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.     

Multiple eruptive squamous cell carcinoma in a patient with chronic plaque psoriasis on adalimumab

A 67‐year‐old man with chronic plaque psoriasis previously treated with psoralen plus PUVA, ciclosporin, methotrexate and acitretin developed eruptive squamous cell carcinoma after seven doses of adalimumab. We review the association of squamous cell carcinoma with immunosuppressive agents used for the treatment of chronic plaque psoriasis. Initiation of tumour necrosis factor (TNF)‐α inhibitors in a patient at high risk of non‐melanoma skin cancer may warrant chemoprophylaxis with acitretin.     

A novel technique to diagnose non‐melanoma skin cancer by thermal conductivity measurements: Correlations with cancer stromal factors

The skin surface temperature reflects the physiological state of the human body. Quantitative methods of identification of skin cancers based on accurate measurement of effective thermal conductivity (ETC) are among the promising diagnostic tools for differentiating non‐invasive and invasive melanomas before surgical treatment. To validate these findings, in this report, the diagnostic methods for invasive and non‐invasive extramammary Paget’s disease (EMPD) and squamous cell carcinoma (SCC) were further tested by measuring the absolute value of skin surface temperature and the ETC of the skin. In addition, to investigate the stromal factors that might affect ETC, immunohistochemical staining for LL37, periostin (POSTN), MMP12, and MMP28 was performed. The invasive SCC and EMPD group showed a relatively higher skin surface temperature compared to the in situ SCC group. The non‐invasive EMPD and SCC group showed significantly lower values of ETC at lesions, whereas the invasive EMPD group showed significantly higher ETC values at lesions compared to healthy skin. Immunohistochemical staining showed that the percentage of LL37‐producing cells was significantly increased in invasive EMPD and SCC compared to that in non‐invasive EMPD and SCC. Moreover, Spearman's rank correlation test showed a significant inverse correlation between the percentage of MMP12‐positive cells and increased levels of ETC‐expressing areas in EMPD and SCC (r = ?.5997). The present study suggested that differences in ETC could be a novel high‐accuracy diagnostic technique for non‐melanoma skin cancer, especially for detecting dermal invasion of SCC and EMPD.     

Current approaches to skin cancer management in organ transplant recipients

Approximately 225,000 people are living with organ transplants in the United States. Organ transplant recipients have a greater risk of developing skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, with an approximately 250 times greater incidence of squamous cell carcinoma in certain transplant recipients, compared with the general population. Because skin cancers are the most common posttransplant malignancy, the resultant morbidity and mortality in these high-risk patients is quite significant.     

Risk of basal cell carcinoma in a randomized clinical trial of aspirin and folic acid for the prevention of colorectal adenomas

Patients with the genetic disorder basal cell naevus syndrome are at risk of developing multiple basal cell carcinomas, a form of skin cancer. Treatment with the non‐steroidal anti‐inflammatory drug called celecoxib appears to reduce the risk. There is some evidence that other non‐steroidal anti‐inflammatory drugs, including aspirin, may slightly reduce the risk of non‐melanoma skin cancers in general. High amounts of folic acid in the diet may be linked to a slightly increased risk of basal cell carcinoma. Adenomas are polyps of the large bowel (colon and rectum) which are often multiple; they can develop into bowel cancer. They can be detected and removed by colonoscopy, which is repeated at regular intervals. Aspirin and folic acid may prevent the recurrence of these adenomas. The authors of this study, based in the United States and Canada, studied over a thousand patients with colorectal adenomas (aged 21‐80) who were participating in a trial of aspirin and folic acid in prevention of further polyps, over a 3‐6 year period. The authors looked at pathology reports to see if there was a different incidence of basal cell carcinoma in patients on aspirin/folic acid or placebo (no treatment). 104 of 958 patients eligible for the study developed basal cell carcinoma. Overall, aspirin and/or folic acid therapy had no significant effect on the development of basal cell carcinoma, although aspirin appeared to reduce the risk of further skin cancers in the small group who had been previously diagnosed with skin cancer. They conclude that the protective effect of aspirin against skin cancer is limited to individuals with a high risk of developing skin cancer.     

