxP3+TILs as well as CD8+mTILs and TAMs were calculated. RESULTS: FoxP3 + TILs and CD8 + mTILs correlated positively with each other (p<0.001). FoxP3+TILs had a positive correlation with CD68+and CD163+TAMs (p≤0.038), while CD8 + mTILs correlated only with CD68+TAMs (p<0.001). In the HER2 + and hormone receptor-positive Luminal B subgroup, high numbers of FoxP3+TILs were associated with shorter disease-free survival (DFS) (54% vs. 79%, p = 0.040). The benefit from adjuvant trastuzumab was extremely significant among patients with a high CD8 + mTILs/CD68 + TAMs ratio, with overall survival (OS) 84% vs. 33% (p = 0.003) and breast cancer-specific survival (BCSS) 88% vs. 48% (p = 0.009) among patients treated with or without trastuzumab, respectively. CONCLUSION: In the HER2 + Luminal B subgroup, high FoxP3 + TILs were associated with shorter DFS. A high CD8 + mTILs/CD68 + TAMs ratio seems to associate with impressive efficacy of trastuzumab.

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.

Pinoresinol stimulates keratinocyte proliferation and downregulates TNF-α secretion in peripheral blood mononuclear cells: An experimental in vitro study.

Background and Aims: Natural coniferous resins are used in traditional medicine for the treatment of skin wounds. Coniferous wood resins ("callus" resin) are a mixture of abietic (resin) acids, lignans such as pinoresinol, and p-coumaric acid. The wound-healing properties of resins are thought to be related to their antimicrobial properties, but also to their effects on cell proliferation and inflammation. The purpose of this study was to identify and investigate the effects of novel aqueous dispersions of resin and its main components in the proliferation of human primary keratinocytes in vitro and in the expression of proinflammatory cytokines in human peripheral blood mononuclear cells. Methods: The proliferation studies were performed under low and high calcium conditions with or without added growth stimulators at the time points of 2 and 6 days using AlamarBlue Cell Viability Reagent. The cytokine release assay was carried out by incubating the cells with the test articles for 18 h, after which the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and IL-8 were measured in the supernatant by enzyme-linked immunosorbent assay. Results: Resin and the purified lignan PINO, but not p-coumaric acid or abietic acid (industrial tall oil rosin), enhanced the proliferation of human keratinocytes in vitro and inhibited the expression of TNF-α, and to a lesser extent the expression of IL-1ß in peripheral blood mononuclear cells. Conclusions: In this study, novel aqueous dispersions of spruce resin were used to investigate the effects of main resin components on keratinocyte proliferation and on the expression of key proinflammatory cytokines known to be associated with chronic wounds. The observations suggest that lignans, such as PINO, but not resin acids, are the components of resins that mediate the proliferative and TNF-α-suppressing effects. Lignans including PINO were identified as novel potential compounds in the treatment of chronic skin ulcers.

Malignant and in situ subtypes of melanoma are associated with basal and squamous cell carcinoma and its precancerous lesions

Background: Patients with cutaneous malignant melanoma (CMM) are at increased risk of non-melanoma skin cancers (NMSCs) and possibly precancerous lesions. Objectives: To analyse the association between CMM and not only NMSCs but also precursor lesions, actinic keratosis (AK) and Bowen disease (BD). Materials & Methods: The Finnish Cancer Registry data was used to calculate the age-standardized incidence ratio during 2000-2013 for basal (BCC) and squamous (SCC) cell carcinoma in patients with CMM. All tissue material collected from 70,420 subjects during 2000-2013 and reposited in the Biobank of Eastern Finland was used to calculate the age-standardized prevalence of BCC, SCC, BD and AK in CMM patients. Results: In both genders, the age-standardized incidence ratio of BCC and SCC was increased in CMM patients. The age-standardized prevalence of NMSCs and precursor lesions was higher in patients with CMM than in those without CMM, and was higher in CMM patients with immunosuppression (IS) than in those without IS. The association of M-Snomed subtypes, lentigo maligna (LM), melanoma in situ (MIS) and malignant melanoma (MM) with AK and/or BD was stronger than with BCC. LM revealed the highest association with the combination of AKBD-SCC. Male subjects showed a higher age-standardized prevalence of CMM, MM and BCC than females, but the opposite was observed for AK. Conclusion: Melanoma increases the risk of NMSCs, and IS may enhance this risk. Both malignant and in situ subtypes of melanoma associate with not only BCC and SCC, but also precancerous lesions.

Sequential Increase in Complement Factor I, iC3b, and Cells Expressing CD11b or CD14 in Cutaneous Vasculitis.

