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Background: Cutaneous malignant melanoma (CMM) is curable if detected in its early stages. However, the clinical recognition of CMM is challenging. An American research group has shown promising results in detecting CMM based on RNA profiles sampled from suspicious lesions with tape strips. We aim to further develop this technique and validate if RNA profiles sampled with tape strips can detect CMM., Methods: This prospective cohort study will include approximately 200 lesions clinically suspected of CMM requiring surgical removal. Tape stripping of the lesions will be performed just before surgical excision. Subsequently, RNA on the tape strips is analyzed using quantitative real-time polymerase chain reaction with TaqMan technology. The results are combined into a binary outcome where positive indicates CMM and negative indicates no CMM. The histopathological diagnosis of the lesions will be used as the gold standard. The main outcome is the results of the RNA test and the histopathological diagnosis, which, combined, provide the sensitivity and specificity of the test., Discussion: The accuracy of the clinical examination in CMM diagnostics is limited. This clinical trial will explore the ability to use RNA analysis to improve the management of suspicious lesions by enhancing early diagnostic accuracy. Hopefully, it can reduce the number of benign lesions being surgically removed to rule out CMM and decrease patient morbidity., Trial Registration: The project was approved by The Committee on Health Research Ethics of the Capital Region of Denmark (H-15010559) and registered at the Danish Data Protection Agency (BFH-2015-065)., Competing Interests: The authors have declared that no competing interests exist.

Aims: Actinic keratosis (AK) is a precursor of cutaneous squamous cell carcinoma (SCC). No validated parameters can predict which AKs will progress into SCCs, but especially thick AKs are under suspicion. The clinical and histopathological thickness of AKs is strongly correlated. This study aimed to investigate the thicknesses and degree of dysplasia of AKs contiguous with SCCs assuming these AKs represent the AKs that have undergone malignant transformation., Methods: Files of the Pathology Department, Hospital of Southern Jutland, Denmark, were reviewed. 111 cases met the inclusion criteria: a skin biopsy containing an invasive SCC. All SCCs merged with an AK at the edge. Degree of dysplasia, epidermal thickness and stratum corneum thicknesses of AKs were measured., Results: All AKs showed severe dysplasia. Most AKs had a stratum corneum thickness under 0.1 mm and an epidermal thickness under 0.5 mm, corresponding to clinically thin and non-hyperkeratotic AKs., Conclusions: Our result suggests malignant progression potential of AKs regardless of thickness., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and red tattoos may be associated with increased risk of skin cancer due to potential carcinogens in tattoo inks. This combination has not been studied previously. Immunocompetent C3.Cg/TifBomTac hairless mice (n=99) were tattooed on their back with a popular red tattoo ink. This often used ink is banned for use on humans because of high content of the potential carcinogen 2-anisidine. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured. All UV-irradiated mice developed SCCs. The time to the onset of the first and second tumor was identical in the red-tattooed group compared with the control group (182 vs 186 days and 196 vs 203 days, P=ns). Statistically, the third tumor appeared slightly faster in the red-tattooed group than in the controls (214 vs 224 days, P=.043). For the second and third tumor, the growth rate was faster in the red-tattooed group compared with the control (31 vs 49 days, P=.009 and 30 vs 38 days, P=.036). In conclusion, no spontaneous cancers were observed in skin tattooed with a red ink containing 2-anisidine. However, red tattoos exposed to UVR showed faster tumor onset regarding the third tumor, and faster growth rate of the second and third tumor indicating red ink acts as a cocarcinogen with UVR. The cocarcinogenic effect was weak and may not be clinically relevant., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Black tattoos may involve risk of cancer owing to polycyclic aromatic hydrocarbons including benzo(a)pyrene (BaP) in inks. Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and black tattoo may therefore potentially be very problematic, but has not been previously studied., Methods: Immunocompetent C3.Cg/TifBomTac mice (n = 99) were tattooed on the back with Starbrite Tribal Black(™) . This ink has a high content of the carcinogen BaP. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured. Controls were 'tattooed' without ink., Results: All irradiated mice developed SCCs while no malignant tumours were found in the nonirradiated group. In the tattooed and irradiated group, the development of the first, second and third SCC was significantly delayed in comparison with the irradiated controls without black tattoos (212, 232, 247 days vs. 163, 183, 191 days, P < 0.001)., Conclusion: In UVR-irradiated black tattoos, remarkably, the development of UVR-induced skin cancer was delayed by the tattoos. Skin reflectance measurement indicated that the protective effect of black pigment in the dermis might be attributed to UVR absorption by black pigment below the epidermis and thereby reduction of backscattered radiation., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nutlin-3a increases p53 levels after UVB radiation, which could result in a decrease in DNA damage and thus lead to a lower risk of non-melanoma skin cancer. Especially, organ transplant recipients might derive benefit from such a topical formulation with an active ingredient to prevent DNA damage., Purpose: To investigate whether topical nutlin-3a can decrease photocarcinogenesis induced by simulated solar radiation., Methods: 72 hairless C3.Cg/TifBomTac mice were treated 3 days/week topically with 100 μl nutlin-3a (9 mM) [Groups 1 and 3 (120 days)) or 100 μl vehicle (Group 2). Three hours later, all mice were exposed to simulated solar radiation (a radiometric equivalent of three standard erythema dose units)., Results: The median time to tumours did not differ between the mice treated with nutlin-3a and with the vehicle. The median time to the first and second tumours did not differ between 'nutlin-3a-120 days' and vehicle-treated mice, but there was a small significant difference in the median time to the third tumour (211 vs. 196 days, P = 0.043). However, after Bonferroni correction, there was no difference at all., Conclusion: Nutlin-3a had no reductive effect on photocarcinogenesis and we do not believe in nutlin-3a as a potential drug against DNA damage in a topical formulation for organ transplant patients., (© 2012 John Wiley & Sons A/S.)

