Skin Cancer
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Skin cancer is the most common type of cancer and accounts for half of all new cancers in Western populations. It occurs more often in people with light coloured skin who have had a high exposure to sunlight. The two most frequent types of skin cancer are Basal Cell Carcinomas and Squamous Cell Carcinoma (often grouped under "non-melanoma skin cancer"). The third most frequent skin cancer is Melanoma, this is a malignancy of the cells which give the skin it's colour (melanocytes). In addition there are a number of other, less common cancers starting in the skin including Merkel cell tumours, cutaneous lymphomas, and sarcomas (see the pages on sarcoma and lymphoma in this guide).

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Prevention of Skin Cancer
Non Melanoma Skin Cancer
-- Basal Cell Carcinoma
-- Squamous Cell Carcinoma
Cutaneous T-cell Lymphoma
Dermatofibrosarcoma Protuberans
Merkel Cell Cancer

Information Patients and the Public (10 links)

Information for Health Professionals / Researchers (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Esmer O, Karadag R, Bayramlar H, et al.
Bilateral lower eyelid basosquamous cell carcinoma: a rare case.
J Pak Med Assoc. 2014; 64(7):837-9 [PubMed] Related Publications
Basosquamous cell carcinoma is a subtype of basal cell cancer. It is known to be more aggressive than basal cell cancer. A 70-year-old male patient was admitted to our clinic for evaluation of cosmetic problems caused by masses on both lower eyelids for at least two years. The mass excision from and reconstruction of lower eyelids were performed. Histopathological examination of the resected masses was consistent with basosquamous cell carcinoma. We present a case of basosquamous cell carcinoma involving bilateral lower eyelids with a different clinical appearance. To the best of our knowledge, this is the first report of bilateral basosquamous cell carcinoma in a patient.

O'Kane GM, Lyons T, McDonald I, et al.
Vismodegib in the treatment of advanced BCC.
Ir Med J. 2014 Jul-Aug; 107(7):215-6 [PubMed] Related Publications
Basal-cell carcinoma (BCC) is the most commonly diagnosed malignancy, comprising over 80 per thousand of non-melanoma skin cancers. Surgical excision is adequate treatment for most BCC's. Options are however limited for the minority of patients presenting with locally advanced inoperable or metastatic BCC. The Hedgehog signalling pathway is a critical driver in the pathogenesis of both sporadic and hereditary BCC. On 31st January 2012, based on a phase II clinical trial the US Food and Drug Administration approved Vismodegib (Erivedge, Roche) a first-in-class, small-molecule oral Hedgehog-inhibitor for the treatment of locally advanced inoperable and metastatic BCC. We present our experience treating the first Irish patient with this agent.

Related: Basal Cell Carcinoma

Gbabe OF, Okwundu CI, Dedicoat M, Freeman EE
Treatment of severe or progressive Kaposi's sarcoma in HIV-infected adults.
Cochrane Database Syst Rev. 2014; 8:CD003256 [PubMed] Article available free on PMC after 13/08/2015 Related Publications
BACKGROUND: Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients.
OBJECTIVES: To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.
SELECTION CRITERIA: Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.
DATA COLLECTION AND ANALYSIS: Two review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens.
MAIN RESULTS: We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non-statistically significant overall mortality benefit from liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events.
AUTHORS' CONCLUSIONS: The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between liposomal doxorubicin, liposomal daunorubicin and paclitaxel.

Related: Bleomycin Doxorubicin Etoposide Kaposi Sarcoma Vincristine

Greinert R, Breitbart EW, Mohr P, Volkmer B
Health initiatives for the prevention of skin cancer.
Adv Exp Med Biol. 2014; 810:485-99 [PubMed] Related Publications
Skin cancer is the most frequent type of cancer in white population worldwide. However, because the most prominent risk factor-solar UV-radiation and/or artificial UV from sunbeds-is known, skin cancer is highly preventable be primary prevention. This prevention needs, that the public is informed by simple and balanced messages about the possible harms and benefits of UV-exposure and how a person should behave under certain conditions of UV-exposure. For this purpose information and recommendations for the public must be age- and target-group specific to cover all periods of life and to reach all sub-groups of a population, continuously. There is a need that political institutions together with Health Institutions and Societies (e.g., European Commission, WHO, EUROSKIN, ICNIRP, etc.), which are responsible for primary prevention of skin cancer, find a common language to inform the public, in order not to confuse it. This is especially important in connection with the ongoing Vitamin D debate, where possible positive effects of UV have to be balanced with the well known skin cancer risk of UV. A continuously ongoing evaluation of interventions and programs in primary prevention is a pre-requisite to assess the effectiveness of strategies. There is surely no "no message fits all" approach, but balanced information in health initiatives for prevention of skin cancer, which use evidence-base strategies, will further be needed in the future to reduce the incidence, morbidity and mortality skin cancer.