Pattern of skin cancer among Saudi patients attending a tertiary care center in Dhahran,Eastern Province of Saudi Arabia. A 20‐year retrospective study

Skin cancer is the ninth most common malignancy in Saudi Arabia. It represented 3.2% of all newly diagnosed cancer cases in the year 2010. The aim of this study was to determine the epidemiology of skin cancer in relation to age, sex, and anatomic location among Saudi patients attending the Johns Hopkins Aramco Healthcare center in Dhahran, Eastern province of Saudi Arabia. We retrospectively reviewed the surgical pathology records of Saudi nationals from 1995 to 2014 at the Johns Hopkins Aramco Healthcare center, which directly provides for the healthcare needs of Saudi Aramco company employees and dependents in the Eastern Province of Saudi Arabia. Tumor metastases to skin, skin involvement by primary breast carcinoma, and B‐cell leukemia/lymphoma with secondary involvement by skin were excluded. The total number of primary skin tumors was 204. The commonest cutaneous malignancies were basal cell carcinoma (36%) followed by squamous cell carcinoma (23%), with the head and neck being the commonest location for both tumors. Mycosis fungoides (MF) was the third most common malignancy (11%). Malignant melanoma was the fourth commonest skin malignancy (7%) with the lower extremities being the commonest location. The four most common skin cancers in our tertiary center in the Eastern Province of Saudi Arabia were squamous cell carcinoma, basal cell carcinoma, MF, and malignant melanoma. Other regions of Saudi Arabia report a similar pattern of skin cancers as our center, with MF having a higher frequency at our center.     

Lymphoma‐associated skin cancer: incidence,natural history,and clinical management

The link between immunosuppression and skin cancer has been well described. The two most common situations involving immunosuppression‐associated skin cancer are solid organ transplantation and non‐Hodgkin lymphoma (NHL), including chronic lymphocytic leukemia (CLL). Patients with lymphoma are more likely to have development of a secondary malignancy, with skin cancer being the most common. The most common types of skin cancer in patients with NHL/CLL include melanoma, squamous cell carcinoma, basal cell carcinoma, and Merkel cell carcinoma. Many skin cancers demonstrate increased aggressiveness in patients with NHL/CLL and are associated with higher recurrence rates, increased regional metastasis, and death secondary to skin cancer metastases. This review delineates the current research regarding the relationship between NHL/CLL and cutaneous malignancy. Immunosuppressed patients with skin cancer should be treated promptly and aggressively to decrease recurrence and metastases. Regular skin self‐examinations, dermatologic examinations, sun‐protective habits, and education may prove beneficial in this high‐risk patient population.     

The epidemiology of skin cancer

Summary Melanoma and non-melanoma (basal and squamous cell carcinoma) skin cancer (NMSC) are now the most common types of cancer in the white populations and the incidence of skin cancer has reached epidemic proportions. According to recent population-based studies from Australia the incidence rate is over 2% for basal cell carcinoma in males and 1% for squamous cell carcinoma, and there are over 50 new cases of melanoma per 100 000.     

Skin cancer in skin of color

Skin cancer is less common in persons with skin of color than in light-skinned Caucasians but is often associated with greater morbidity and mortality. Thus, it is crucial that physicians become familiar with skin cancer in persons of color so as to maximize the likelihood of early detection of these tumors. In dark-skinned ethnic groups, squamous cell carcinoma is most common; squamous cell carcinoma and melanoma usually occur on nonsun-exposed sites; and ultraviolet radiation is not an important etiologic factor for skin cancer with the exception of basal cell carcinoma. Races of intermediate pigmentation, such as Hispanics and Asians, share epidemiologic and clinical features of dark-skinned ethnic groups and Caucasians. Skin cancers pose a significant risk in skin of color and clinicians should focus on preventive measures in these groups such as regular skin exams, self-examination, public education, and screening programs. LEARNING OBJECTIVE: At the completion of this learning activity, participants should be familiar with the epidemiology and unique clinical features of skin cancer in skin of color and be aware of strategies to prevent skin cancer in skin of color.     

