Putative cancer stem cells in cutaneous malignancies

Recent experimental data offer convincing evidence for the existence of cancer stem cells in leukaemia, brain tumors and breast cancer. These cells are responsible for the maintenance of tumor growth and relapses after cytoreductive treatments. This paper provides a brief overview of current data supporting the idea of cancer stem cells in the pathogenesis of cutaneous malignancies, including skin carcinoma, malignant melanoma and cutaneous T-cell lymphoma. The characterization of putative cancer stem cells is important to develop new therapies selectively targeting these cells.     

Therapeutic potential of the anti‐diabetic agent metformin in targeting the skin cancer stem cell diaspora

Type II diabetes is associated with increased prevalence of cancer including both melanoma and squamous cell carcinoma (SCC) of the skin. Emerging evidence from epidemiological studies suggest that diabetic patients on metformin have a lower risk of cancer incidence and mortality in a broad range of neoplasms. In both melanoma and SCC, populations of cancer stem cells (CSC) contribute to tumor initiation and metastasis. We propose that metformin constitutes a new class of targeted therapy that acts on the skin CSC diaspora. We posit that metformin selectively and simultaneously targets CSCs of the primary tumor as well as in metastatic niches thereby disrupting the dynamic dispersal of circulating CSCs between the primary tumor and metastatic site. This hypothesis suggests a new concept in dermato‐oncology that treatment of type II diabetes and prevention of skin cancer are two sides of the same coin.     

Epidemiology of non-melanoma skin cancer and solar keratoses in Australia: a tale of self-immolation in Elysian fields

Non-melanoma skin cancers (NMSC) are the commonest cancers in Australia. Their incidence rate is more than three times the rate of all other cancers combined. The incidence rate continues to rise to a stage where they now affect at least 1% of the population annually, necessitating treatment of more than 150,000 people per year. Exposure to sunlight in susceptible people appears to be the major environmental carcinogen in causation of these tumours. The exact nature of sunlight exposure necessary to induce them is still not entirely clear. Childhood exposure to sunlight stands out as being the major contributor to the development of all the common skin cancers. Solar keratoses are risk factors for NMSC and are precursors of squamous cell carcinoma. They appear to be more sensitive measures of carcinogenic sunlight exposure than frank invasive tumours. They are labile, and fluctuate in appearance clinically over time. Regular use of sunscreen can prevent new solar keratoses and increase clinical remission in existing ones. This is early evidence of the value of regular and adequate photoprotection in the long-term reduction of NMSC in Australia.     

The role of radiotherapy in the management of non-melanoma skin cancer

The global incidence of non-melanoma skin cancer continues to increase as the global population ages with the highest incidence in the world occurring in Australian and New Zealand patients. There are numerous treatment options available for non-melanoma skin cancer patients of which radiotherapy is an efficacious and versatile tissue preserving non-surgical (or medical) option. In patients where excision may not be an option (medically/technically inoperable) or considered less ideal (e.g. cosmetic outcome), radiotherapy offers an excellent option. Following surgery, adjuvant radiotherapy in patients with unfavourable pathology can decrease the risk of recurrence and associated morbidity. Elderly and co-morbid patients with poor performance status can benefit from short-course hypofractionated radiotherapy in the setting where surgery is not an option. As with any modality, radiotherapy has advantages and disadvantages and it is therefore important for clinicians to appreciate these. We aim to present an update for clinicians that manage patients with non-melanoma skin cancer on the role of radiotherapy.     

Epidemiology of nonmelanoma skin cancer (NMSC) in Europe: accurate and comparable data are needed for effective public health monitoring and interventions

Summary Nonmelanoma skin cancer (NMSC) is the most common malignancy occurring in white populations. It is currently becoming an important challenge in terms of public health management as the increasing incidence rates will probably have a tremendous impact on healthcare costs. Possible factors driving this rise in NMSC numbers are increases in both acute and prolonged UV exposure together with increasing numbers of older people in the population. A better understanding of NMSC epidemiology in Europe is essential if an evidence-based European-wide public health policy is to be developed. It is obvious this can only be achieved by recording and analysing comparative epidemiological data. Finally, by improving the skin examination training for physicians, developing guidelines and exchanging best practices, a high level of healthcare could be provided for NMSC.     

Changing trends in non-melanoma skin cancer in South Wales, 1988-98

BACKGROUND: In 1988 our department carried out a population-based epidemiological study of non-melanoma skin cancer (NMSC) incidence, over a 6-month period, in West Glamorgan, South Wales. Objectives To reassess the incidence of NMSC in this defined population over a similar 6-month period 10 years after the initial study. METHODS: All cases of basal cell carcinoma and squamous cell carcinoma diagnosed in West Glamorgan are recorded by the local skin cancer registry. All cases for the relevant 6-month period were analysed. RESULTS: Using these figures, we have identified a significant rise in the crude incidence of NMSC from 173.5 10 years ago to 265.4 per 100,000 population per annum. We also applied the world standard population for age to our crude figures, demonstrating a combined male and female world population-corrected rate of 129.9 per 100,000 population. CONCLUSIONS: In our population the crude incidence of NMSC has risen significantly over 10 years. Additionally, the combined male and female world population-corrected rate appears to be the highest published standardized incidence of NMSC to date from any European country.     