Jou PC, Tomecki KJ
Sunscreens in the United States: current status and future outlook.
Adv Exp Med Biol. 2014; 810:464-84 [PubMed] Related Publications
Incidence rates of nonmelanoma skin cancer and melanoma has been on the rise in the United States for the past 20 years. UV radiation (UVR) exposure remains the most preventable environmental risk factor for these cancers. Aside from sun avoidance, sunscreens remain our best protection. UVR directly damages DNA and cause indirect cellular damage through the creation of reactive oxygen species, the sum of which leads to cutaneous immunosuppression and a tumorigenic milieu. The current generation of sunscreens protect from UVR through two main mechanisms: absorption and deflection. In the US, new Food and Drug Association rules require sunscreen manufacturers to evaluate their products not only on sun protection factor but also on broad spectrum UVA protection by the end of 2013. New labeling requirements will also be instituted. The American Academy of Dermatology and the American Academy of Pediatrics have provided specific recommendations for proper sun protection and sunscreen usage. Plant polyphenols such as those isolated from green tea, pomegranate, and grape seed remain an interesting avenue of research as additives to sunscreens or stand-alone products that appear to modulate the immunosuppressive effects of UVR on the skin. Additionally, although UVR induces endogenous cutaneous production of vitamin D, its damaging effects overshadow this positive benefit, especially in light of the ease of achieving recommended amounts of vitamin D through diet and supplementation.

Related: Melanoma USA

Bens G
Adv Exp Med Biol. 2014; 810:429-63 [PubMed] Related Publications
Sunscreens have become since more than 40 years the most popular means of protection against UV radiation (UVR) in Western countries. Organic and inorganic filters with different absorption spectrum exist. They filter or scatter UVR. Protection from UVB is quantified as a minimal erythema dose-based sun protection factor. UVA protection testing is less standardized: Persistent pigment darkening and critical wavelength are currently used methods. Marketing and labeling of sunscreens underlay national regulation which explains major differences between the European and the US sunscreen market. Sunscreens are most performing in sunburn prevention. Broad spectrum UVB and UVA protection and regular application in sufficient amounts are essential for prevention of skin cancers, UV-induced immunosuppression, and skin aging. A significant benefit from regular sunscreen use has not yet been demonstrated for primary prevention of basal cell carcinoma and melanoma. Concerning the prevention of actinic keratoses, squamous cell carcinomas, and skin aging, the effect of sunscreens is significant, but it remains incomplete. Some organic UV filters (PABA derivatives, cinnamates, benzophenones, and octocrylene) have been described to cause photoallergy. Percutaneous absorption and endocrine disrupting activity of small-sized organic and nano-sized inorganic UV filters have been reported. On lesional skin and in pediatric settings, these products should be used with caution. Cutaneous vitamin D synthesis depending on skin-carcinogenic UVB radiation, the potential risk of vitamin D deficiency by sunscreen use has become a major subject of public health debate. Sunscreens indeed impair vitamin D synthesis if they are used in the recommended amount of 2 mg/cm2, but not in lesser thickness below 1.5 mg/cm2 that corresponds better to what users apply in real life conditions. Large molecular last generation UVB-UVA broad spectrum sunscreens have a better benefit-risk ratio than former organic filters: They offer better protection in the UVA band, they are non toxic and non allergenic. A better outcome of sunscreen efficacy especially in primary skin cancer prevention may be achieved with these molecules.

Related: Squamous Cell Carcinoma - Skin Cancer

Moan J, Grigalavicius M, Dahlback A, et al.
Ultraviolet-radiation and health: optimal time for sun exposure.
Adv Exp Med Biol. 2014; 810:423-8 [PubMed] Related Publications
Positive as well as negative health effects of exposure of human skin to UV radiation depend on spectra and fluence rates, both of which being dependent on latitude, time of the day and several other factors. The major positive effects are related to vitamin D photosynthesis and the major negative effect is skin cancer development. The action spectra for these effects are different. This lead us to conclude that for optimal vitamin D synthesis at minimal risk of cutaneous malignant melanoma (CMM), the best time for sun exposure is between 10 a.m. and 1 p.m. Thus, the common health recommendation (that sun exposure should be avoided between the hours of 10 a.m. and 4 p.m. and postponed to the afternoon) may be wrong.

Related: Melanoma

Webb AR, Engelsen O
Ultraviolet exposure scenarios: risks of erythema from recommendations on cutaneous vitamin D synthesis.
Adv Exp Med Biol. 2014; 810:406-22 [PubMed] Related Publications
Exposure to sunlight is a major source of vitamin D for most people yet public health advice focuses overwhelmingly on avoiding exposure of unprotected skin because of the risks oferythema and skin cancer. We have calculated the exposure required to gain a number of proposed oral-equivalent doses of vitamin D, as functions of latitude, season, skin type and skin area exposed, together with the associated risk of erythema, expressed in minimum erythema doses. The model results show that the current recommended daily intake of 400 IU is readily achievable through casual sun exposure in the midday lunch hour, with no risk of erythema, for all latitudes some of the year and for all the year at some (low) latitudes. At the higher proposed vitamin D dose of 1000 IU lunchtime sun exposure is still a viable route to the vitamin, but requires the commitment to expose greater areas of skin, or is effective for a shorter period of the year. The highest vitamin D requirement considered was 4000 IU per day. For much of the globe and much of the year, this is not achievable in a lunchtime hour and where it is possible large areas of skin must be exposed to prevent erythema. When the only variable considered was skin type, latitudinal and seasonal limits on adequate vitamin D production were more restrictive for skin type 5 than skin type 2.

