Cellular heterogeneity and microenvironmental control of skin cancer.

Healthy tissues harbour a surprisingly high number of cells that carry well-known cancer-causing mutations without impacting their physiological function. In recent years, strong evidence accumulated that the immediate environment of mutant cells profoundly impact their prospect of malignant progression. In this review, focusing on the skin, we investigate potential key mechanisms that ensure tissue homeostasis despite the presence of mutant cells, as well as critical factors that may nudge the balance from homeostasis to tumour formation. Functional in vivo studies and single-cell transcriptome analyses have revealed a tremendous cellular heterogeneity and plasticity within epidermal (stem) cells and their respective niches, revealing for example wild-type epithelial cells, fibroblasts or immune-cell subsets as critical in preventing cancer formation and malignant progression. It's the same cells, however, that can drive carcinogenesis. Therefore, understanding the abundance and molecular variation of cell types in health and disease, and how they interact and modulate the local signalling environment will thus be key for new therapeutic avenues in our battle against cancer.

Chronic, nonhealing leg ulcer.

When this patient's chronic stasis ulcer failed to respond to the usual treatment of dressings, elevation, and diuretics, our suspicions led us to an unexpected diagnosis.

Shift work and risk of skin cancer: A systematic review and meta-analysis.

Shift work with circadian disruption has been considered as a carcinogenic risk factor for skin cancer. The few prior studies that investigated the association between shift work and skin cancer have inconclusive results. Our main objective was to evaluate the associations between shift work and the risks of different types of skin cancer. We systematically searched PubMed, Web of Science, Cochrane Library, EMBASE and Science Direct until October 2018 for studies that included a relationship between shift work and skin cancer. Our search yielded 193 articles and 9 studies met the criteria for our review. The included studies involved 3,579,147 participants and 17,308 skin cancer cases. Overall, ever shift work, was associated with increased risk of melanoma (RR = 1.10, 95% CI = 1.05-1.16) and a significant decrease in the risk of BCC (RR = 0.90, 95% CI = 0.88-0.93). No association between shift work and the risk of SCC was detected. Interestingly, our dose response analysis demonstrated that the risk of melanoma cumulatively increases by 2% for every year of shift work (RR = 1.02; 95% CI = 1.00-1.03). In conclusion, shift work is associated with increased risk of melanoma and deceased risk of BCC. Further studies are needed to confirm our findings and to elucidate the related potential biological mechanisms.

Human basal cell carcinoma: the induction of anagen hair follicle differentiation.

BACKGROUND: Consistent with cancer stem cell driven pattern of growth, human basal cell carcinomas (BCCs) demonstrate differentiation along hair follicle (HF) lineages. AIM: To define the pattern of differentiation and therapeutic targets that promote BCC differentiation and therefore BCC cancer stem cell exhaustion. METHODS: An alkaline phosphatase substrate kit was used to determine dermal papilla cells within the BCC stroma. Autonomous HF cycle-dependent gene expression was identified by analysis of the human homologues of a murine gene set (total 2289 genes) that is differentially expressed in hair cycle phases. The findings were validated by quantitative real-time PCR and immunofluorescence, as well as in vitro transforming growth factor (TGF)-ß2 stimulation of BCC cancer stem cell colonies. RESULTS: As in the HF, keratin expression in the inner root sheath and matrix in BCC correlated with proliferative index and was tightly regulated, despite the absence of dermal papilla cells. Cross-species microarray analysis comparing human BCC and murine synchronous HF growth cycle datasets revealed 74% concordance with telogen differentiation compared with anagen (23%, P < 0.01) and catagen (49%; P < 0.01). Incomplete anagen differentiation within BCC was characterized by reduced expression of the anagen master regulator DLX3 (-5.5-fold), and increased expression of telogen-associated genes: AEBP1 (2.2-fold), DEFB8 (35.3-fold), MMP3 (106.0-fold) and MMP12 (12.9-fold). Restoration of dermal papilla signals by in vitro addition of TGF-ß2 enhanced anagen differentiation. CONCLUSION: Our findings show that BCC cells differentiate along HF lineages and may be susceptible to exogenous HF cycle modulators.

Association between Blood Group and Nonmelanoma Skin Cancers (Basal Cell Carcinoma and Squamous Cell Carcinoma).