Oxidative stress in malignant melanoma and non-melanoma skin cancer

BACKGROUND: Solar ultraviolet (UV) radiation is considered to be a major aetiological factor in melanoma and non-melanoma skin cancer. A growing body of evidence indicates that oxidative stress is involved in photocarcinogenesis. However, in vivo data for human skin are still lacking. Reactive oxygen species participate in a number of pathophysiological processes including DNA damage and lipid peroxidation (LPO) and are considered to be a key factor in tumour progression. OBJECTIVES: We hypothesized that in human skin cancer the natural redox balance is disturbed and that this imbalance may result in an accumulation of LPO products. METHODS: To test this, skin biopsies of superficial spreading melanoma were compared with age-matched benign melanocytic naevi and young healthy controls. Additionally, non-melanoma skin cancers (basal cell carcinoma, squamous cell carcinoma) and actinic keratosis were investigated (n = 18 each). Expression of the antioxidant enzymes, copper-zinc superoxide dismutase, manganese superoxide dismutase and catalase was analysed by immunohistochemical techniques. To detect LPO products, protein-bound malondialdehyde (MDA) was visualized. RESULTS: In human melanoma biopsies, a significant overexpression of the antioxidant enzymes was found when compared with surrounding non-tumour tissue, benign melanocytic naevi, and young controls. Intriguingly, the LPO marker MDA was significantly increased in melanoma tissue. MDA was located not only in typical melanoma cells, but also occurred in surrounding keratinocytes. In contrast, a severely disturbed antioxidant balance with diminished antioxidant enzymes was found in non-melanoma tumours, whereas MDA was elevated only in squamous cell carcinomas. CONCLUSIONS: These findings indicate that oxidative stress may play different roles in the pathogenesis of human skin cancers. In non-melanoma skin cancer, a diminished antioxidant defence caused by chronic UV exposure might contribute to multistep carcinogenesis, whereas melanoma cells exhibit increased oxidative stress which could damage surrounding tissue and thus support the progression of metastasis.     

Prospective trial of curettage and cryosurgery in the management of non-facial, superficial, and minimally invasive basal and squamous cell carcinoma

Background As a variation of the curettage and destruction technique, cryosurgery can be used in place of electrodesiccation for the destructive component when managing superficial basal and squamous cell carcinomas. There are few studies, though, demonstrating the long‐term cure rate associated with similar methods. This study seeks to determine the long‐term cure rate associated with curettage and cryosurgery in the treatment of small, non‐facial, superficial basal and squamous cell carcinomas. Materials and methods Sixty‐nine patients with 100 non‐facial tumors, ≤2 cm in diameter, consisting of superficial basal cell carcinoma, superficial nodular basal cell carcinoma with papillary dermal invasion, squamous cell carcinoma in situ, and squamous cell carcinoma with papillary dermal invasion were prospectively treated with curettage and cryotherapy, and subsequently evaluated at 1‐ and 5‐year intervals. Results No tumor recurred after one year of follow‐up, and one recurrence occurred within the 5‐year interval, for a 99% recurrence‐free endpoint. Six patients died of unrelated causes after one year, and before five years, and were thus lost to follow‐up. Conclusions Curettage and cryosurgery is a simple, highly effective, and reliable treatment method for select, low‐risk non‐melanoma skin cancers.     

PTH‐independent hypercalcaemia and non‐melanoma skin cancer

Background Recently, it became more evident that skin is a target for neuroendocrine signals. Aims (1) To evaluate the relationship between tumour aggressiveness and hypercalcaemia in patients with non‐melanoma skin cancer; (2) to identify clinical, functional, biological alterations caused by this setting; (3) calcium redistribution from extracellular fluids to intracellular compartments; (4) to describe several molecular aspects of hypercalcaemia development. Materials and methods This study was conducted between January 2000 and May 2009 in Dermatoveneorological Center, Bucharest. From the 1232 cases that were investigated, there were 32 patients with keratoachantoma, 468 patients with basal cell carcinoma, 412 patients with squamous cell carcinoma and 320 healthy volunteers. All the patients were screened by clinical and paraclinical examinations (haematology, biochemistry, immunology). After biochemical confirmation of hypercalcaemia, patients had endocrine tests, electrocardiography and imagistic approaches. Total serum calcium was measured in extracellular fluids (serum, urine) by spectrophotometric methods. Ionized calcium was calculated depending on total serum calcium and total proteins. Corrected serum total calcium (cTCa) levels were calculated using albumin and total serum calcium levels. In tumour tissues and intact skin, calcium was assayed by physical methods of analysis: Instrumental Neutron Activation Analysis (INAA), Proton‐Induced X‐ray Emission (PIXE). Intact PTH was measured by ELISA. Results PTH‐independent hypercalcaemia prevalence is low in SCC patients (1.21%). Hypercalcaemia manifestations are multiple including: digestive, renal, neuromuscular, and cardiovascular abnormalities. In these patients, intact PTH (iPTH) is normal, urinary calcium is decreased, serum albumin is reduced, and calcium concentration in tumour tissue is significantly increased compared to healthy tissue. Conclusions PTH‐independent hypercalcaemia has a low prevalence in SCC patients. Hypercalcaemia is correlated with susceptibility to develop metastases in SCC. A possible mechanism is PTHrp hypersecretion by malignant keratinocytes.     