Reichrath J, Reichrath S
Sunlight, vitamin D and malignant melanoma: an update.
Adv Exp Med Biol. 2014; 810:390-405 [PubMed] Related Publications
Solar radiation represents an essential requirement for life, not only by spending the thermal energy for photosynthesis in plants, which provides our atmosphere with oxygen, but also by facilitating the cutaneous synthesis of vitamin D in vertebrates and many other organisms. It is well known that humans and most vertebrates have to obtain an adequate source of vitamin D, in order to develop and maintain a healthy mineralized skeleton and in order to be protected against cancer and a broad variety of other diseases. On the other hand, solar UV radiation can be assumed to be the most relevant environmental carcinogen causing melanoma and nonmelanoma skin cancer with increasing incidences. During the last decades, epidemiological studies and experimental animal models, including genetically engineered mice, the Xiphophorus hybrid fish, the south american oppossum and human skin xenografts, have further elucidated the multi-step process of UV-induced melanomagenesis. It has to be emphasized that, in contrast to intermittent, short-term high-dose solar UV-exposure, more chronic less intense exposure (which is recommended by many experts in the field to obtain a sufficient vitamin D status) has not been found to be a risk factor for the development of melanoma and in fact has been found in several studies to be protective. Interestingly, several independent lines of investigation have demonstrated convincing evidence that vitamin D and/or analogs may be effective in the prevention and treatment of melanoma. This essay summarizes our present understanding about the pathogenic role of UV radiation and of vitamin D for malignant melanoma.

Related: Melanoma

Juzeniene A, Baturaite Z, Moan J
Sun exposure and melanomas on sun-shielded and sun-exposed body areas.
Adv Exp Med Biol. 2014; 810:375-89 [PubMed] Related Publications
Malignant melanoma is a tumor that arises from melanocytes and accounts for around 4% of all malignancies in Europe and Northern America and for about 11% in Australia and New Zealand. About 10% of primary melanomas arise from sites not exposed to sun. Acral lentiginous melanoma, mucosal melanoma (in the oral cavities, nasal sinuses, genital tract and rectum) and uveal melanoma are all on non-sun-exposed tissues. Epidemiologic aspects ofmelanomas on non-sun-exposed areas in comparison with melanomas in sun-exposed areas have been reviewed. We focus on the relationship between melanoma incidence, geographic latitude of residence, race/ethnicity and host factors as well as time trends.

Related: Australia Melanoma

Moan JE, Baturaite Z, Dahlback A, Porojnicu AC
Ultraviolet radiation and cutaneous malignant melanoma.
Adv Exp Med Biol. 2014; 810:359-74 [PubMed] Related Publications
Essential features of the epidemiology and photobiology of cutaneous malignant melanoma (CMM) in Norway were studied in comparison with data from countries at lower latitudes. Arguments for and against a relationship between ultraviolet radiation (UV) from sun and artificial light and CMM are discussed. Our data indicate that UV is a carcinogen for CMM and that intermittent exposures are notably melanomagenic. This hypothesis was supported both by latitude gradients, by time trends and by changing patterns of tumor density on different body localizations. However, even though UV radiation generates CMM, it may also have a protective action and/or an action that improves prognosis. There appears to be no, or even an inverse latitude gradient for CMM arising on non-UV exposed body localizations (uveal melanoma, CMMs arising in the vulva, perianal/anorectal regions, etc.). Furthermore, CMM prognosis was gradually improved over all years of increasing incidence (up to 1990), but during the past 20 years, incidence rates stabilized and prognosis was not improved significantly. Comparisons of skin cancer data from Norway, Australia and New Zealand indicate that squamous cell carcinoma and basal cell carcinoma are mainly related to annual solar UVB fluences, while UVA fluences play a larger role of CMM.

Related: Australia Basal Cell Carcinoma Squamous Cell Carcinoma - Skin Cancer Melanoma

Berwick M, Pestak C, Thomas N
Solar ultraviolet exposure and mortality from skin tumors.
Adv Exp Med Biol. 2014; 810:342-58 [PubMed] Related Publications
Solar UV radiation (UVR) exposure is clearly associated with increased mortality from nonmelanoma skin cancer--usually squamous cell carcinoma. However, the association with cutaneous melanoma is unclear from the evidence in ecologic studies and several analytic studies have conflicting results regarding the effect of high levels of intermittent UV exposure prior to diagnosis on mortality. Understanding this conundrum is critical to present coherent public health messages and to improve the mortality rates from melanoma.