BACKGROUND: Development of nonmelanoma skin cancers (NMSCs) has been associated with certain risk factors, but studies of the association between ABO blood group and NMSCs have been rare and inconclusive. The aim of this study was to assess the association of the previously known risk factors and blood group as a new potential risk factor in NMSCs. METHODS: The study included 401 patients, 202 men, and 199 women, which included 367 diagnosed cases of basal cell carcinoma and 148 diagnosed cases of squamous cell carcinoma. The control group consisted of 438 subjects, 198 men, and 240 women. A standardized questionnaire adapted for this targeted study was used. The relation between the dependent variable (NMSCs) and independent variables was investigated by logistic regression. RESULTS: Compared to the non AB blood group, the risk of developing NMSCs was significantly higher in the AB blood group (MOR = 2.28; 95% CI = 1.41-3.69). We established a logistic model that could best describe the probability of NMSCs development. CONCLUSION: Study results are expected to instigate basic research into the role of A and B antigens in normal skin epithelium, NMSCs etiopathogenesis, possible effect on metastatic potential and disease prognosis, potential tumor immunotherapy, and targeted detection and prevention in subjects at an increased risk of NMSCs development.

Retalho retroauricular ilhado para reconstrução parcial de orelha: relato de casos / Retroauricular island flap for partial ear reconstruction: case reports

Defeitos parciais de orelha podem ser tratados de diversas formas, dentre elas o fechamento primário, cicatrização por segunda intenção ou retalhos. Diversas opções técnicas foram descritas para a sua reconstrução de modo a manter o contorno natural da orelha, sem sacrificar tecido sadio ou alterar sua estética e função. Apresentamos neste artigo dois casos atendidos no Instituto do Câncer do Hospital de Base de São José do Rio Preto de reconstrução de defeitos condrocutâneos de orelha após ressecção de carcinoma basocelular em região central da orelha, com a confecção de retalho retroauricular ilhado transposto através de uma janela cartilaginosa e com o pedículo desepidermizado. Área doadora com fechamento primário. Tal procedimento constitui técnica segura, pois a região retroauricular é ricamente vascularizada, é de fácil execução, em único estágio e com resultado estético e funcional satisfatório.

Partial ear defects can be treated in several ways, including primary closure, healing by secondary intention, or flaps. Several surgical options have been described for reconstruction in order to maintain the natural contour of the ear, without sacrificing healthy tissues or changing the aesthetics and function. In this article, we present two cases of reconstruction of chondrocutaneous defects of the ear after resection of basal cell carcinoma in the central region of the ear, with the production of a retroauricular island flap transposed through a cartilaginous window with the de-epidermized pedicle. The donor area healed following a primary closure. This procedure can be performed in a single stage, yields satisfactory aesthetic and functional results, and is safe because the retroauricular region is richly vascularized.

Basal cell carcinoma: Epidemiology; pathophysiology; clinical and histological subtypes; and disease associations.

As the most common human cancer worldwide and continuing to increase in incidence, basal cell carcinoma is associated with significant morbidity and cost. Continued advances in research have refined both our insight and approach to this seemingly ubiquitous disease. This 2-part continuing medical education article will provide a comprehensive and contemporary review of basal cell carcinoma. The first article in this series describes our current understanding of this disease regarding epidemiology, cost, clinical and histopathologic presentations, carcinogenesis, natural history, and disease associations.

Characterizing the tissue dielectric constant of skin basal cell cancer lesions.

BACKGROUND: Measuring tissue dielectric constant (TDC) of cancer tissues to distinguish them from normal or non-cancerous tissues has been an active area of research that has targeted several different cancer types usually using in vitro specimens. The goal of this study was to determine if and to what extent TDC values measured in vivo at 300 MHz using a simple hand-held measuring device might differentiate between skin cancer lesions and non-cancerous skin. MATERIALS AND METHODS: Triplicate TDC measurements were made in 32 patients who were subsequently diagnosed with skin basal cell carcinoma (BCC) and in 14 patients subsequently diagnosed as having non-cancerous lesions. Lesion TDC values were compared to contralateral unaffected skin and between lesion types. RESULTS: A significantly lower TDC value (mean ± SD) of BCC lesions (TDCL ) vs TDC values of contralateral non-affected skin (TDCC ) was found (22.4 ± 16.2 vs 38.1 ± 15.2, P < .00001). A similar pattern was found for non-cancerous lesions with lesion TDC values less than non-affected skin (14.5 ± 9.0 vs 29.1 ± 9.0, P < .0001). However, TDC values were not statistically different between BCC lesions and non-cancerous lesions (22.4 ± 16.2 vs 14.5 ± 9.0, P = .096) and calculated TDCL /TDCC ratios between BCC lesions and non-cancerous lesions also were not significantly different (0.596 ± 0.345 vs 0.501 ± 0.261, P = .364). CONCLUSIONS: (1) Main results do not support using TDC measurements to differentiate in vivo skin cancer lesions from non-cancerous lesions. (2) TDC values strongly suggest reduced water content of both cancerous and non-cancerous lesions. (3) Lesion TDC measurements provide reference values for future studies.

