Eye and hair colour, skin type and constitutive skin pigmentation as risk factors for basal cell carcinoma and cutaneous malignant melanoma. A Danish case-control study

To assess the importance of hair and eye colour, skin type and constitutive skin pigmentation as risk factors for basal cell carcinoma and cutaneous malignant melanoma in fair-skinned Caucasians, we conducted two identical case-control studies in Denmark. We studied 145 cases with basal cell carcinoma and 174 matched controls, and 168 cases with cutaneous malignant melanoma and 176 matched controls. Controls were matched on age, gender and place of residence. Subjects indicated their hair colour before 7 years of age, and at 25 years of age and their skin phototype. Interviewers assessed the present hair colour and eye colour, and the constitutive skin pigmentation was measured objectively by skin reflectance of UV unexposed buttock skin. There were no differences between basal cell carcinoma cases and controls in hair colour or eye colour or constitutive skin pigmentation, but more cases were of skin type II than skin type IV; skin type 11 was a risk factor for basal cell carcinoma with an odds ratio (OR) of 2.3. For cutaneous malignant melanoma, more cases than controls were red-haired or blond and of skin type II, but there was no difference in constitutive skin pigmentation. Hair colour and skin type were found to be independent risk factors for cutaneous malignant melanoma; red hair vs. black/brown: OR >9.7, blond hair vs. brown/black: OR = 2.4, and skin type 11 vs. type IV: OR=2.0. There were no gender-related differences in risk factors for basal cell carcinoma and cutaneous malignant melanoma.     

CXCR7在常见皮肤恶性肿瘤及其细胞株中的表达及意义

目的 探讨趋化因子受体CXCR7在皮肤鳞状细胞癌、基底细胞癌、侵袭性皮肤黑素瘤及其细胞株中的表达及其意义。方法 收集30例皮肤鳞状细胞癌、25例基底细胞癌、30例皮肤黑素瘤的癌组织,采用免疫组织化学方法,检测CXCR7蛋白表达水平。采用RT-PCR、细胞免疫组化方法检测CXCR7在A375、M14、A431、HaCaT细胞株中mRNA及蛋白水平。结果 CXCR7在侵袭性皮肤黑素瘤中表达明显,高表达率为80%（24/30）,皮肤鳞状细胞癌及基底细胞癌分别为26.67%（8/30）、8%（2/25）;皮肤黑素瘤CXCR7高表达率与鳞状细胞癌、基底细胞癌比较,差异均有统计学意义（χ2值分别为17.16和28.36,P值均 < 0.05）。CXCR7 mRNA在A375、M14、A431细胞株中均可检出,其中A375表达最强,而HaCaT细胞不表达;细胞免疫组化显示,仅在A375细胞见棕黄色颗粒着色。结论 皮肤黑素瘤及其细胞株A375高表达CXCR7,其可能参与了其恶性侵袭与转移。     

水通道蛋白3在四种皮肤肿瘤中的表达

目的 探讨水通道蛋白3（AQP3）在四种皮肤肿瘤组织中的表达及意义。方法 应用免疫组织化学方法检测30例脂溢性角化病、15例Bowen病、32例鳞状细胞癌、17例恶性黑素瘤及15例正常人皮肤组织中AQP3的表达。结果 脂溢性角化病、Bowen病、鳞状细胞癌、恶性黑素瘤及正常人表皮组织中均存在AQP3蛋白的表达;脂溢性角化病皮损中AQP3表达水平与正常人对照组差异无统计学意义（P > 0.05）;Bowen病、鳞状细胞癌及恶性黑素瘤皮损中AQP3蛋白表达显著高于正常人对照组（P < 0.01）,其中鳞状细胞癌与恶性黑素瘤的表达最强,均显著高于Bowen病（P < 0.01）,但鳞状细胞癌与恶性黑素瘤比较差异无统计学意义（P > 0.05）。此外,在鳞状细胞癌中AQP3的表达与肿瘤的分化有显著相关性（P < 0.01）;在已转移恶性黑素瘤中AQP3的表达显著高于未转移恶性黑素瘤（P < 0.05）。结论 AQP3在皮肤恶性肿瘤中表达上调。     