Related: Squamous Cell Carcinoma - Skin Cancer Melanoma

Albert B, Hahn H
Interaction of hedgehog and vitamin D signaling pathways in basal cell carcinomas.
Adv Exp Med Biol. 2014; 810:329-41 [PubMed] Related Publications
Basal Cell Carcinomas (BCCs) are the most commonly diagnosed tumors among people in the western world. Most BCCs are caused by mutational inactivation of the tumor suppressor Patched (PTCH), which results in activation of Smoothened (SMO) and of the Hedgehog (HH) signaling pathway. Recent studies indicate that BCC progression involves a crosstalk between Hh signaling, vitamin D derivatives and the vitamin D receptor (Vdr) signaling pathway. This has been demonstrated in BCC-bearing Ptch mutant mice and BCC cell lines, in which both vitamin D3 and its active metabolite calcitriol (1alpha-25(OH)2D3) exert antitumor effects. Interestingly, the antitumor effects are mainly ascribed to an inhibition of Hh signaling. Furthermore, as evident from studies in Vdr deficient mice, calcitriol may also repress the activity of Hh signaling in a Vdr-dependent fashion thereby establishing an additional inhibitory feedback on Hh signaling activity. In this chapter, we discuss the current understanding and controversial findings of the inhibition of Hh signaling by vitamin D derivatives and the implication of these findings for BCC carcinogenesis.

Related: Basal Cell Carcinoma Signal Transduction

Bikle DD
The vitamin D receptor: a tumor suppressor in skin.
Adv Exp Med Biol. 2014; 810:282-302 [PubMed] Related Publications
Cutaneous malignancies including melanomas and non melanoma skin cancers (NMSC) are the most common types of cancer, occurring at a rate of over 1 million per year in the United States. The major cell in the epidermis, the keratinocyte, not only produces vitamin D but contains the enzymatic machinery to metabolize vitamin D to its active metabolite, 1,25(OH)2D, and expresses the receptor for this metabolite, the vitamin D receptor (VDR), allowing the cell to respond to the 1,25(OH)2D that it produces. In vitro, 1,25(OH)2D stimulates the differentiation and inhibits the proliferation of these cells and so would be expected to be tumor suppressive. However, epidemiologic evidence demonstrating a negative relationship between circulating levels of the substrate for CYP27B1, 25OHD, and the incidence of these malignancies is mixed, raising the question whether vitamin D is protective in the in vivo setting. UV radiation (UV), both UVB and UVA, as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVB is also required for vitamin D synthesis in the skin. This complicates conclusions reached from epidemiologic studies in that UVB is associated with higher 25OHD levels as well as increased incidence of cutaneous malignancies. Based on our own data and that reported in the literature we hypothesize that vitamin D signaling in the skin suppresses UVR induced epidermal tumor formation. In this chapter we will first discuss recent data regarding potential mechanisms by which vitamin D signaling suppresses tumor formation, then focus on three general mechanisms that mediate tumor suppression by VDR in the skin: inhibition of proliferation and stimulation of differentiation, immune regulation, and stimulation of DNA damage repair (DDR).

Related: Signal Transduction

Vogt T
Therapy of metastatic malignant melanoma: on the way to individualized disease control.
Adv Exp Med Biol. 2014; 810:272-81 [PubMed] Related Publications
After decades of therapeutic frustration, the identification of some fundamental molecular drivers finally set the stage for the development of targeted therapies of metastatic malignant melanoma. With the invention of B-RAF inhibitors, targeting the mutated and activated B-RAF molecule in the MAP kinase cascade, objective responses can be achieved in about 50% of those cases harbouring this specific mutation. However, the effects are often short-lived with an average duration of 5-6 months. Hence, the challenge is to make such remissions stable and prevent secondary resistance. Currently, both the combination of targeted drugs and the invention of effective immunomodulating antibodies, e.g., anti-CTLA4 as well as anti-PD1, hold great promise to proceed on the way to individualized disease control, if not, as a remote aim, cure of this deadly cancer. Finally, progress has been made in identification and targeting of cancer stem cells, which seem to exhibit a kind of primary drug resistance and create the source of relapses and growth of clones with acquired secondary drug resistance.

Related: BRAF gene PDCD1

Reichrath J
Solar ultraviolet radiation, vitamin D and skin cancer surveillance in organ transplant recipients (OTRs): an update.
Adv Exp Med Biol. 2014; 810:253-71 [PubMed] Related Publications
During the last decades, the annual numbers of performed solid organ transplants have continuously increased world-wide. Solid organ transplant recipients (OTR) have a greater risk to develop malignancies, with skin cancer representing the most common neoplasia. Additionally, OTRs in general develop a more aggressive form of malignancies. In consequence, dermatologic surveillance is of high importance for OTRs and these patients represent an increasing and significant challenge to clinicians including dermatologists. In OTRs, patient and organ survival have increased considerably and continuously over the past two decades as a result of better immunosuppressive regimens and better posttransplant care. Great progress has been made in our understanding that individual immunosuppressive regiments differ in their effect on skin cancer risk in OTRs, and that effects of individual immunosuppressive regiments on skin cancer risk depend on various other factors including viral infections. Since sunlight is the major source of vitamin D for most humans, OTRs, who have to protect themselves consequently against solar or artificial UV radiation, are at high risk of developing vitamin D deficiency. Vitamin D deficiency is not only associated with increased risk for metabolic bone disease, but with other severe health problems including various types of malignancies. As a consequence, screening for and treatment of vitamin D deficiency is warranted in OTRs. In this review, we give an update on our present understanding of skin cancer surveillance in OTRs.