Epidermal urocanic acid concentration and photoisomerization reactivity in patients with cutaneous malignant melanoma or basal cell carcinoma.

The relationship of epidermal urocanic acid concentration and photoisomerization reactivity to human skin cancer was studied. Twelve cutaneous malignant melanoma patients, 10 basal cell carcinoma patients and 22 healthy matched controls were enrolled in the study. A solar simulating ultraviolet irradiator was used for phototesting the minimal erythema dose. Using the Finn Chamber technique, urocanic acid was sampled from the healthy skin of the upper back, prior to and after exposure to suberythemal UV doses. The mean values of total and trans-urocanic acid were higher in basal cell carcinoma patients than in controls, but this difference was not statistically significant. No corresponding phenomenon was evident in the case of cutaneous malignant melanoma patients and their controls. Photoisomerization induced by irradiation with 1 mJ/cm2 CIE (Commission Internationale de l'Eclairage) was statistically significantly lower in cutaneous malignant melanoma patients than in controls (p=0.04). A similar trend was seen in basal cell carcinoma patients vs. their controls, but the difference was not significant.     

UV‐Hauttumoren

In this review the epidemiology and pathogenetic aspects of UV‐induced malignant skin tumours (basal cell carcinoma, squamous cell carcinoma and melanoma) are discussed with regard to current literature. Whereas present knowledge, in particular, gained from experimental data, permits substantial conclusions about the development of squamous cell carcinoma, the situation for basal cell carcinoma and melanoma does not appear to be unequivocally clear. One reason for this can be explained by the fact that there exist no adequate animal models for these tumours that could exactly reflect the biological behaviour in man. Although there is no doubt about a causal role of sun exposure, this relationship is based on mere epidemiological facts.     

Sunscreen abuse for intentional sun exposure

Skin cancer is caused by exposure to ultraviolet radiation (UV) and the sun is the main source of this radiation. Sunscreens were initially formulated to prevent sunburns; laboratory studies later revealed that in rodents they could reduce UV-induced skin cancer which resembles human squamous cell carcinoma. Three randomized trials in older adults showed the ability of sunscreens to moderately reduce the occurrence of solar keratoses and of squamous cell carcinoma. However, no effect was observed for basal cell carcinoma. There is no animal model for human melanoma and observational studies often found sunscreen use associated with a higher risk of nevus, melanoma and basal cell carcinoma. These higher risks were found when sun exposure appeared to be intentional, that is, with the desire to acquire a tan, a healthy look or simply to spend as long as possible in the sun with as much skin exposed as possible. Three randomized trials showed that sunscreen use by sun sensitive subjects engaging in intentional sun exposure could increase the duration of exposure without decreasing sunburn occurrence. This increased duration could be the reason why melanoma risk is increased when sunscreen is used. Hence, sunscreen abuse may extend sun exposure duration thus allowing sun exposure behaviours that would not be possible otherwise. Advertising for sunscreens and labeling of sunscreen bottles should inform consumers of the carcinogenic hazards associated with sunscreen abuse. It would be good to use a personal UV dosimeter which would give an alert when one's individual sunburn threshold in the absence of sunscreen use is nearing. The combination of sunscreen and a UV dosimeter may be an option for reducing the melanoma risk among sun worshippers.     