Urocanic acid isomers in patients with basal cell carcinoma and cutaneous malignant melanoma

Urocanic acid (UCA) is a major chromophore for ultraviolet (UV) radiation in the skin. On UV exposure, the naturally occurring trans -isomer converts to the cis -isomer in a dose-dependent manner. Accumulating evidence indicates that cis -UCA acts as an initiator of the UV-induced suppression of certain skin immune functions. This immunomodulation is recognized as an important factor in the development of skin cancer. In this study, pigmentation and UCA isomers were measured in 29 patients with previous basal cell carcinoma (BCC), 23 patients with previous cutaneous malignant melanoma (MM), and 32 healthy controls. Measurements were performed on UV-exposed (forehead, upper back) and UV non-exposed (buttock) skin. No significant differences in pigmentation percentage, total UCA concentration, relative (%) or absolute (nmol/cm²) cis -UCA concentration were observed between the groups in any of the body sites studied. The net production of cis -UCA after irradiation with a single test UV dose was evaluated. The relative production of cis -UCA following irradiation was significantly higher in both cancer groups when compared with the control group, while no significant difference was found between the BCC and the MM patients.     

Atypical Fibroxanthoma: An Unusual Skin Neoplasm in Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder related to defective deoxyribonucleic acid (DNA) repair. Various cutaneous manifestations related to ultraviolet (UV) damage characterize the clinical course. Primary malignant cutaneous neoplasms like squamous cell carcinoma, basal cell carcinoma and malignant melanoma have been reported. Atypical fibroxanthoma is a rare dermal neoplasm occurring in UV-damaged skin. We report an unusual case of atypical fibroxanthoma in a 20-year-old male with XP.     

The measurement of constitutive and facultative skin pigmentation and estimation of sun exposure in caucasians with basal cell carcinoma and cutaneous malignant melanoma

In two identical and simultaneously performed case–control studies of basal cell carcinoma (BCC) and cutaneous malignant melanoma (CMM) with age-matched, sex-matched and residence-matched controls, skin pigmentation was measured objectively by skin reflectance spectroscopy in 145 BCC patients and 174 matched controls and in 168 CMM patients and 176 matched controls. Measurements were performed at the forehead, the upper chest, the upper back, the lateral and medial aspects of the upper arm, and the buttocks. Self-estimation of sun exposure in childhood, in youth and in adulthood was performed by all subjects. There were no statistically significant differences in constitutive skin pigmentation at the buttocks between BCC patients and controls ( P  = 0.96) or between CMM patients and controls ( P  = 0.13). Facultative skin pigmentation in ultraviolet-exposed sites was not significantly different between BCC patients and controls except that women patients had higher pigmentation at the lateral side of the upper arm. For CMM, men patients had higher pigmentation at the lateral side of the upper arm. Self-estimations of sun exposure did not show differences between patients and controls but indicated high exposure levels in childhood and youth and in adult leisure time. Sun exposure estimated by increase in facultative pigmentation above the constitutive level (the Sun Exposure Index) was not significantly different between BCC patients and controls, whereas CMM men patients had higher estimates for the lateral side of the upper arm, the chest and the back.     

皮肤黑色素瘤中PITX1表达及其与临床病理特征和预后的关系

目的研究垂体同源框1(PITX1)表达与皮肤黑色素瘤(CMM)临床病理参数的关系,并探讨PITX1表达与CMM预后之间关系。方法2012年1月2014年2月在本院诊治的CMM患者43例为研究对象,选取同期在本院进行整形手术的皮肤正常者37例为对照。采用免疫组化法检测不同皮肤组织PITX1表达水平,分析PITX1表达与CMM临床病理参数及预后之间的关系。结果PITX1在CMM组织中阳性表达率与良性皮肤增生组织比较明显较低,差异有统计学意义(P<0.05)。PITX1相对表达水平与患者肿瘤溃疡情况、坏死情况、Breslow厚度、Clark分级、肿瘤发展进程(TNM)分期、淋巴结转移等有关,差异均有统计学意义(P<0.05)。Kaplan-Meier生存曲线分析表明,PITX1阳性表达者3年存活率显著高于PITX1表达阴性者(90.91%vs.46.88%,P<0.05)。COX分析结果表明,PITX1、TNM分期是影响CMM患者预后的独立危险因素(HR=2.157,95%CI为1.168~3.983,P<0.05;HR=2.097,95%CI为1.073~4.098,P<0.05)。结论PITX1在CMM组织低表达,是影响CMM患者预后的独立危险因素。     

Naevi as a risk factor for basal cell carcinoma in Caucasians: a Danish case-control study.

