Development Of Basal Cell Carcinoma Research Articles

Morphoeic Basal Cell Carcinoma – An Unusual Tumor Variant at an Unusual Site

Basal cell carcinomas (BCC) are malignant neoplasm arising from the basal layer of epidermis, seen almost exclusively on hair-bearing areas of skin. There are many clinical and histopathological variants in BCC. The tumor commonly seen at the site of excessive sun exposure. It is a locally invasive tumor with rare metastasis. The most common site for the development of morphoeic BCC is over the face. Clinically, morphoeic BCC presents as morphea such as sclerotic plaque and histopathologically as densely hyalinized stroma with angulated strands of neoplastic basaloid cells. Ulceration of the lesion is uncommon in this type. We report a case of morphoeic BCC, an unusual tumor variant occurring over the back.

Current Perspectives on the Role of Matrix Metalloproteinases in the Pathogenesis of Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common skin malignancy, which rarely metastasizes but has a great ability to infiltrate and invade the surrounding tissues. One of the molecular players involved in the metastatic process are matrix metalloproteinases (MMPs). MMPs are enzymes that can degrade various components of the extracellular matrix. In the skin, the expression of MMPs is increased in response to various stimuli, including ultraviolet (UV) radiation, one of the main factors involved in the development of BCC. By modulating various processes that are linked to tumor growth, such as invasion and angiogenesis, MMPs have been associated with UV-related carcinogenesis. The sources of MMPs are multiple, as they can be released by both neoplastic and tumor microenvironment cells. Inhibiting the action of MMPs could be a useful therapeutic option in BCC management. In this review that reunites the latest advances in this domain, we discuss the role of MMPs in the pathogenesis and evolution of BCC, as molecules involved in tumor aggressiveness and risk of recurrence, in order to offer a fresh and updated perspective on this field.

Anatomical distribution of basal cell carcinoma in Israel using relative tumor density scores.

Ultraviolet radiation (UVR) is considered a major risk factor for the development of basal cell carcinoma (BCC). Calculating the relative tumor density (RTD) by adjusting the proportion of BCC lesions relative to the skin surface area at a specific site enables comparison of the proportion of tumors at different anatomical sites and better understanding of the association with sun exposure. To characterize anatomical distribution of BCC in the Israeli population using RTD score. A retrospective, cross-sectional study that includes all histologically confirmed BCC samples obtained from a major national pathological institute, which receives specimens from numerous surgeons throughout Israel, during the first trimester of 2012. A total of 1,712 skin lesions were diagnosed as BCC during the study period. RTD in the head and neck area was the highest over the body (RTD=6.6). We found that RTD over the upper arms in males was higher than the proportion of skin surface area (RTD=1.1). A comparison of RTD values in subsites of the head and neck region indicates that men have higher RTD values for the ears, neck, and scalp than women. However, the nose and eyes areas have female predominance. Using RTD scores, our study demonstrates the unique UVR exposure pattern in the Mediterranean climate of Israel and supports the notion that UVR is an important risk factor for the development of BCC lesions.

Risk Prediction Model for Basal Cell Carcinoma in Cardiac Allograft Recipients

Basal cell carcinoma (BCC) is the second most common skin cancers in posttransplant patients. Long-term immunosuppression predisposes the patients to higher risk. This study was undertaken to develop a risk prediction model using the United Network for Organ Sharing (UNOS) database. Heart transplant recipients (2000~2015) from the UNOS database were analyzed. The Cox proportional hazards model was applied to screen the predictors associated with the development of BCC. Stepwise forward selection with Akaike information criterion was done to obtain the multivariate model. Area under the curve was derived from the receiver operating characteristics curve to assess the quality of the prediction model. A risk scoring system was developed to stratify patients into different risk groups, and the occurrence rates of posttransplant BCC among different groups were compared. There were 24,374 patients who received heart transplantation within this study period, and 1211 recipients have been reported with BCC. The multivariate model provides area under the curves at 5, 8, and 10 years posttransplant of 0.77, 0.76, and 0.76, respectively, in the derivation set and 0.75, 0.74, and 0.74, respectively, in the validation set. The predicted and observed probabilities of developing BCC in 5 years agree well across different risk groups. Kaplan-Meier survival curves were generated, which demonstrate significant differences between subjects in different risk groups. A risk prediction model has been generated for the first time for BCC with a c-statistic of ≥0.74 in both derivation and validation sets, making it a good tool for risk stratification.