Controversial role of mast cells in skin cancers.

Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumor initiation and progression. The stromal microenvironment can promote tumor development. Mast cells, widely distributed throughout all tissues, are a stromal component of many solid and haematologic tumors. Mast cells can be found in human and mouse models of skin cancers such as melanoma, basal and squamous cell carcinomas, primary cutaneous lymphomas, haemangiomas and Merkel cell carcinoma. However, human and animal studies addressing potential functions of mast cells and their mediators in skin cancers have provided conflicting results. In several studies, mast cells play a pro-tumorigenic role, whereas in others, they play an anti-tumorigenic role. Other studies have failed to demonstrate a clear role for tumor-associated mast cells. Many unanswered questions need to be addressed before we understand whether tumor-associated mast cells are adversaries, allies or simply innocent bystanders in different types and subtypes of skin cancers.

Surgical Treatment with Locoregional Flap for the Nose.

Nonmelanotic skin cancers (NMSCs) are the most frequent of all neoplasms and nasal pyramid represents the most common site for the presentation of such cutaneous malignancies, particularly in sun-exposed areas: ala, dorsum, and tip. Multiple options exist to restore functional and aesthetic integrity after skin loss for oncological reasons; nevertheless, the management of nasal defects can be often challenging and the best "reconstruction" is still to be found. In this study, we retrospectively reviewed a total of 310 patients who presented to our Department of Plastic and Reconstructive Surgery for postoncological nasal reconstruction between January 2011 and January 2016. Nasal region was classified into 3 groups according to the anatomical zones affected by the lesion: proximal, middle, and distal third. We included an additional fourth group for complex defects involving more than one subunit. Reconstruction with loco regional flaps was performed in all cases. Radical tumor control and a satisfactory aesthetic and functional result are the primary goals for the reconstructive surgeon. Despite tremendous technical enhancements in nasal reconstruction techniques, optimal results are usually obtained when "like is used to repair like." Accurate evaluation of the patients clinical condition and local defect should be always considered in order to select the best surgical option.

Body mass index and risk of non-melanoma skin cancer: cumulative evidence from prospective studies.

Prospective epidemiologic studies that investigated the association between body mass index (BMI) and non-melanoma skin cancer (NMSC) yielded inconsistent findings. A dose-response meta-analysis was conducted to quantitatively summarize the evidence. PubMed and Embase databases were searched for relevant studies. Study-specific relative risk (RR) and 95% confidence interval (CI) for an increase in BMI of 5 kg/m2 was computed with the generalized least squares trend estimation, and these risk estimates were combined with the random-effects model. Nine publications were included in the final analyses, consisting of 18 independent cohorts with 22 risk estimates (971,795 participants and 50,561 NMSC cases). Results of the dose-response analyses showed a nonlinear inverse relationship between BMI and NMSC (RR = 0.88, 95% CI: 0.85-0.91, I2 = 71.2%, P-nonlinearity <0.001), which persisted when limiting to the studies with adjustment for important potential confounders including sun exposure and sensitivity factors. The risk estimates were very similar for squamous cell carcinoma and basal cell carcinoma. Sex appeared a source of heterogeneity (P-difference = 0.06), with a weaker, but still significant inverse association in men than in women. This dose-response meta-analysis suggests a nonlinear inverse association between BMI and NMSC.

Personal history of psoriasis and risk of nonmelanoma skin cancer (NMSC) among women in the United States: A population-based cohort study.

BACKGROUND: To our knowledge, no prospective studies have examined the association between personal history of psoriasis and risk of nonmelanoma skin cancer. OBJECTIVE: We sought to examine this association based on 2 prospective cohorts, the Nurses' Health Study and Nurses' Health Study II. METHODS: Diagnoses of nonmelanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma (SCC), were obtained by self-reported questionnaires. Information on clinician-diagnosed psoriasis and diagnosis year was collected and validated with a supplementary questionnaire. RESULTS: After 2,487,941 and 2,478,148 person-years of follow-up, we documented 1725 SCC cases and 16,075 basal cell carcinoma cases, respectively. For the combined cohorts, personal history of psoriasis was associated with an elevated risk of SCC, with a multivariate-adjusted relative risk (RR) of 1.51 (95% confidence interval [CI] 1.11-2.05). The associations appeared stronger with increasing psoriasis severity, with RR of 1.42 (95% CI 0.94-2.15) in the mild psoriasis group and RR of 1.99 (95% CI 0.74-5.32) in the moderate to severe psoriasis group (P trend = .03). There was no association between psoriasis and the risk of basal cell carcinoma (RR 0.95; 95% CI 0.75-1.18). LIMITATIONS: Lack of treatment data may bias the result. CONCLUSION: Personal history of psoriasis may be associated with an increased risk of SCC. Further investigations are warranted to understand the underlying mechanisms.