Background: Squamous cell carcinoma (SCC) is linked with the lifelong cumulative effect of ultraviolet radiation (UVR). In contrast, epidemiological data have shown that sunburn in childhood is a stronger risk factor for cutaneous malignant melanoma than continuous UVR, indicating a higher carcinogenic sensitivity early in life., Methods: We investigated how a high neonatal dose of UVR affects the development of SCC in mice irradiated later in life. We used simulated solar radiation (sun) and solarium radiation (solarium). Ninety-nine C3.Cg/TifBomTac-immunocompetent hairless mice received 0, 25 or 35 standard erythema doses (SED) UVR when they were 4 days old followed by 4 SED sun or 4 SED solarium three times/weekly from 9 weeks of age., Results: Tumours developed faster in mice treated with 35 SED UVR + 4 SED sun compared with 4 SED sun, but no change was observed in the cumulative dose required to achieve tumours. Tumours also developed faster in mice treated with 35 SED UVR + 4 SED solarium compared with 4 SED solarium, and a difference was also observed in the cumulative dose required to achieve tumours. If the Skin Cancer Utrecht-Philadelphia-murine spectrum was used to weigh the delivered irradiance instead of the International Commission on Illumination erythema action spectrum, tumours developed after the same accumulated dose., Conclusion: In conclusion, this study does not indicate increased sensitivity to induction of SCC early in life., (© 2012 John Wiley & Sons A/S.)

Topical corticosteroids such as hydrocortisone-17-butyrate (HCB) and clobetasol-17-propionate (CP) and vitamin D(3) derivatives such as calcipotriol (CAL) are widely used to treat psoriasis. The immunosuppressive effects of corticosteroids make their topical use a concern for skin carcinogenicity. Few studies have assessed the effect of topical corticosteroids and topical vitamin D(3) derivatives on photocarcinogenesis induced by ultraviolet radiation. We investigated whether HCB, CP, or CAL can accelerate photocarcinogenesis using simulated solar radiation (SSR). HCB, CP, or CAL was applied topically to the backs of hairless, female, C3.Cg/TifBomTac-immunocompetent mice in 16 groups of 25 mice each. The drugs were applied three times weekly followed by 0, 2, 4, or 6 standard erythema doses (SED) of SSR for 365 days or until death. No change was observed in the time required for tumor development in mice treated with HCB and 2 SED (HCB-2SED) and HCB-6SED. However, the time required for tumor development increased with HCB-4SED treatment. Treatment with CP-2SED did not change the time to onset of the first and second tumor, but all other CP treatments in combination with SSR increased the time. CAL-2SED decreased the time to onset of the first tumor but not of the second and third tumor. CAL-4SED and CAL-6 SED did not change or increased the time to tumor development. Our data indicated that topical administration of HCB and CAL did not alter the photocarcinogenesis of SSR and that topical CP administration had a photoprotective effect. Thus, HCB, CP, and CAL do not increase photocarcinogenesis induced by SSR., (© 2010 John Wiley & Sons A/S.)