Metformin is associated with decreased risk of basal cell carcinoma: A whole-population case-control study from Iceland

Metformin has anticarcinogenic properties and is also known to inhibit the sonic hedgehog pathway, but population-based studies analyzing the potential protective effect for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are needed. To delineate the association between metformin use and invasive SCC, SCC in situ (SCCis), and BCC. A population-based case-control study design was employed using all 6880 patients diagnosed in Iceland between 2003-2017 with first-time BCC, SCCis, or invasive SCC, and 69,620 population controls. Multivariate odds ratios (ORs) were calculated using conditional logistic regression. Metformin was associated with a lower risk of developing BCC (OR, 0.71; 95% confidence interval [CI], 0.61-0.83), even at low doses. No increased risk of developing SCC was observed. SCCis risk was mildly elevated in the 501-1500 daily dose unit category (OR, 1.40; 95% CI, 1.00-1.96). This study was retrospective in nature with the inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities. Metformin is associated with decreased risk of BCC development, even at low doses. Metformin might have potential as a chemoprotective agent for patients at high risk of BCC, although this will need confirmation in future studies.

Capillary malformation as a locus minoris resistentiae for the development of basal cell carcinoma

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Skin cancers in Italian lung transplant recipients: Incidence and risk factors analysis.

Only a few studies reported the incidence and risk factors of skin cancers in lung transplant recipients. The aim of this study was to determine the cumulative incidence of skin cancers in a cohort of patients undergoing lung transplantation and to define predictors of their development. About 247 consecutive patients receiving lung transplantation at the Thoracic Surgery Unit of University Hospital of Padova between May 1995 and October 2016 were studied. Cumulative incidence of skin cancers was estimated considering death as a competing event. The effect of potential predictors was evaluated with univariate and multivariable Cox models for competing risks. About 37 (15.0%) patients developed skin tumors. The cumulative incidence of any skin cancer was 14.2% at 5 years, 21.4% at 10 years, and 24.3% at 15 years posttransplantation. Age at transplantation, male gender, phototype II, and voriconazole use were independent risk factors for development of squamous cell carcinoma. Only male gender and phototype II were independent risk factors for development of basal cell carcinoma. Since lung transplant recipients have a greater risk of developing skin cancers, the management of these patients needs a multidisciplinary approach, in which dermatologists and transplant physicians have a primary role.

Programmed cell death 1 (PDCD1) gene haplotypes and susceptibility of patients to basal cell carcinoma.

Programmed death-1 (PD-1), as an immunoinhibitory receptor encoded by programmed cell death-1 (PDCD1) gene, has a pivotal role in tolerance to self-antigens. Mutations of PDCD1 may participate in susceptibility to basal cell carcinoma (BCC) as the most common of skin cancer. We studied the impacts of two single nucleotide polymorphisms (SNPs) within PDCD1 and their haplotypes in BCC susceptibility in an Iranian population. The blood samples were collected from 210 BCC and 220 healthy individuals. After the extraction of genomic DNA, the genotypes and alleles of PD1.1 G/A (rs36084323) and PD1.6 G/A (rs10204525) SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Four haplotypes were estimated by these SNPs. Our data revealed that genotype and allele frequencies of PD1.1 and PD1.6 polymorphisms in BCC patients were similar to those in healthy individuals. The results of estimated haplotypes for PDCD1 indicated that GG and AA haplotypes of PDCD1 had protective effects on BCC susceptibility (OR = 0.7, 95% CI = 0.51-0.96, p = 0.03 and OR = 0.57, 95% CI = 0.35-0.91, p = 0.02, respectively), while GA and AG haplotypes served as the risk factors for developing BCC (OR = 1.76, 95% CI = 1.09-2.84, p = 0.02 and OR = 3.87, 95% CI = 1.95-7.69, p = <0.001, respectively). Based on these findings, frequency distributions of PDCD1 haplotypes have important roles in the determination of BCC development in the Iranian population. However, larger multicenter studies are required to confirm this conclusion.