Chemokine receptor expression in non-melanoma skin cancer

Background:  Previous studies suggest that chemokines and chemokine receptors have a role in the metastatic process. A correlation exists between the specific expression of these chemoattractive, pro-inflammatory cytokines and the ability of cancer to disseminate. Prior studies have shown that in metastatic melanoma and squamous cell carcinoma of the head and neck upregulation of CXC (α) chemokine receptor (CXCR)4 and CC (β) chemokine receptor (CCR)7 expression is accompanied by downregulation of the chemokine receptor CCR6. However, the expression patterns of CCR6, CCR7 and CXCR4 in non-melanoma skin cancer have yet to be elucidated.
Methods:  The expression patterns of CCR6, CCR7 and CXCR4 were determined using an immunohistochemical approach on formalin-fixed, paraffin-embedded normal, pre-cancerous actinic (solar) keratosis, squamous cell carcinoma and basal cell carcinoma tissues.
Results:  Analysis of chemokine receptor expression showed downregulation of CCR6 and upregulation of CCR7 and CXCR4 in potentially metastatic non-melanoma skin cancer, invasive squamous cell carcinoma, but this pattern did not exist in non-melanoma skin cancer with no metastatic potential, basal cell carcinoma; or actinic keratosis, when compared with normal skin.
Conclusions:  Chemokine receptor expression may influence the biological behavior of non-melanoma skin cancer. The exact mechanism by which this occurs requires further study.     

Results of second‐stage screening for skin cancers in Oita Prefecture,Japan

We performed skin cancer screenings for 2 or 3 days annually from 2006 through 2013 in Oita Prefecture, Japan. Screening of approximately 3000 people in total allowed us to identify and treat several skin cancers, including five cases of malignant melanoma, four of squamous cell carcinoma, 16 of basal cell carcinoma, 11 of Bowen's disease, 17 of actinic keratosis, one of extramammary Paget's disease and one of metastatic breast carcinoma. The sensitivity and specificity for the category defined by an identified lesion associated with risk of cancer and requiring further examination (category C) were 92.7% and 95%, respectively. We cannot estimate the outcome of our skin cancer screenings in terms of cancer mortality because of the small number of subjects examined and the brief follow‐up period. However, we did estimate the effectiveness of these screenings in terms of stages or sizes of cancerous lesions. The relative numbers of subjects with malignant melanoma at various clinical stages, identified during skin cancer screenings and during a routine visit to our hospital, were significantly different. We also compared, statistically, the sizes of lesions in Bowen's disease that were found during cancer screenings and during a direct visit to our hospital. The former lesions were smaller than the latter. Our data suggest the benefits of our skin cancer screenings and the importance of campaigns and education to encourage people to visit dermatologists for the detection of skin cancers at an early stage.     

The influence of painful sunburns and lifetime sun exposure on the risk of actinic keratoses,seborrheic warts,melanocytic nevi,atypical nevi,and skin cancer

Painful sunburns are implicated in the pathogenesis of squamous cell carcinoma, basal cell carcinoma, and malignant melanoma. Chronic exposure to ultraviolet radiation is known as the most important risk factor for the development of actinic keratoses and squamous cell carcinoma. The purpose of the study was to assess the effect of painful sunburns and lifetime sun exposure on the development of actinic keratoses and seborrheic warts in relation to the development of squamous cell carcinoma and basal cell carcinoma, and on the development of melanocytic nevi and atypical nevi in relation to the development of malignant melanoma. We made use of a cohort of 966 individuals who participated in a case-control study to investigate environmental and genetic risk factors for skin cancer. Exposure measurements for sunlight were collected and actinic keratoses, seborrheic warts, melanocytic nevi, and atypical nevi were counted. Relative risks were estimated using exposure odds ratios from cross-tabulation. Multivariate logistic regression was used to adjust for potential confounders. The recall of painful sunburns before the age of 20 y was associated with an increased risk of squamous cell carcinoma, nodular basal cell carcinoma, and multifocal superficial basal cell carcinoma as well as actinic keratoses. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.5 (0.97; 2.3); 1.6 (1.1; 2.2); 2.6 (1.7; 3.8); and 1.9 (1.4; 2.6) for the three types of nonmelanoma skin cancer and actinic keratoses, respectively. Painful sunburns before the age of 20 y were also associated with an increased risk of malignant melanoma and the development of its precursors, melanocytic nevi and atypical nevi. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.4 (0.86; 2.1); 1.5 (1.1; 2.0); and 1.4 (0.88; 2.3) for malignant melanoma and the two types of precursors, respectively. Lifetime sun exposure was predominantly associated with an increased risk of squamous cell carcinoma (p-value for trend=0.03) and actinic keratoses (p-value for trend <0.0001) and to a lesser degree with the two types of basal cell carcinoma. By contrast, lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma, despite the fact that lifetime sun exposure did not diminish the number of melanocytic nevi or atypical nevi. Neither painful sunburns nor lifetime sun exposure were associated with an increased risk of seborrheic warts.