Optical coherence tomography of basal cell carcinoma: density and signal attenuation.

BACKGROUND: Basal cell carcinoma (BCC) is the most prevalent malignancy in Caucasians. Optical coherence tomography (OCT) is a non-invasive optical imaging technology using the principle of interferometry. OCT has shown a great potential in diagnosing, monitoring, and follow-up of BCC. So far most OCT studies on the subject of BCC have had a qualitative focus, i.e. on morphological analysis of the OCT images. The aim of this study was to explore the use of quantitative OCT measurements, density, and attenuation coefficient in BCC lesions as a way to improve the OCT evaluation of BCC. METHODS: The study was based on OCT images of 58 histologically verified BCC lesions and the corresponding normal adjacent skin. The study population was divided into two groups based on the OCT morphology of the BCC lesions: the "Disrupt BCC group" and the "Nodular BCC group". Density and attenuation coefficients were measured in the OCT images by specially designed software and the regions of interests (ROI) were placed directly on (ROI1) and under the visible BCC lesions (ROI2). The results were compared to the OCT images of normal adjacent skin. RESULTS: Disrupt BCC group: The densities of BCC lesions were significant lower (P = 0.002), than the normal skin in ROI1. Attenuation measurements were found to be significantly greater (P = 0.012) in BCC lesions compared to normal skin in ROI1. Nodular BCC group: Attenuation measurements were found to be significantly lower (P = 0.017) in BCC lesions compared to normal skin in ROI1. CONCLUSIONS: Our study suggests a quantitative potential of OCT in the context of BCC. This study is exploratory and requires independent verification.

Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit.

The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFκB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression.

A Model to Predict the Risk of Keratinocyte Carcinomas.

Basal cell and squamous cell carcinomas of the skin are the commonest cancers in humans, yet no validated tools exist to estimate future risks of developing keratinocyte carcinomas. To develop a prediction tool, we used baseline data from a prospective cohort study (n = 38,726) in Queensland, Australia, and used data linkage to capture all surgically excised keratinocyte carcinomas arising within the cohort. Predictive factors were identified through stepwise logistic regression models. In secondary analyses, we derived separate models within strata of prior skin cancer history, age, and sex. The primary model included terms for 10 items. Factors with the strongest effects were >20 prior skin cancers excised (odds ratio 8.57, 95% confidence interval [95% CI] 6.73-10.91), >50 skin lesions destroyed (odds ratio 3.37, 95% CI 2.85-3.99), age ≥ 70 years (odds ratio 3.47, 95% CI 2.53-4.77), and fair skin color (odds ratio 1.75, 95% CI 1.42-2.15). Discrimination in the validation dataset was high (area under the receiver operator characteristic curve 0.80, 95% CI 0.79-0.81) and the model appeared well calibrated. Among those reporting no prior history of skin cancer, a similar model with 10 factors predicted keratinocyte carcinoma events with reasonable discrimination (area under the receiver operator characteristic curve 0.72, 95% CI 0.70-0.75). Algorithms using self-reported patient data have high accuracy for predicting risks of keratinocyte carcinomas.

Skin color parameters and Fitzpatrick phototypes in estimating the risk of skin cancer: A case-control study in the Polish population.

BACKGROUND: Light skin pigmentation is a known risk factor for skin cancer. OBJECTIVE: Skin color parameters and Fitzpatrick phototypes were evaluated in terms of their usefulness in predicting the risk of skin cancer. METHODS: A case-control study involved 133 individuals with skin cancer (100 with basal cell carcinoma, 21 with squamous cell carcinoma, 12 with melanoma) and 156 healthy individuals. All of them had skin phototype determined and spectrophotometric skin color measurements were done on the inner surfaces of their arms and on the buttock. Using those data, prediction models were built and subjected to 17-fold stratified cross-validation. RESULTS: A model, based on skin phototypes, was characterized by area under the receiver operating characteristic curve = 0.576 and exhibited a lower predictive power than the models, which were mostly based on spectrophotometric variables describing pigmentation levels. The best predictors of skin cancer were R coordinate of RGB color space (area under the receiver operating characteristic curve 0.687) and melanin index (area under the receiver operating characteristic curve 0.683) for skin on the buttock. LIMITATIONS: A small number of patients were studied. Models were not externally validated. CONCLUSIONS: Skin color parameters are more accurate predictors of skin cancer occurrence than skin phototypes. Spectrophotometry is a quick, easy, and affordable method offering relatively good predictive power.