Differences in RNA and microRNA Expression Between PTCH1- and SUFU-mutated Medulloblastoma.

Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). Our results help towards finding new treatable molecular targets for these types of medulloblastomas.

Role of cytoplasmic localization of discoidin domain receptor 1 in basal-cell carcinoma

Objective The objective of this study was to investigate the role of discoidin domain receptors (DDR1) in the pathogenesis of basal-cell carcinoma (BCC) through its immunohistochemical expression and to correlate its expression with clinicopathological parameters. Background BCC is the most common type of nonmelanoma skin cancer. The pathogenesis is usually combined with environmental factors, mainly ultraviolet irradiation through long-term sun exposure. Patients and methods This retrospective case–control study was carried out on 77 patients presented with BCC and 20 age-matched and gender-matched apparently healthy volunteers. Skin biopsies from controls and BCC cases were retrieved from the archives of Pathology Department, Faculty of Medicine, Menoufia University for histopathological and immunohistochemical DDR1 evaluation. Results Cytoplasmic localization of DDR1 could be incriminated in the development and progression of BCC. DDR1 offers potential targeted therapy in cancer, as none of the control groups showed cytoplasmic epithelial localization DDR1, whereas (90.9%) cytoplasmic epithelial localizations were demonstrated in BCC (P 0.001 and 0.005, respectively). Conclusion Cytoplasmic localization of DDR1 has a role in the pathogenesis of BCC which can be a new therapeutic target in BCC.

A Comparative Study of Pigmented and Non-pigmented Basal Cell Carcinoma in Reflectance Confocal Microscopy.

Basal cell carcinoma (BCC) is a common skin cancer, especially in the elderly population. The probability of BCC development increases past the age of 55. Dermoscopy and reflectance confocal microscopy (RCM) are two modern tools useful in the diagnosis of BCC. This is a retrospective study conducted on a group of 21 patients with a confirmed diagnosis of BCC. All patients were examined by dermoscopy and RCM. Dermoscopic images were taken using a videodermoscope. RCM was performed in three layers: epidermal, dermoepidermal junction (DEJ), and superficial dermal layer. In each layer, a few RCM criteria of basal cell carcinoma diagnosis were taken into consideration. Dermoscopy of pigmented BCCs revealed blue globules of pigment (p<0.05), gray and blue ovoid nests, which were absent in the entire non-pigmented carcinomas group. In RCM, the epidermis showed no differences between pigmented and non-pigmented carcinomas, however, significant differences were observed at the DEJ. In pigmented BCCs, cordlike structures and plump atypical cells were observed (p<0.05), while in non-pigmented carcinomas, dark silhouettes were present (p<0.05). To our knowledge, that is the first study comparing features between pigmented and non-pigmented BCC by RCM. Pigmented and non-pigmented BCCs presented different features in both dermoscopy and RCM. Furthermore, RCM revealed more discriminating features at the DEJ than dermoscopy, thus can be more efficient in the differential diagnosis of difficult BCC.

Spreading of Isolated Ptch Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice.

Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a CD4Cre-mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin of CD4Cre-targeted BCC progenitors as rare Keratin 5+ epidermal cells and show that wildtype Patched offspring of these cells spread over the hair follicle/skin complex with increasing mouse age. Intriguingly, Patched mutant counterparts are undetectable in age-matched untreated skin but are getting traceable upon applying the chemical tumorigenesis protocol. Together, our data show that biallelic Patched depletion in rare Keratin 5+ epidermal cells is not sufficient to drive BCC development, because the spread of these cells is physiologically suppressed. However, bypassing the repression of Patched mutant cells, e.g., by exogenous stimuli, leads to an accumulation of BCC precursor cells and, finally, to tumor development.

18445 Basal cell carcinoma gene mutations and polymorphisms differ between Asian, Hispanic, and Caucasian patients

Introduction: Basal cell carcinoma (BCC) is the most common cancer worldwide, with ∼4.3 million cases annually. Research on the development of BCC has identified several genes that have a role in BCC pathogenesis, namely SMO and PTCH1. While BCC mutations have been extensively studied in Caucasian patients, research is lacking in patients of other races. Many BCC drug treatments, such as vismodegib, target specific products of mutated genes. Thus, discovering a potential difference in gene mutations for patients of different races has significant clinical relevance.