The number of melanocytic naevi in Caucasians is related to previous exposure to the sun and is a well-documented major risk factor for cutaneous malignant melanoma. Basal cell carcinoma, which is the most common form of skin cancer, has also been shown to be related to exposure to the sun. To investigate whether the number of common naevi is a risk factor for basal cell carcinoma in Caucasians we performed whole-body counting of naevi > or =2 mm in a Danish case-control study with 145 cases of primary basal cell carcinoma and 119 controls matched on age, gender and place of residence. Naevi were recorded according to size and body region and the skin phototype was assessed. There was no correlation between self-reported skin type and the number of naevi. Females with basal cell carcinoma had more naevi than did female controls (median number of naevi: 65 and 32, respectively) while males with basal cell carcinoma did not differ from male controls (median number of naevi: 48 and 43, respectively). Female cases had more small size naevi (2 mm), intermediate size naevi (3-4 mm) and large size naevi (> or =5 mm) than did female controls. Females with basal cell carcinoma had a substantially higher number of naevi on the arms and the legs than did female controls, but also had more naevi on the trunk. For females, the risk for basal cell carcinoma increased with increasing number of naevi. Naevi were not a risk factor for basal cell carcinoma in males.     

Epidermal thickness,skin pigmentation and constitutive photosensitivity

The important factors for UV sensitivity in humans are considered to be the skin pigmentation and the epidermal thickness. In this study on 73 Caucasians (age 20–85 years), we investigated in UV unexposed buttock skin the relationship between the UV sensitivity and constitutive skin pigmentation and thickness of the stratum corneum and the cellular part of the epidermis, in 34 normal people and in 39 skin cancer patients (20 patients with cutaneous malignant melanoma and 19 patients with basal cell carcinoma of the skin). Skin pigmentation was measured by skin reflectance spectroscopy, and UV sensitivity by phototest with a solar simulator. Thicknesses of the stratum corneum and the cellular part of the epidermis were determined by light microscopic evaluation of skin biopsies from the phototest areas. We found that epidermal thickness was independent of skin type and was not correlated to constitutive skin pigmentation. Thickness of the stratum corneum was statistically not different in normal persons and in skin cancer patients (P=0.4l) and was independent of gender (P=0.61) and age (P=0.56), while thickness of the cellular epidermis decreased with age (P<0.01). Stratum corneum thickness was found to be of minor importance for the constitutive UV sensitivity (accounting for on average 11% of the total photoprotection), which was mainly determined by the constitutive skin pigmentation (goodness-of-fit for correlation r=0.83). A theoretical model for the relationship of UV dose to induction of clinical erythema grade and skin pigmentation and thickness of the stratum corneum was developed. Objective measurements of skin pigmentation in UV unexposed skin by skin reflectance spectroscopy in Caucasians, normal people and people with cutaneous malignant melanoma and basal cell carcinoma of the skin predicts the constitutive UV sensitivity with a high degree of precision.     

Skin temperature of UV-induced erythema correlated to laser Doppler flowmetry and skin reflectance measured redness