Mast cells contribute to the pathogenesis of cutaneous vasculitis through complement C3 that is cleaved to C3b and then to iC3b by complement factor I. The receptor of iC3b, CD11b, is expressed on neutrophils and monocytes and CD14 on monocytes. Their role in vasculitis is obscure. In this study, frozen skin biopsies from the nonlesional skin, initial petechial lesion, and palpable purpura lesion from 10 patients with immunocomplex-mediated small vessel vasculitis were studied immunohistochemically for complement factor I, iC3b, CD11b, and CD14. Peripheral blood mononuclear cells from 5 healthy subjects were used to study cell migration and cytokine secretion. Already, the nonlesional skin revealed marked immunostaining of complement factor I, iC3b, CD11b, and CD14, and their expression increased sequentially in initial petechial and palpable purpura lesions. Mast cell C3c correlated to iC3b, and both of them correlated to CD11b+ and CD14+ cells, in the nonlesional skin. The stimulation of mononuclear cells with 0.01-0.1 µg/ml iC3b induced cell migration in the transwell assay. C3a stimulated slightly interleukin-8 secretion, whereas 1 µg/ml iC3b inhibited it slightly, in 4/5 subjects. In conclusion, the C3-C3b-iC3b axis is activated already in the early vasculitis lesion leading to progressive accumulation of CD11b+ and CD14+ cells.

Case: Unexpected development of severe penicillin allergy and review of literature.

A 54-year-old man developed a severe anaphylactic penicillin allergy after 16 years and 5 standard erysipelas treatments by intravenous benzylpenicillin and/or oral phenoxymethylpenicillin without any symptoms of allergy. It is recommended to analyze specific IgE antibodies for phenoxymethylpenicillin, benzylpenicillin, amoxicillin, and cefaclor to select an appropriate antibiotic.

Mast Cells in Human Cutaneous Neurofibromas: Density, Subtypes, and Association with Clinical Features in Neurofibromatosis 1.

BACKGROUND: Cutaneous neurofibromas (cNFs) are hallmarks of neurofibromatosis 1 (NF1) and cause the main disease burden in adults with NF1. Mast cells are a known component of cNFs. However, no comprehensive characterization of mast cells in cNFs is available, and their contributions to cNF growth and symptoms such as itch are not known. METHODS: We collected 60 cNFs from ten individuals with NF1, studied their mast cell proteinase content, and compared the mast cell numbers to selected clinical features of the tumors and patients. The tumors were immunolabeled for the mast cell markers CD117, tryptase, and chymase, and the percentage of immunopositive cells was determined using computer-assisted methods. RESULTS: The median proportions of positive cells were 5.5% (range 0.1-14.4) for CD117, 4.0% (1.2-7.0) for tryptase, and 5.0% (1.1-15.9) for chymase. The median densities of cells immunopositive for CD117, tryptase, and chymase were 280, 243, and 250 cells/mm2, respectively. Small tumors, growing tumors, and tumors from patients below the median age of 33 years displayed a high proportion of mast cells. Cells expressing both tryptase and chymase were the predominant mast cell type in cNFs, followed by cells expressing chymase only. CONCLUSION: The results highlight the abundance of mast cells in cNFs and that their number and subtypes clearly differ from those previously reported in unaffected skin.

Mast cell chymase is in contact with melanoma cells in vivo and it detaches melanoma cells from the substratum in vitro.

Background: Mast cell chymase, a chymotryptic serine proteinase, is a powerful enzyme that may liberate adherent tumor cells thereby promoting tumor spread. Methods: This study investigated interactions between cells containing immunoreactive chymase and melanoma cells in 101 melanoma and 50 nevus specimens as well as used recombinant human (rh)-chymase and WM115 and G361 primary melanoma cell lines in culture. Results: Rh-chymase at low concentration (0.1 µg/mL) detached both melanoma cell lines from noncoated or collagen-coated plastic surface, but this effect was regulated by heparin and heparinase. After prolonged treatment at high rh-chymase (1-5 µg/mL) the growth pattern of detached and re-seeded cells was abnormal. Decreased migration and proliferation at up to 0.005-0.01 µg/mL rh-chymase was noticed in WM115 cells, while rh-chymase at 1-5 µg/mL partially reduced the viability of G361 cells. Of importance is the finding that melanoma cell lines are not uniform as there was variation between cell lines with regard to the concentration of rh-chymase needed for these effects. Sonicates prepared from the cell lysates did not inhibit the enzymatic activity of rh-chymase. The interactions were confirmed morphologically by detecting apparent contacts between chymase+ cells and melanoma cells in melanoma specimens. Conclusions: These results suggest that chymase can detach melanoma cells from the tumor, but this effect is regulated by heparin, and their proliferation, migration or viability can be reduced by chymase. Thus, the effect of chymase may be antitumorigenic, rather than protumorigenic.

High regional mortality due to malignant melanoma in Eastern Finland may be explained by the increase in aggressive melanoma types.