Beyond Mohs surgery and excisions: A focused review of treatment options for subtypes of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. It originates from undifferentiated cells in the basal cell layer of the epidermis or from the outer root sheath of the hair follicle. The most important factor in development of BCC is ultraviolet radiation. Surgery is considered the gold standard of treatment for BCC. However, nonsurgical options are available for individuals who are unsuitable for surgery. The purpose of this review is to summarize the efficacy and indications of alternative, nonsurgical treatments that can be used in the management of BCC. An extensive literature review was performed for the nonsurgical options for the treatment of BCC. Resources searched included PubMed and Google Scholars, limited to the years 1995 to 2020. Key words searched included BCC, destructive methods, photodynamic therapy (PDT), radiotherapy, topical medication, laser, hedgehog pathway inhibitors (HPIs). The most relevant results such as systematic reviews, randomized controlled trials, or comparative studies were selected to provide a summary for the most common nonsurgical methods used for treating BCC. Effective nonsurgical treatments for BCC include destructive methods (eg, curettage alone, cryosurgery, or electrodessication), PDT, topical medications, radiotherapy, laser, and HPIs. Nonsurgical therapeutic alternatives are safe and effective for the treatment of BCC. Factors such as tumor location, size, and histopathological subtype should be taken into consideration when selecting optimal treatment. In addition to clinical factors, cosmetic results and patient preference should be considered.

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research.

Gorlin syndrome is a skeletal disorder caused by a gain of function mutation in Hedgehog (Hh) signaling. The Hh family comprises of many signaling mediators, which, through complex mechanisms, play several important roles in various stages of development. The Hh information pathway is essential for bone tissue development. It is also the major driver gene in the development of basal cell carcinoma and medulloblastoma. In this review, we first present the recent advances in Gorlin syndrome research, in particular, the signaling mediators of the Hh pathway and their functions at the genetic level. Then, we discuss the phenotypes of mutant mice and Hh signaling-related molecules in humans revealed by studies using induced pluripotent stem cells.

Recent Advances in Signaling Pathways Comprehension as Carcinogenesis Triggers in Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common malignant skin tumor. BCC displays a different behavior compared with other neoplasms, has a slow evolution, and metastasizes very rarely, but sometimes it causes an important local destruction. Chronic ultraviolet exposure along with genetic factors are the most important risk factors involved in BCC development. Mutations in the PTCH1 gene are associated with Gorlin syndrome, an autosomal dominant disorder characterized by the occurrence of multiple BCCs, but are also the most frequent mutations observed in sporadic BCCs. PTCH1 encodes for PTCH1 protein, the most important negative regulator of the Hedgehog (Hh) pathway. There are numerous studies confirming Hh pathway involvement in BCC pathogenesis. Although Hh pathway has been intensively investigated, it remains incompletely elucidated. Recent studies on BCC tumorigenesis have shown that in addition to Hh pathway, there are other signaling pathways involved in BCC development. In this review, we present recent advances in BCC carcinogenesis.

Enhanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma

Neurotransmitters are reported to be involved in tumor initiation and progression. This study aimed to elucidate the prognostic value of γ-aminobutyric acid type A receptor δ subunit (GABRD) in colon adenocarcinoma (COAD) using the data from The Cancer Genome Atlas (TCGA) database. The GABRD mRNA expression levels in the COAD and normal tissues were compared using the Wilcoxon rank-sum test. The correlation between clinicopathologic characteristics and GABRD expression was analyzed by Wilcoxon rank-sum test or Kruskal-Wallis test and logistic regression. The prognostic value of GABRD mRNA expression in patients with COAD was determined using the Kaplan-Meier curve and Cox regression analysis. Finally, the molecular mechanisms of GABRD in COAD were predicted by gene set enrichment analysis (GSEA). The COAD tissues exhibited higher GABRD mRNA expression levels than the normal tissues. The logistic regression analysis revealed that GABRD mRNA expression was correlated with TNM stage, N stage, M stage, and microsatellite instability (MSI) status. The Kaplan-Meier survival curve and log-rank test revealed that patients with COAD exhibiting high GABRD mRNA expression were associated with poor overall survival (OS). The multivariate analysis indicated that increased GABRD mRNA expression was an independent prognostic factor and was correlated with a poor OS. The GSEA revealed that GABRD was involved in signaling pathways, including cell adhesion molecules, gap junction, melanogenesis, and mTOR signaling pathway, as well as the signaling pathways associated with basal cell carcinoma or bladder cancer development. In summary, enhanced GABRD mRNA expression may be a potential independent prognostic biomarker for COAD.