Background/aims: The sensitivity of human skin to UV radiation is investigated by visual grading of the resulting erythema reactions 24 h after exposure to a series of increasing UV doses. Visual erythema assessment is, however, subjective and depends on pigmentation and redness of the adjacent un-irradiated skin and can be aided by skin reflectance spectroscopy and laser Doppler blood flow measurements. Erythema is accompanied by a raised skin temperature, and this reaction might be utilised as a simple objective measurement of UV sensitivity. Methods: Sixteen patients with cutaneous malignant melanoma, 16 patients with basal cell carcinoma, and 36 healthy people were phototested with simulated sunlight on previously UV un-exposed buttock skin. The resulting erythema reactions were graded visually 20-24 h post-exposure and measured by skin reflectance spectroscopy and laser Doppler flowmetry, and the surface skin temperature was determined in the erythema reactions and in adjacent un-irradiated skin by a contact thermometer. Results: Skin surface temperature in UV-induced erythema reactions was dose dependent, was statistically identical in skin cancer patients and in healthy people, and was age independent. The average temperature increase in barely perceptible erythema was 0.7°C (SD=1.1°C), and in bright red erythema it was 3.5°C (SD=2.0°C). Skin surface temperature increases were correlated to measurements by skin reflectance spectroscopy and by laser Doppler flowmetry. Conclusions: Skin surface temperature changes can be used as a simple objective measurement of UV sensitivity in healthy people and in skin cancer patients and may be particularly useful in heavily pigmented people where visual assessment of erythema is difficult or impossible.     

Dermal echogenicity: a biological indicator of individual cumulative UVR exposure?

Dermal alterations due to chronic UVR exposure may influence dermal ultrasound echogenicity, and a subepidermal low-echogenic band has been proposed as a marker of photoaging. The aim of this study was to determine whether dermal echogenicity could be used as a biological UVR dosimeter. We included 201 subjects (138 healthy volunteers, 31 patients with basal cell carcinoma, and 32 patients with cutaneous malignant melanoma). The number of low-echogenic pixels in the upper dermis relative to the lower dermis (LEP_u/l) was determined in sun-exposed and sun-protected skin. Individual UVR exposure data were collected retrospectively and prospectively using a questionnaire and electronic personal UVR dosimeters. Age, but not sex, skin type, constitutive pigmentation or smoking, correlated significantly with LEP_u/l at all body sites. Different measures of individual UVR exposure were significantly positively correlated with LEP_u/l (together r²=0.39, dorsal forearm), but separately the correlations were poor (r²=0.04–0.19). LEP_u/l was higher in the dorsal forearm in a group with high UVR exposure compared to a low-exposure group (P=0.007). Skin cancer patients in general had a lower LEP_u/l than healthy subjects. The results indicate that the age-related increase in LEP_u/l might be attributed mainly to UVR exposure, and that the methods used to obtain the UVR exposure data might not be sufficiently sensitive or specific. Genetic factors might also influence LEP_u/l. We consider LEP_u/l to be a sensitive and specific marker for UVR exposure at the dorsal aspect of the forearm in healthy subjects.Abbreviations BCC basal cell carcinoma - LEP_u/l number of low echogenic pixels in the upper dermis relative to the lower dermis - MED minimal erythema dose - MM cutaneous malignant melanoma - PPF pigment protection factor - SED standard erythema dose - UVR ultraviolet radiation     

Studies of cellular mediated immunity in malignant melanoma patients by leukocyte adherence inhibition test

Summary Sixteen malignant melanoma patients with different levels of tumor progression, two patients with melanoma in situ (Clark 1) two bronchogenic carcinoma patients and nine healthy controls were tested by means of the leukocyte adherence inhibition (LAI) test to assess the function of their cellular mediated immunity. Blood leukocytes were incubated with allogeneic melanoma-associated antigen obtained from potassium chloride extract of tumor cells.Fifteen malignant melanoma patients with clinical stage I–III (Clark level 2–5) showed positive LAI-reaction when leukocytes were tested with melanoma associated antigen. Leukocyte adherence inhibition was neither monitored in healthy controls, in patients with melanoma in situ, nor in those two patients with squamous and oat cell type bronchogenic carcinoma. Extracts prepared from normal skin showed no inhibitive effect on leukocyte adherence in malignant melanoma patients and controls.A decreased percentage of LAI was observed in malignant melanoma patients with disseminated disease due to an increased spontaneous leukocyte adherence in these patients. This increase in spontaneous leukocyte adherence was probably caused by non-specific activation of adherent cells (macrophages) as a result of the prolonged therapy and/or the progressive tumor levels in these patients.This work was supported by the Agnes-and Georg-Blumenthal-Stiftung 26/7/4     