Organ transplantation and skin cancer: basic problems and new perspectives

Please cite this paper as: Organ transplantation and skin cancer: basic problems and new perspectives. Experimental Dermatology 2010; 19: 473–483. Abstract: Solid organ transplant and subsequent graft survival have increased worldwide, while immunosuppression has prevented rejection with increasing success. Side effects of cutaneous infection and neoplasm, however, affect the majority of solid organ transplant recipients (OTRs). Squamous cell carcinoma of the skin (SCC) is the most common neoplasm overall following organ transplant with a risk that is 60–100 times greater than for the immunocompetent population. This review focuses on questions of ongoing debate about SCC formation in OTRs such as viral carcinogenesis, systemic photoprotection, photosensitization by drugs, the impact of immunosuppressive drugs and inflammation as a driver of carcinogenesis.     

Case–control study of chronic low‐level exposure of inorganic arsenic species and non‐melanoma skin cancer

A significant relationship between arsenic exposure and non‐melanoma skin cancer (NMSC) is well known. The toxicity of arsenics which develop NMSC is dependent on their species. Accordingly, total arsenic levels are unreliable for risk assessment of NMSC. However, there are few studies on quantitative exposure assessment of arsenic species in NMSC patients. To validate the contribution of each arsenic species to NMSC, we compared the creatinine‐adjusted urinary concentration of arsenic species in NMSC patients and community controls. A total of 124 biopsy‐proven NMSC cases and 125 age‐ and sex‐matched community controls, drinking tap water with low‐level arsenic concentration (<5 μg/L), were included in the study. High‐performance liquid chromatography and inductively coupled plasma mass spectrometry were used for the measurement. The NMSC group was found to have significantly higher levels of total inorganic arsenic, trivalent and pentavalent arsenic and monomethylarsonic acid than the control group. Total arsenic, organic arsenic and dimethylarsonic acid levels were lower in the NMSC group. We suggest that inorganic arsenic species, trivalent arsenic and pentavalent arsenic may influence the prevalence of NMSC, in spite of these levels being lower than the Agency for Toxic Substances and Disease Registry‐recommended standard or the levels reported by other highly contaminated areas and neighboring countries in East Asia. Furthermore, it also suggests that total arsenic level cannot represent the risk of NMSC.     

Systematic comparison of nonmelanoma skin cancer microarray datasets reveals lack of consensus genes

Summary Background DNA microarray technology has revealed vast numbers of gene expression alterations associated with human malignancies. Assigning validity and biological significance to these changes, however, remains a considerable hurdle. Recently, microarray analysis has been applied to the study of nonmelanoma skin cancer. Objectives To compare experimental data rigorously in order to strengthen conclusions regarding the pathogenesis of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), and to evaluate systematically the experimental and statistical parameters that may impact the degree of consensus among differentially expressed genes (DEGs) between studies. Methods We performed a systematic comparison of 10 studies that applied DNA microarray technology to study BCC/SCC. Results A total of 1133 DEGs collectively reported across the studies were compared, and 64 DEG overlaps were found: 18 DEG overlaps in SCC vs. SCC study comparisons, 18 DEG overlaps in BCC vs. BCC study comparisons and 28 DEG overlaps in BCC vs. SCC study comparisons. We documented differences in several experimental methods that may account for the relative lack of consensus between studies, including sample type, tissue procurement/handling, microarray chip and statistical analysis. The two most dysregulated biological pathways across all studies involved genes with enzymatic and structural/adhesion functions. Conclusions DEGs that were found to overlap across two or more studies and biological pathways with the largest representation of DEGs across studies may be particularly relevant to disease pathogenesis and serve as targets for future therapy. In future work, more consistent experimental methods across laboratories may improve the validity of reported DEGs and strengthen conclusions drawn from microarray data.     

Patient experiences and outcomes following facial skin cancer surgery: A qualitative study

Early melanoma and non‐melanoma skin cancer of the facial area are primarily treated with surgery. Little is known about the outcomes of treatment for facial skin cancer patients. The objective of the study was to identify concerns about aesthetics, procedures and health from the patients' perspective after facial skin surgery. Semi‐structured in‐depth interviews were conducted with 15 participants. Line‐by‐line coding was used to establish categories and develop themes. We identified five major themes on the impact of skin cancer surgery: appearance‐related concerns; psychological (e.g., fear of new cancers or recurrence); social (e.g. impact on social activities and interaction); physical (e.g. pain and swelling) concerns and satisfaction with the experience of care (e.g., satisfaction with surgeon). The priority of participants was the removal of the facial skin cancer, as this reduced their overall worry. The aesthetic outcome was secondary but important, as it had important implications on the participants' social and psychological functioning. The participants' experience with the care provided by the surgeon and staff also contributed to their satisfaction with their treatment. This conceptual framework provides the basis for the development of a new patient‐reported outcome instrument.     