Association study indicates combined effect of interleukin-10 and angiotensin-converting enzyme in basal cell carcinoma development.

Cytokines involved in inflammatory and immune response have been associated with risk for development of basal cell carcinoma (BCC). In this study, three functional DNA polymorphisms affecting gene expression were investigated in 54 BCC patients and 111 healthy controls: interleukin-1b (IL-1b) +3953C/T, interleukin-10 (IL-10) -1082G/A and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms. Significant increase of the variant alleles was observed in IL-10 -1082G (P = 0.019) and in ACE D (P = 0.003) in BCC patients in comparison to controls. Multivariate logistic regression models evaluated the contribution of homozygous and heterozygous variant polymorphisms to the risk for BCC development. The studied polymorphisms influencing the expression of IL-10 and ACE genes were recognized as potential predictive factors for BCC. These findings suggest a possible molecular mechanism leading to BCC development that is likely to involve the activation of angiotensin receptors in combination with increased plasma levels of IL-10 in patients.

Impairment of Base Excision Repair in Dermal Fibroblasts Isolated From Nevoid Basal Cell Carcinoma Patients.

The nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome is an autosomal dominant disorder whose incidence is estimated at about 1 per 55,600–256,000 individuals. It is characterized by several developmental abnormalities and an increased predisposition to the development of basal cell carcinomas (BCCs). Cutaneous fibroblasts from Gorlin patients have been shown to exhibit an increased sensitivity to ionizing radiations. Mutations in the tumor suppressor gene PTCH1, which is part of the Sonic Hedgehog (SHH) signaling pathway, are responsible for these clinical manifestations. As several genetic mutations in the DNA repair genes are responsible of photo or radiosensitivity and high predisposition to cancers, we hypothesized that these effects in Gorlin syndrome might be due to a defect in the DNA damage response (DDR) and/or the DNA repair capacities. Therefore, the objective of this work was to investigate the sensitivity of skin fibroblasts from NBCCS patients to different DNA damaging agents and to determine the ability of these agents to modulate the DNA repair capacities. Gorlin fibroblasts showed high radiosensitivity and also less resistance to oxidative stress-inducing agents when compared to control fibroblasts obtained from healthy individuals. Gorlin fibroblasts harboring PTCH1 mutations were more sensitive to the exposure to ionizing radiation and to UVA. However, no difference in cell viability was shown after exposure to UVB or bleomycin. As BER is responsible for the repair of oxidative DNA damage, we decided to assess the BER pathway efficacy in Gorlin fibroblasts. Interestingly, a concomitant decrease of both BER gene expression and BER protein activity was observed in Gorlin fibroblasts when compared to control. Our results suggest that low levels of DNA repair within Gorlin cells may lead to an accumulation of oxidative DNA damage that could participate and partly explain the radiosensitivity and the BCC-prone phenotype in Gorlin syndrome.

Basal Cell Carcinoma: A Comprehensive Review.

Basal cell carcinoma (BCC) is the most common type of carcinoma worldwide. BCC development is the result of a complex interaction between environmental, phenotypic and genetic factors. However, despite the progress in the field, BCC biology and mechanisms of resistance against systemic treatments have been poorly investigated. The aim of the present review is to provide a revision of BCC histological and molecular features, including microRNA (miRNA) dysregulation, with a specific focus on the molecular basis of BCC systemic therapies. Papers from the last ten years regarding BCC genetic and phenotypic alterations, as well as the mechanism of resistance against hedgehog pathway inhibitors vismodegib and sonidegib were included. The involvement of miRNAs in BCC resistance to systemic therapies is emerging as a new field of knowledge.