1333例皮肤恶性肿瘤回顾性分析

目的了解重庆地区皮肤恶性肿瘤的发病情况及特点。方法收集和回顾性分析第三军医大学西南医院皮肤科1991年～2010年经组织病理确诊的皮肤恶性肿瘤患者临床资料。结果共统计1333例皮肤恶性肿瘤患者,男女之比为1．26：1,其中基底细胞癌454例（占34．06％）、鳞状细胞癌235例（占17．63％）、鲍恩病136例（占10．20％）、恶性黑素瘤133例（占9．98％）、乳房及乳房外Paget病104例（占7．80％）。临床诊断与组织病理诊断符合率为72．4％,符合率最高的是乳房及乳房外Paget病（93．27％）。基底细胞癌主要发生于头面部和颈部,鲍恩病多见于躯干部位,恶性黑素瘤的主要发病部位在足跖。结论相对于国内外其他研究资料,重庆地区的皮肤恶性肿瘤发病情况具有一定的自身特点。     

Parameters related to oxygen free radicals in human skin: a study comparing healthy epidermis and skin cancer tissue

In vitro studies with tumor cells have demonstrated that oxygen free radicals are involved in the development of skin cancers and that variations in the body's defense mechanisms can modify the course of the disease. To assess the validity of this hypothesis in spontaneous tumors, we determined glutathione S-transferase, superoxide dismutase, reduced and oxidized glutathione, and thiobarbituric acid reactive substances in healthy whole skin (n = 95), dermis (n = 73), and epidermis (n = 69). The values were compared with those obtained in three types of skin cancer: basal cell carcinoma (n = 16), squamous cell carcinoma (n = 6), and melanoma (n = 33). In healthy skin, glutathione S-transferase, superoxide dismutase, reduced glutathione, and oxidized glutathione were higher in epidermis than in dermis, whereas thiobarbituric acid reactive substances were higher in dermis than in epidermis; whole skin had intermediate values. These results suggest that there is an induction of some anti-oxygen free radicals mechanisms in epidermis as a result of increased oxygen free radicals production. Glutathione S-transferase and thiobarbituric acid reactive substances were higher in all types of tumor than in healthy epidermis but oxidized glutathione was lower. Reduced glutathione and superoxide dismutase activity were lower in basal cell carcinoma and squamous cell carcinoma samples. Glutathione S-transferase increased, whereas superoxide dismutase and thiobarbituric acid reactive substances decreased in melanoma samples in direct relation to the Clark levels. Higher glutathione S-transferase activity, particularly in the most invasive forms of melanoma, indicates that this type of cancer is more malignant. Similarly, a decrease in superoxide dismutase activity can also encourage progression of the tumor. These results are in accord with those from tumor cell cultures and could suggest new strategies (gene therapy) for managing skin cancer.     

Can ultraviolet erythema be used to identify the basal cell carcinoma phenotype?

Since a prolonged duration of a strong UBV erythema has been suggested as a marker for propensity to develop skin cancer, we objectively followed the duration and intensity of erythemas induced by UVB and UVA radiation for 28 days in 18 patients with basal cell carcinoma (BCC), and in 15 healthy controls using reflectance spectrophotometry. The erythema index, defined as the difference in redness between UV-exposed skin and normal, adjacent skin on the lower abdomen, did not differ significantly between the two groups at 24 h, when the reaction was maximal, following a dose of 6 MED of UVB. Erythema values after 7 and 14 days were slightly higher in the BCC group, but this difference did not reach statistical significance. At day 7 some patients in the BCC group showed very strong erythemas. At days 21 and 28 the two groups had almost identical erythemal reactions. Following a standard dose of UVA of 100 J/cm², patients with BCC and healthy controls both showed weak erythemal reactions, which declined somewhat over the study period. No significant differences in pigmentary response were noted between the BCC and the control group, neither following UVB nor UVA. Although individual patients with BCC deviate from the normal erythemal curve for UVB, the UVB response is not a suitable predictive instrument in screening patients with the basal cell carcinoma phenotype.     

Infrared spectra of basal cell carcinomas are distinct from non-tumor-bearing skin components.