Related: Basal Cell Carcinoma Squamous Cell Carcinoma - Skin Cancer

Emmert S, Schön MP, Haenssle HA
Molecular biology of basal and squamous cell carcinomas.
Adv Exp Med Biol. 2014; 810:234-52 [PubMed] Related Publications
The prevalent keratinocyte-derived neoplasms of the skin are basal cell carcinoma and squamous cell carcinoma. Both so called nonmelanoma skin cancers comprise the most common cancers in humans by far. Common risk factors for both tumor entities include sun-exposure, DNA repair deficiencies leading to chromosomal instability, or immunosuppression. Yet, fundamental differences in the development of the two different entities have been and are currently unveiled. The constitutive activation of the sonic hedgehog signaling pathway by acquired mutations in the PTCH and SMO genes appears to represent the early basal cell carcinoma developmental determinant. Although other signaling pathways are also affected, small hedgehog inhibitory molecules evolve as the most promising basal cell carcinoma treatment options systemically as well as topically in current clinical trials. For squamous cell carcinoma development mutations in the p53 gene, especially UV-induced mutations, have been identified as early events. Yet, other signaling pathways including epidermal growth factor receptor, RAS, Fyn, or p16INK4a signaling may play significant roles in squamous cell carcinoma development. The improved understanding of the molecular events leading to different tumor entities by de-differentiation of the same cell type have begun to pave the way for modulating new molecular targets therapeutically with small molecules.

Related: Basal Cell Carcinoma Signal Transduction KRAS gene FYN

Reichrath J, Rass K
Ultraviolet damage, DNA repair and vitamin D in nonmelanoma skin cancer and in malignant melanoma: an update.
Adv Exp Med Biol. 2014; 810:208-33 [PubMed] Related Publications
Skin exposure with UV radiation (UV) is the main cause of skin cancer development. Epidemiological data indicate that excessive or cumulative UV exposure takes place years and decades before the resulting malignancies arise. The most important defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV-induced cellular damage. Low pigmentation capacity in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures. The important function of nucleotide excision DNA repair (NER) to protect against skin cancer becomes obvious by the rare genetic disease xeroderma pigmentosum, in which diverse NER genes are mutated. In animal models, it has been demonstrated that UVB is more effective to induce skin cancer than UVA. UV-induced DNA photoproducts are able to cause specific mutations (UV-signature) in susceptible genes for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In SCC development, UV-signature mutations in the p53 tumor suppressor gene are the most common event, as precancerous lesions reveal -80% and SCCs > 90% UV-specific p53 mutations. Mutations in Hedgehog pathway related genes, especially PTCH1, are well known to represent the most significant pathogenic event in BCC. However, specific UV-induced mutations can be found only in -50% of sporadic BCCs. Thus, cumulative UVB radiation cannot be considered to represent the only etiologic risk factor for BCC development. During the last decades, experimental animal models, including genetically engineered mice, the Xiphophorus hybrid fish, the South American oppossum and human skin xenografts, have further elucidated the important role of the DNA repair system in the multi-step process of UV-induced melanomagenesis. An increasing body of evidence now indicates that nucleotide excision repair is not the only DNA repair pathway that is involved in UV-induced tumorigenesis of melanoma and nonmelanoma skin cancer. An interesting new perspective in DNA damage and repair research lies in the participation of mammalian mismatch repair (MMR) in UV damage correction. As MMR enzyme hMSH2 displays a p53 target gene, is induced by UVB radiation and is involved in NER pathways, studies have now been initiated to elucidate the physiological and pathophysiological role of MMR in malignant melanoma and nonmelanoma skin cancer development. Interestingly, increasing evidence now demonstrates an important function of the vitamin D endocrine system (VDES) for prevention of BCC, SCC and melanoma, identifying the vitamin D receptor as a tumor suppressor in the skin.