Background: Hexyl aminolevulinate (HAL) is a long-chained 5-aminolevulinic acid-ester that has been proposed as a novel photosensitizing agent to methyl aminolevulinate (MAL) in topical photodynamic therapy (PDT). The more lipophilic HAL, may improve treatment outcome for non-melanoma skin cancer., Objective: To compare the prophylactic and therapeutic effects of HAL- and MAL-PDT for ultraviolet-induced squamous cell carcinomas (SCCs) in hairless mice., Methods: Mice (n = 249) were irradiated with solar UV-radiation (UVR) until SCC occurred. Before any skin changes developed, two prophylactic PDT treatments were given, using creams of HAL (2%, 6%, 20%) or MAL (20%) followed by illumination (632 nm, Aktilite, Photocure). Two therapeutic PDT-treatments were given by randomization to the first developed SCC of 1 mm. Primary end-points were time to first SCC of 1 mm and complete SCC clearance. Secondary end-points were time to SCC-recurrence, PpIX fluorescence and skin reactions to PDT., Results: The median time to first SCC was significantly longer for mice treated with prophylactic HAL-PDT (2%, 6% and 20% HAL, 264 days) and MAL-PDT (20% MAL, 269 days) than mice exposed to UVR (186 days) and UVR + placebo-PDT (199 days) (P < 0.0001). The therapeutic efficacy of HAL- and MAL-PDT showed cure rates of 23-61.5% (P = 0.11). Similar PpIX fluorescence intensity and severity of clinical reactions were seen for HAL- and MAL-groups, although mice developed more intense hyper-pigmentation when treated with 20% MAL-PDT compared with 2% HAL-PDT., Conclusions: PDT with HAL (2%, 6% and 20%) and MAL (20%) is equally effective to prevent and treat UV-induced SCC in hairless mice.

Topical benzoyl peroxide (BPO) gel has long been used to treat acne vulgaris and has recently been combined with clindamycin (BPO-clin). No skin malignancies have been reported after clinical use of BPO, but there has been concern about the possible carcinogenicity of BPO alone and in combination with UV radiation. BPO can promote skin tumorigenesis in a mouse skin chemical carcinogenesis model. As acne vulgaris is frequently localized on sun-exposed areas, we investigated whether BPO or BPO-clin accelerates photocarcinogenesis in combination with simulated solar radiation (SSR) in 12 groups of 25 hairless female C3.Cg/TifBomTac-immunocompetent mice. BPO or BPO-clin was applied topically to the back five times each week, followed by SSR three times each week (2, 3, or 4 standard erythema doses) 3-4 h later, for 365 days or until death. Generally BPO and BPO-clin did not accelerate the time to first, second or third tumor. Therefore, there is no evidence suggesting that BPO or BPO-clin is photocarcinogenic. However, we found significantly higher mortality in the SSR exposed groups receiving BPO and BPO-clin compared with groups receiving only BPO or BPO-clin. Our results show that BPO and the combination of BPO and clindamycin do not accelerate photocarcinogenesis, but are toxic in hairless mice. Based on the current data, the cancer risk associated with the use of BPO and BPO-clin in sun-exposed areas is minimal. Thus, while the carcinogenic potential of BPO is not fully understood, at the present time, evidence suggests that this compound is safe to use.

Background: Ultraviolet (UV) radiation induces non-melanoma skin cancer (NMSC), and UV prophylaxis is essential to prevent skin cancer. It is unclear whether patients diagnosed with squamous cell carcinomas (SCC) may benefit from reduced UV exposures in terms of delaying the development of new tumors. The objective was to evaluate the significance of discontinued or reduced UV exposure for the development of subsequent skin tumors., Methods: Seven groups of mice (n = 175) were irradiated with UV doses of 2 and 4 standard erythema doses (SED) that were continued, reduced or discontinued at the time of appearance of the first skin tumor., Results: The development of new tumors was delayed, corresponding to the degree of reductions in UV dose in an inversely linear manner. Discontinuation of UV doses delayed the median times to the second tumor by 24 days (2 SED, P = 0.0549) and 33.5 days (4 SED, P < 0.0001), and when reduced to 1 SED, the median delays were 18 days (2 SED, P = 0.0469) and 33 days (4 SED, P < 0.0001). The median delay to the third tumor was after UV reduction 47 days (4 SED, P < 0.0001) and 35 days (2 SED, P = 0.151), and after UV discontinuation 49 days (4 SED, P < 0.0001) and 44 days (2 SED, P = 0.111)., Conclusion: This suggests that patients with SCC may benefit from reduced UV exposure.