Infrared spectroscopy, by probing the molecular vibration of chemical bonds, directly indicates tissue biochemistry. An expanding body of literature suggests that infrared spectra distinguish diseased from normal tissue. The authors used infrared spectroscopy to examine basal cell carcinoma to explore distinctive characteristics of basal cell carcinoma versus normal skin samples and other skin neoplasms. Spectra of epidermis, tumor, follicle sheath, and dermis were acquired from unstained frozen sections, and analyzed qualitatively, by t-tests and by linear discriminant analyses. Dermal spectra were significantly different from the other skin components mainly due to absorptions from collagen in dermis. Spectra of normal epidermis and basal cell carcinoma were significantly different by virtue of subtle differences in protein structure and nucleic acid content. Linear discriminant analysis characterized spectra as arising from basal cell carcinoma, epidermis, or follicle sheath with 98.7% accuracy. Use of linear discriminant analysis accurately classified spectra as arising from epidermis overlying basal cell carcinoma versus epidermis overlying nontumor-bearing skin in 98.0% of cases. Spectra of basal cell carcinoma, squamous cell carcinoma, nevi, and malignant melanoma were qualitatively similar. Distinction of basal cell carcinoma, squamous cell carcinoma, and melanocytic lesions by linear discriminant analyses, however, was 93.5% accurate. Therefore, spectral separation of abnormal versus normal tissue was achieved with high sensitivity and specificity, which points to infrared spectroscopy as a potentially useful screening tool for cutaneous neoplasia.     

Bacteriology of psoriatic plaques

Qualitative and quantitative studies of cutaneous bacterial flora were carried out in psoriatic patients and normal healthy controls. In psoriatics, the flora isolated from the affected skin was compared with the flora of adjacent normal skin. No significant qualitative difference was observed. The total number of bacteria isolated from the psoriatic plaque was significantly higher than on the adjacent normal skin. Flora of normal skin of psoriatics when compared with the skin of healthy controls did not reveal any qualitative difference, but a statistically significant difference was observed in the total bacterial counts. The nasal carriage rate of Staphylococcus aureus in psoriatics was higher than the control groups.     

Multiple basal cell carcinomas and malignant melanoma following radiotherapy for ankylosing spondylitis

We present the case of a 53-year-old Caucasian woman with seven basal cell carcinomas and one malignant melanoma in situ along her back overlying her spine, which was irradiated in 1968 for ankylosing spondylitis. These lesions developed between 1997 and 1999. She has no other known risk factors for cutaneous malignancy, in particular no history of excessive sun exposure. She has skin type 2. Molecular studies of glutathione S-transferase and cytochrome P450 status showed her genotype not to constitute an overall increased inherited susceptibility. We therefore postulate that all her skin cancers have arisen as a consequence of her radiotherapy. To our knowledge this is the first case of multiple basal cell carcinoma in addition to a malignant melanoma following radiotherapy for benign disease.     

Chemoprevention of skin cancer in xeroderma pigmentosum.

Xeroderma pigmentosum is a rare recessive disease with sun sensitivity, increased freckling and defective DNA repair. Xeroderma pigmentosum patients have more than a 1000-fold increased risk of developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. We studied chemoprevention of new skin cancers with oral retinoids in xeroderma pigmentosum patients who had multiple skin cancers. Xeroderma pigmentosum patients were cleared of all pre-existing tumors surgically and then treated with high dose (2 mg/kg/day) oral isotretinoin (13-cis retinoic acid, Accutane) for two years and then for one year off treatment. Patients were examined at regular intervals for new tumor formation and for side effects. Five xeroderma pigmentosum patients had a total of 121 basal or squamous cell carcinomas in 2 years before treatment and only 25 tumors during 2 years of treatment. The tumor frequency increased 8.5-fold after the drug was discontinued (New Engl J Med 318: 1633-1637, 1988). Toxicity (cutaneous, triglyceride, liver-function or skeletal abnormalities) prompted subsequent use of a low dose protocol. Patients were treated initially with 0.5 mg/kg/day oral isotretinoin and the dose was increased sequentially to 1.0 or 1.5 mg/kg/day. We found that toxicity was less with the lower doses. The lowest effective, least toxic dose varied among the xeroderma pigmentosum patients.