Related: Basal Cell Carcinoma Melanoma TP53 MSH2

Smola S
Human papillomaviruses and skin cancer.
Adv Exp Med Biol. 2014; 810:192-207 [PubMed] Related Publications
Human papillomaviruses (HPVs) infect squamous epithelia and can induce hyperproliferative lesions. More than 120 different HPV types have been characterized and classified into five different genera. While mucosal high-risk HPVs have a well-established causal role in anogenital carcinogenesis, the biology of cutaneous HPVs is less well understood. The clinical relevance of genus beta-PV infection has clearly been demonstrated in patients suffering from epidermodysplasia verruciformis (EV), a rare inherited disease associated with ahigh rate of skin cancer. In the normal population genus beta-PV are suspected to have an etiologic role in skin carcinogenesis as well but this is still controversially discussed. Their oncogenic potency has been investigated in mouse models and in vitro. In 2009, the International Agency for Research on Cancer (IARC) classified the genus beta HPV types 5 and 8 as "possible carcinogenic" biological agents (group 2B) in EV disease. This chapter will give an overview on the knowns and unknowns of infections with genus beta-PV and discuss their potential impact on skin carcinogenesis in the general population.

Related: Squamous Cell Carcinoma - Skin Cancer

Yu SH, Bordeaux JS, Baron ED
The immune system and skin cancer.
Adv Exp Med Biol. 2014; 810:182-91 [PubMed] Related Publications
Carcinogenesis involves multiple mechanisms that disturb genomic integrity and encourage abnormal proliferation. The immune system plays an integral role in maintaining homeostasis and these mechanisms may arrest or enhance dysplasia. There exists a large body of evidence from organ transplantation literature supporting the significance of the immune suppression in the development of skin cancer. Nonmelanoma skin cancers are the most frequent neoplasms after organ transplantation, with organ transplant recipients having a 65-fold increase in squamous cell carcinoma incidence and 10-fold increase in basal cell carcinoma incidence. Similarly, UV-radiation (UVR) induced immunosuppression is correlated with the development of cutaneous malignancies in a dose-dependent manner. This was first shown several decades ago by Margaret Kripke, when transplanted tumors were rejected in mice with competent immune systems, but grew unchecked in immunosuppressed specimens. After UV exposure, chromophores initiate a cascade that leads to immunosuppression via derangement of Langerhans cells' antigen-presenting capacity. UV-irradiated Langerhans cells present antigens to Th2 cells, but fail to stimulate Th1 cells. A subset of T regulatory cells, specific for the antigen encountered after UVR, is also stimulated to proliferate. In general UV irradiation leads to a greater number of T regulatory cells and fewer effector T cells in the skin, shiftingthe balance from T-cell-mediated immunity to immunosuppression. These regulatory cells have the phenotype CD4+, CD25+, Foxp3+, CTLA-4+. These and many other changes in local immunity lead to a suppressed immune state, which allow for skin cancer development.

Related: Basal Cell Carcinoma Squamous Cell Carcinoma - Skin Cancer

Carless MA, Griffiths LR
Cytogenetics of melanoma and nonmelanoma skin cancer.
Adv Exp Med Biol. 2014; 810:160-81 [PubMed] Related Publications
Cytogenetic analysis of melanoma and nonmelanoma skin cancers has revealed recurrent aberrations, the frequency of which is reflective of malignant potential. Highly aberrant karyotypes are seen in melanoma, squamous cell carcinoma, actinic keratosis, Merkel cell carcinoma and cutaneous lymphomas with more stable karyotypes seen in basal cell carcinoma, keratoacanthoma, Bowen's disease and dermatofibrosarcoma protuberans. Some aberrations are common among a number of skin cancer types including rearrangements and numerical abnormalities of chromosome 1, -3p, +3q, partial or entire trisomy 6, trisomy 7, +8q, -9p, +9q, partial or entire loss of chromosome 10, -17p, +17q and partial or entire gain of chromosome 20. Combination of cytogenetic analysis with other molecular genetic techniques has enabled the identification of not only aberrant chromosomal regions, but also the genes that contribute to a malignant phenotype. This review provides a comprehensive summary of the pertinent cytogenetic aberrations associated with a variety of melanoma and nonmelanoma skin cancers.

Related: Basal Cell Carcinoma Squamous Cell Carcinoma - Skin Cancer Melanoma

Müller CS
Histology of melanoma and nonmelanoma skin cancer.
Adv Exp Med Biol. 2014; 810:141-59 [PubMed] Related Publications
Incidence of skin tumors is increasing among elderly patients, and the multi-morbidities which occur in the elderly are a great challenge for dermatologists. Basis of every treatment of skin cancer patients is a reliable diagnosis. Therefore, histopathology serves as the gold standard in clinical dermatooncology and dermatologic surgery. This chapter provides a comprehensive review on the main types of melanoma and nonmelanoma skin cancers, including precursor lesions.