皮肤间充质干细胞在促进皮肤愈合中的作用

间充质干细胞(mesenchymal stem cells,MSCs)是当前干细胞研究的热点之一。目前,皮肤愈合正逐渐受到重视。现有的研究认为骨髓间充质干细胞(BM-MSCs)能从多个方面促进皮肤愈合,如促进表皮生长、促进真皮成纤维细胞的增生等。皮肤间充质干细胞(SMSCs)和BM-MSCs均为MSCs,具有很多的相似性,且SMSCs较BM-MSCs更容易得到。所以可从目前对BM-MSCs的研究预测到SMSCs在皮肤创伤愈合中的研究前景,且将来很可能会替代BM-MSCs。     

Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey

BACKGROUND: Reduction of immunosuppression is considered a reasonable adjuvant therapeutic strategy in solid-organ transplant recipients experiencing multiple or high-risk skin cancers. However, the literature provides no guidance about what threshold of cancer development would warrant initiation of reduction of immunosuppression. OBJECTIVES: To develop expert consensus guidelines for initiation of reduction of transplant-associated immunosuppression for solid-organ transplant recipients with severe skin cancer. METHODS: An expert consensus panel was convened by the International Transplant Skin Cancer Collaborative and Skin Care for Organ Transplant Patients Europe Reduction of Immunosuppression Task Force. Thirteen hypothetical patient scenarios with graduated morbidity and mortality risks were presented and mean and mode expert opinions about appropriate level of reduction of systemic immunosuppression (mild, moderate, severe) were generated. RESULTS: Mild reduction of transplant-associated immunosuppression was considered warranted once multiple skin cancers per year developed or with individual high-risk skin cancers. Moderate reduction was considered appropriate when patients experienced > 25 skin cancers per year or for skin cancers with a 10% 3-year risk of mortality. Severe reduction was considered warranted only for life-threatening skin cancers. CONCLUSIONS: Reduction of immunosuppression is considered a reasonable adjuvant management strategy for transplant recipients with numerous or life-threatening skin cancers. Proposed guidelines are presented for the graduated reduction of immunosuppression coincident with the increasing skin cancer risks.     

Incidence and prevalence of non‐melanoma skin cancer in Australia: A systematic review

Non‐melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is the most common cancer occurring in people with fair skin. Australia has been reported to have the highest incidence of NMSC in the world. Using a systematic search of the literature in EMBASE and Medline, we identified 21 studies that investigated the incidence or prevalence of NMSC in Australia. Studies published between 1948 and 2011 were identified and included in the analysis. There were six studies that were conducted on national level, two at state level and 13 at the regional level. Overall, the incidence of NMSC had steadily increased over calendar‐years in Australia. The incidence of NMSC per 100 000 person‐years was estimated to be 555 in 1985; 977 in 1990; 1109 in 1995; 1170 in 2002 and 2448 in 2011. The incidence was higher for men than women and higher for BCC than SCC. Incidence varied across the states of Australia, with the highest in Queensland. The prevalence of NMSC was estimated to be 2% in Australia in 2002. The incidence and prevalence of NMSC still need to be accurately established at both national and state levels to determine the costs and burden of the disease on the public health system in Australia.     

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.     

Occupational exposure to non‐artificial UV‐light and non‐melanocytic skin cancer – a systematic review concerning a new occupational disease

Background: Although UV exposure is the most important risk factor for cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), a systematic review analyzing the risk of occupational UV exposure is missing. Methods: Based on a systematic literature search in PubMed (until 05/2009) supplemented by hand search, the association between occupational UV exposure and SCC and BCC was analyzed. Literature search and data abstraction was done independently by 2 reviewers. The association between occupational UV exposure and cancer risk is presented as odds ratios (OR). Results: We identified 25 relevant epidemiologic studies (5 cohort studies, 17 case‐control studies, 3 cross‐sectional studies). 12 studies described a positive association between occupational UV exposure and risk of SCC with OR > 3 in 6 studies and OR 1.5–2.0 in another 6 studies. 3 studies did not find a relevant association (OR: 1.0–1.4). A significant positive association between occupational UV exposure and BCC was reported in 5 studies; 11 studies did not find a significant association. Conclusions: The association between occupational UV exposure and SCC is well and consistently documented epidemiologically (approximately 2‐fold increased risk), so that the criteria for a new occupational disease are fulfilled. The association with BCC is unclear due to significant methodological limitations in the published studies.