BACKGROUND: A regional skin cancer prevention program in Eastern Finland revealed a relatively high age-standardized mortality due to malignant melanoma during 2013-2017. An explanation for this is needed. PURPOSE: To analyse the 543 melanoma samples in 524 subjects collected during 2000-2013 at Kuopio University Hospital and reposited in the Biobank of Eastern Finland. A focus was directed to factors related to metastasis. METHODS: The samples were analysed anonymously by examining the histopathological report, referral text and the list of diagnoses. A possible state of immunosuppression was evaluated. RESULTS: The mean age at the diagnosis of malignant melanoma (MM), lentigo maligna (LM) and melanoma in situ was relatively high, i.e., 66.2, 72.1 and 63.3, respectively. Especially the MM type increased markedly during 2000-2013. In further analyses of a representative cohort of 337 samples, the proportion of nodular melanoma and LM/LMM melanoma was relatively high, 35.6 and 22.0%, respectively, but that from superficial spreading melanoma relatively low (33.8%). Metastasis correlated with immunosuppression, male gender, Clark level, Breslow thickness, ulceration, mitosis count, invasion into vessels and/or perineural area, microsatellites, melanoma subtype, body site, recidivism, and the absence of dysplastic nevus cells. CONCLUSION: The marked increase in aggressive melanomas with associated metastasis, and the relatively high age at diagnosis, can partially explain the mortality.

Association of Elevated Serum Tryptase with Cutaneous Photodamage and Skin Cancers.

INTRODUCTION: Mast cells and their major protein, the serine proteinase tryptase, can be involved in cutaneous photodamage and carcinogenesis. The serum test of tryptase (S-tryptase) measures total tryptase protein (active tryptase and inactive protryptases), and S-tryptase is elevated in a variety of diseases, for example, in mastocytosis and α-tryptasemia. OBJECTIVES: The objective of this study is to study whether S-tryptase is a marker of cutaneous photodamage and carcinogenesis. METHODS: Adult subjects (n = 399, aged 21-79) evaluated to be at risk for skin cancers were recruited at the dermatological policlinic and examined for photodamage severity, mole count, actinic keratoses (AKs), skin cancers, and immunosuppression (IS). A blood sample was analyzed for S-tryptase using the ImmunoCAP® Tryptase fluoroenzymeimmunoassay. RESULTS: There was no difference in S-tryptase between non-IS (n = 321) and IS (n = 78) subjects or between genders. S-tryptase correlated slightly to photodamage and AKs in 321 non-IS subjects, and this association can be related, in part, to the age of subjects. In 34 subjects, S-tryptase was elevated (≥13.5 ng/mL), and in 20 males, but not in 14 females, the photodamage level was significantly (p = 0.031) more severe than in 179 males with normal S-tryptase. In contrast, there were more frequently subjects (n = 12) with past or present skin cancer (basal or squamous cell carcinoma or melanoma) in 14 females with elevated S-tryptase than in 186 female controls. So far, no explanation has been found for the elevated S-tryptase. CONCLUSION: There are significant associations between elevated S-tryptase and skin carcinogenesis, but the molecular mechanisms are unclear and gender differences can exist.

Mast Cells and Sensory Nerves Contribute to Neurogenic Inflammation and Pruritus in Chronic Skin Inflammation.

The intimate interaction between mast cells and sensory nerves can be illustrated by the wheal and surrounding flare in an urticarial reaction in human skin. This reaction is typically associated with an intense itch at the reaction site. Upon activation, cutaneous mast cells release powerful mediators, such as histamine, tryptase, cytokines, and growth factors that can directly stimulate corresponding receptors on itch-mediating sensory nerves. These include, e.g., H1- and H4-receptors, protease-activated receptor-2, IL-31 receptor, and the high-affinity receptor of nerve growth factor (TrkA). On the other hand, sensory nerves can release neuropeptides, including substance P and vasoactive intestinal peptide, that are able to stimulate mast cells to release mediators leading to potentiation of the reciprocal interaction, inflammation, and itch. Even though mast cells are well recognized for their role in allergic skin whealing and urticaria, increasing evidence supports the reciprocal function between mast cells and sensory nerves in neurogenic inflammation in chronic skin diseases, such as psoriasis and atopic dermatitis, which are often characterized by distressing itch, and exacerbated by psychological stress. Increased morphological contacts between mast cells and sensory nerves in the lesional skin in psoriasis and atopic dermatitis as well as experimental models in mice and rats support the essential role for mast cell-sensory nerve communication in consequent pruritus. Therefore, we summarize here the present literature pointing to a close association between mast cells and sensory nerves in pruritic skin diseases as well as review the essential supporting findings on pruritic models in mice and rats.

Mast Cells Are a Marked Source for Complement C3 Products That Associate with Increased CD11b-Positive Cells in Keratinocyte Skin Carcinomas.

By using immunohistochemistry and antibodies that identify complement C3c (in C3 and C3b) or CD11b receptor, we report that the proportion C3c+ mast cells and the number of CD11b+ cells are increased in basal cell carcinoma (BCC). Instead, only CD11b+ cells are increased in squamous cell carcinoma/Bowen's disease, and only slightly so in actinic keratosis. Only C3c+ mast cells are increased in psoriasis. Furthermore, C3c+ mast cells correlated positively with CD11b+ cells, and iC3b immunoreactivity was detected around tryptase+ mast cells. Therefore, mast cells may convey immunoregulatory signals through C3, C3b, and iC3b to CD11b+ cells, especially in BCC.