Related: Basal Cell Carcinoma Squamous Cell Carcinoma - Skin Cancer Melanoma

Leiter U, Eigentler T, Garbe C
Epidemiology of skin cancer.
Adv Exp Med Biol. 2014; 810:120-40 [PubMed] Related Publications
Melanoma and nonmelanoma skin cancer (NMSC) are now the most common types of cancer in white populations. Both tumor entities show an increasing incidence rate worldwide but a stable or decreasing mortality rate. NMSC is the most common cancer in white-skinned individuals with a worldwide increasing incidence. NMSC is an increasing problem for health care services worldwide which causes significant morbidity. The rising incidence rates of NMSC are probably caused by a combination of increased exposure to ultraviolet (UV) or sun light, increased outdoor activities, changes in clothing style, increased longevity, ozone depletion, genetics and in some cases, immune suppression. An intensive UV exposure in childhood and adolescence was causative for the development of basal cell carcinoma (BCC) whereas for the etiology of SCC a chronic UV exposure in the earlier decades was accused. Cutaneous melanoma is the most rapidly increasing cancer in white populations, in the last 3 decades incidence rates have risen up to 5-fold. In 2008 melanoma was on place 5 in women and on place 8 in men of the most common solid tumor entities in Germany. The frequency of its occurrence is closely associated with the constitutive color of the skin, and the geographical zone. Changes in outdoor activities and exposure to sunlight during the past 50 years are an important factor for the increasing incidence of melanoma. Mortality rates of melanoma show a stabilization in the USA, Australia and also in European countries. In contrast to SCC, melanoma risk seems to be associated with an intermittent exposure to sunlight. Prevention campaigns aim on reducing incidence and achieving earlier diagnosis, which resulted in an ongoing trend toward thin melanoma since the last two decades. However, the impact of primary prevention measures on incidence rates of melanoma is unlikely to be seen in the near future, rather increasing incidence rates to 40-50/100,000 inhabitants/year should be expected in Europe in the next decades.

Related: Basal Cell Carcinoma Squamous Cell Carcinoma - Skin Cancer Melanoma

Gandini S, Gnagnarella P, Serrano D, et al.
Vitamin D receptor polymorphisms and cancer.
Adv Exp Med Biol. 2014; 810:69-105 [PubMed] Related Publications
It was suggested that vitamin D levels influence cancer development. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of vitamin D. In fact It has been hypothesized that polymorphisms in the VDR gene affect cancer risk and the relevance of VDR gene restriction fragment length polymorphisms for various types of cancer has been investigated by a great number of studies. However, results from previous studies on the association of VDR polymorphisms with different cancer types are somewhat contradictory, and the role of VDR in the etiology of cancer is still equivocal. We have performed a systematic review of the literature to analyze the relevance of more VDR polymorphisms (Fok1, Bsm1, Taq1, Apa1, and Cdx2) for individual malignancies, including cancer of the skin (melanoma and nonmelanoma skin cancer), ovarian cancer, renal cell carcinoma, bladder cancer, non-Hodgkin lymphoma, leukemia, thyroid carcinoma, esophageal adenocarcinoma, hepatocellular carcinoma, sarcoma, head and neck and oral squamous cell carcinoma. Up to June 2012, we identified 79 independent studies for a total of 52427 cases and 62225 controls. Significant associations with VDR polymorphisms have been reported for prostate (Fok1, Bsm1, Taq1), breast (Fok1, Bsm1, Apa1), colon-rectum (Fok1, Bsm1, Taq1) and skin cancer (Fok1, Bsm1, Taq1). Very few studies reported risk estimates for the other cancer sites. Conflicting data have been reported for most malignancies and at present it is still not possible to make any definitive statements about the importance of the VDR genotype for cancer risk. It seems probable that interactions with other factors such as calcium and vitamin D intake, 25(OH)D plasma levels and UV radiation exposure play a decisive role in cancer risk. To conclude, there is some indication that VDR polymorphisms may modulate the risk of some cancer sites and in future studies VDR genetic variation should be integrated also with prediagnostic indicator of vitamin D status.

Related: Breast Cancer Colorectal (Bowel) Cancer Polymorphisms Prostate Cancer

Grant WB
Solar ultraviolet irradiance and cancer incidence and mortality.
Adv Exp Med Biol. 2014; 810:52-68 [PubMed] Related Publications
The solar ultraviolet-B (UVB)/vitamin D/cancer hypothesis was proposed by the brothers Cedric and Frank Garland in 1980. In 2002, the list was increased to 15 types of cancer using data in the 1999 version of the atlas of cancer mortality rates in the United States. Ecological studies of cancer incidence and/or mortality rates with respect to indices of solar UVB doses have also been reported for Australia, China, France, Japan, and Spain with largely similar findings. In addition, several studies using nonmelanoma skin cancer as the index of solar UVB dose have found reduced internal cancer incidence and/or mortality rates, especially in sunny countries. A study of cancer incidence with respect to 54 categories of occupation in five Nordic countries, using lip cancer less lung cancer as the UVB index, found this index inversely correlated with 14 types of internal cancers for males and four for females. Observational studies with respect to UVB doses and serum 25-hydroxyvitamin D [25(OH)D] concentrations also support the hypothesis. Hill's criteria for causality in a biological system to assess whether solar UVB and vitamin D can be considered causal in reducing risk of cancer. The primary criteria for this analysis include strength of association, consistent findings in different populations, biological gradient, plausibility (e.g., mechanisms), and experimental verification (e.g., randomized controlled trials). The totality of evidence is judged to satisfy the criteria very well for breast and colorectal cancer, and moderately well for several other types of cancer.