Pimecrolimus and tacrolimus are topical calcineurin inhibitors developed specifically for the treatment of atopic eczema. Experience with long-term use of topical calcineurin inhibitors is limited and the risk of rare but serious adverse events remains a concern. We have previously demonstrated the absence of carcinogenic effect of tacrolimus alone and in combination with simulated solar radiation (SSR) on hairless mice. The aim of this study is to determine whether pimecrolimus accelerates photocarcinogenesis in combination with SSR or pimecrolimus and tacrolimus accelerate photocarcinogenesis in combination with UVA. We used 11 groups of 25 hairless female C3.Cg/TifBomTac immunocompetent mice (n = 275). Pimecrolimus cream or tacrolimus ointment was applied on their dorsal skin three times weekly followed by SSR (2, 4, or 6 standard erythema doses, SED) or UVA (25 J/cm(2)) 3-4 h later. This was done up to 365 days in the SSR-treated groups and up to 500 days in the UVA-treated groups. Pimecrolimus did not accelerate the time for development of the first, second or third tumor in any of the groups. Median time to the first tumor was 240 days for the control-2SED group compared with pimecrolimus-2SED group (233 days), control-4SED group (156 days) compared with pimecrolimus-4SED group (163 days) and control-6SED group (162 days) compared with pimecrolimus-6SED group (170 days). Only one mouse in each of the three UVA groups developed a tumor. We conclude that pimecrolimus in combination with SSR and both pimecrolimus and tacrolimus in combination with UVA do not accelerate photocarcinogenesis in hairless mice.

Short-wave ultraviolet radiation (UVB) is the most carcinogenic part of the ultraviolet spectrum. The target cells of skin cancer are believed to be the bulge stem cells and/or their offspring, the transit-amplifying cells that reside in the epidermis. However, the amount of UVB penetrating epidermis and reaching the bulge cells is very low, which questions if these cells suffer sufficient DNA damage to transform into cancer stem cells. We performed this study to determine whether UV-induced squamous cell carcinoma (SCC) originates from the epidermis or the hair follicles in mice. Hairless mice had their epidermis removed at different levels using CO(2) laser ablation. Simulated solar irradiations were administered either preoperatively (in total 7 weeks) or pre- and postoperatively (in total 30 weeks). Control groups were untreated or treated only with solar-simulated radiation or with laser. Blinded clinical assessments of skin tumors were carried out weekly during 12 months observation. Only mice irradiated with solar-simulated radiation both pre- and postoperatively developed tumors. Median time to first, second and third tumor ranged from 19 to 20.5 weeks and was not significantly different between the non-laser and laser-treated groups (P > 0.05). The tumor response was thus similar in UV-exposed mice whether they had their epidermis removed or not. No tumors appeared in control groups. Hence, UV-induced SCC of mice originates from cells of the hair follicle, presumably the bulge stem cells, indicating that ultraviolet radiation penetrates epidermis sufficiently to cause irreversible DNA damage in cells located beneath the epidermis.

Background and Objectives: To examine whether carbon dioxide (CO2) laser treatment has a carcinogenic potential or may influence ultraviolet (UV)-induced carcinogenesis., Study Design/materials and Methods: Hairless mice (n = 211) were treated with a Sharplan CO2 laser with FeatherTouch scanner. Simulated solar irradiations were administrated either pre-operatively or pre- and post-operatively. Weekly clinical assessments of skin tumors were performed blinded during the entire observation period of 12 months., Results: No tumors appeared (a) in mice just treated with CO2 laser, (b) in mice exposed to UV irradiation only before CO2 laser treatment or (c) in untreated control mice. Tumors developed in CO2 laser treated mice that were exposed to UV-irradiation both pre- and post-operatively and in UV-irradiated control mice. The time to first, second, and third tumors ranged from 18 to 20 weeks and no significant differences were demonstrated., Conclusions: CO2 laser treatment does not have a carcinogenic potential in itself, nor does CO2 laser treatment influence UV-induced carcinogenesis.