Related: Breast Cancer Colorectal (Bowel) Cancer Lung Cancer

Holick MF
Sunlight, ultraviolet radiation, vitamin D and skin cancer: how much sunlight do we need?
Adv Exp Med Biol. 2014; 810:1-16 [PubMed] Related Publications
Vitamin D is the sunshine vitamin for good reason. During exposure to sunlight, the UV B photons enter the skin and photolyze 7-dehydrocholesterol to previtamin D3 which in turn is isomerized by the body's temperature to vitamin D3. Most humans have depended on sun for their vitamin D requirement. Skin pigment, sunscreen use, aging, time of day, season and latitude dramatically affect previtamin 13 synthesis. Vitamin D deficiency was thought to have been conquered, but it is now recognized that more than 50% of the world's population is at risk for vitamin D deficiency. This deficiency is in part due to the inadequate fortification of foods with vitamin D and the misconception that a healthy diet contains an adequate amount of vitamin D. Vitamin D deficiency causes growth retardation and rickets in children and will precipitate and exacerbate osteopenia, osteoporosis and increase risk of fracture in adults. The vitamin D deficiency has been associated pandemic with other serious consequences including increased risk of common cancers, autoimmune diseases, infectious diseases and cardiovascular disease. There needs to be a renewed appreciation of the beneficial effect of moderate sunlight for providing all humans with their vitamin D requirement for health.

Hata A, Sekine Y, Koh E, Hiroshima K
Operative wound implantation of inflammatory sarcomatoid carcinoma of the lung.
Ann Thorac Surg. 2014; 98(3):1111-3 [PubMed] Related Publications
We describe a patient with iatrogenic chest wall implantation of inflammatory sarcomatoid carcinoma. A 43-year-old man underwent right partial lung resection for hemopneumothorax, with large bullae and an alveolar accumulation of histiocytes found on pathology. Three months later, a subcutaneous tumor appeared at a thoracoscopic port site. Needle aspiration of this tumor suggested a malignant neoplasm; therefore, a right upper lobectomy and chest wall resection were performed, and a pathologic diagnosis of sarcomatoid carcinoma was made. Pathologic reexamination of the original sample suggested that the tumor has been implanted in the patient's chest wall at the time of the first operation.

Related: Lung Cancer

Milenović A, Boras VV, Ilić I, et al.
Simultaneous presentation of oral and skin anaplastic large T-cell lymphoma.
Acta Clin Croat. 2014; 53(2):246-51 [PubMed] Related Publications
We present case of oral and skin anaplastic T-cell lymphoma in a 68-year-old woman. The patient presented with extensive ulcerations and necrotic tissue on the left mandibular gingiva. Orthopantomogram finding showed extensive necrolytic lesions of the adjacent mandible. Biopsy finding of oral lesions and subsequently of the skin confirmed the diagnosis of anaplastic T-cell lymphoma. The bridge on the teeth 35-37 was taken out. After three cycles of chemotherapy, oral lesions subsided, unlike skin lesions. Dentists should be aware that differential diagnosis when dealing with oral ulcerations might be the result of certain malignant hematologic diseases.

Related: Oral Cancer

Humphreys TR
Repair of the medial canthus following Mohs micrographic surgery.
Dermatol Surg. 2014; 40 Suppl 9:S96-S102 [PubMed] Related Publications
BACKGROUND: The medial canthus poses unique reconstructive challenges because of its anatomy and contour. The reconstructive goal should be preservation of the natural concavity that defines it because even small alterations can result in perceptible asymmetry.
OBJECTIVE: To present the anatomy of this unique cosmetic subunit and review reconstructive options that preserve contour and function.
MATERIALS AND METHODS: A variety of reconstructive approaches for different subunits of the medial canthus are described and discussed. Technical considerations and complications are discussed.
RESULTS: The choice of repair will depend on the relative location of the defect on the medial canthus and the proximity to adjacent cosmetic subunits.
CONCLUSION: Understanding of the unique contour and anatomy of the medial canthus is essential to choosing the best repair option that preserves contour and symmetry.

Related: Basal Cell Carcinoma

Manolidis S, Ratner D
External auditory canal defect management and reconstruction.
Dermatol Surg. 2014; 40 Suppl 9:S86-95 [PubMed] Related Publications
BACKGROUND: The external auditory canal (EAC) is an area commonly involved by skin cancers. Knowledge of the anatomy of this area and proper evaluation and management of patients with these malignancies is essential.
OBJECTIVE: The purpose of this article is to provide the reader with an understanding of the anatomy of the EAC, the options available for the treatment of EAC cancers, and repair of the resulting surgical defects.
METHODS AND MATERIALS: A review of the current literature was performed to summarize the current literature on this topic.
RESULTS: There are a variety of surgical options available for the treatment of these cancers whose use depends on the location and extent of the tumor. It is important to follow a logical reconstructive algorithm after tumor resection to optimize both functional and cosmetic results.

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