Gene Expression Profiles in Cutaneous Oncology.

Skin cancer is highly curable under most circumstances; however, locally advanced or metastatic disease historically has poor outcomes and limited treatment options. Treatment has recently been advanced by the discovery of pertinent genes influencing pathogenesis and further revolutionized by the advent of specific gene expression profiles (GEPs). GEPs have been developed to help refine current diagnostic and prognostic strategies used in skin cancer with the goal to ultimately help guide management and treatment modalities to improve patient care. This article provides a high-level review of diagnostic and prognostic GEPs that have been developed specifically for squamous cell carcinoma and melanoma.

Cutaneous Squamous Cell Carcinoma Arising in Immunosuppressed Patients: A Systematic Review of Tumor Profiling Studies.

As solid organ transplantation becomes more prevalent, more individuals are living as members of the immunosuppressed population with an elevated risk for cutaneous squamous cell carcinoma (cSCC). Although great progress has been made in understanding the pathogenesis of cSCC in general, little is known about the drivers of tumorigenesis in immunosuppressed patients and organ-transplant recipients, specifically. This systematic review sought to synthesize information regarding the genetic and epigenetic alterations as well as changes in protein and mRNA expression that place this growing population at risk for cSCC, influence treatment response, and promote tumor aggressiveness. This review will provide investigators with a framework to identify future areas of investigation and clinicians with additional insight into how to best manage these patients.

Sequencing of Cutaneous Squamous Cell Carcinoma Primary Tumors and Patient-Matched Metastases Reveals ALK as a Potential Driver in Metastases and Low Mutational Concordance in Immunocompromised Patients.

Cutaneous squamous cell carcinoma is a common skin cancer that is responsible for 1,000,000 cases and up to 9,000 deaths annually in the United States. Metastases occur in 2-5% of patients and are responsible for significant morbidity and mortality. The objective of this study is to perform targeted next-generation sequencing on a cohort of squamous cell carcinoma primary tumors and patient-matched lymph node metastases. An oncology 76-gene panel was run from formalin-fixed paraffin-embedded samples of patient-matched primary squamous cell carcinomas (10) and resultant metastases (10). ALK was discovered to be a driver mutation in metastases using two different algorithms, oncoCLUSTand dNdScv. Mutational concordance between primary tumors and metastases was notably lower in immunosuppressed patients, especially among pathogenic mutations (41.7% vs. 83.3%, P = 0.01). Sequencing of matched squamous cell carcinoma primary tumors and lymph node metastases identified genes and pathways that may have clinical importance, most notably ALK as a potential driver mutation of metastasis. Sequencing of both primary tumors and metastases may improve the efficacy of targeted therapies.

Rare Cutaneous Malignancies in Skin of Color.

BACKGROUND: There is a scarcity of information regarding the clinical characteristics of rare cutaneous malignancies in skin of color that has yet to be comprehensively explored. OBJECTIVE: To review and compile the racial differences in epidemiology, clinical presentation, histology, treatments, and outcomes of 3 rare skin cancers: dermatofibrosarcoma protuberans (DFSP), Merkel cell carcinoma (MCC), and sebaceous carcinoma (SC). METHODS: Several searches with keywords denoting specific skin cancer type and race were conducted on PubMed to complete this narrative review. RESULTS: We analyzed 50 sources that were relevant to the initial objective. CONCLUSION: The literature demonstrates that there are nuances in DFSP, MCC, and SC unique to African Americans, Asians/Pacific Islanders, and Hispanics that may differ significantly from Caucasian counterparts. African Americans consistently suffer from the worst clinical outcomes in all 3 rare cutaneous malignancies reviewed. Greater physician awareness and knowledge of the discussed racial differences is the preliminary step to address these disparities.

Recurrence Status, Perineural Invasion, and Hypothyroidism Are Associated With Lymph Node Metastasis in Cutaneous Squamous Cell Carcinoma: A Case-Control Study.

BACKGROUND: Lymph node metastasis is a critical prognostic indicator for mortality in patients with cutaneous squamous cell carcinoma (SCC). OBJECTIVE: To identify and characterize key risk factors for SCC lymph node metastasis. METHODS: This was a multi-institutional, case-control study of 65 cutaneous SCCs with known lymph node metastasis matched with 195 cutaneous SCCs without lymph node metastasis (3:1 matching). The cases and controls were matched by anatomic location, age, and sex. Odds ratios (ORs) and their 95% confidence intervals (CIs) were generated to determine the association between specific risk factors and lymph node metastasis in a multivariate analysis. RESULTS: Recurrent tumors (p < .001), perineural invasion (p < .001), lymphovascular invasion (p = .002), size of 2 cm or greater (p = .008), and hypothyroidism (p = .03) were significantly more common in the lymph node metastasis cohort. Recurrence (OR 6.3, 95% CI 2.6-15.3), perineural invasion (OR 4.5, 95% CI 1.7-11.8), and hypothyroidism (OR 2.7, 95% CI 1.04-7.0) remained significant on performing a multivariate analysis. CONCLUSION: Lymph node metastasis in SCC is associated with recurrence, perineural invasion, lymphovascular invasion, size of 2 cm or greater, and hypothyroidism. Clinical consideration of these findings within the context of current staging systems may help improve patient outcomes.

Glycosylation of FGFR4 in cholangiocarcinoma regulates receptor processing and cancer signaling.

Recent advances in targeted treatment for cholangiocarcinoma have focused on fibroblast growth factor (FGF) signaling. There are four receptor tyrosine kinases that respond to FGFs, and posttranslational processing has been demonstrated for each FGF receptor. Here, we investigated the role of N-linked glycosylation on the processing and function of FGFR4. We altered glycosylation through enzymatic deglycosylation, small molecule inhibition of glycosyltransferases, or through site-directed mutagenesis of selected asparagine residues in FGFR4. Signaling was tested through caspase activation, migration, and subcellular localization of FGFR4. Our data demonstrate that FGFR4 has multiple glycoforms, with predominant bands relating to the full-length receptor that has a high mannose- or hybrid-type form and a complex-type glycan form. We further identified a set of faster migrating FGFR4 bands that correspond to the intracellular kinase domain, termed FGFR4 intracellular domain (R4-ICD). These glycoforms and R4-ICD were detected in human cholangiocarcinoma tumor samples, where R4-ICD was predominant. Removal of glycans in intact cells by enzymatic deglycosylation resulted in increased processing to R4-ICD. Inhibition of glycosylation using NGI-1, an oligosaccharyltransferase inhibitor, reduced both high mannose- or hybrid- and complex-type glycan forms of FGFR4, increased processing and sensitized to apoptosis. Mutation of Asn-112, Asn-258, Asn-290, or Asn-311 to glutamine modestly reduced apoptosis resistance, while mutation of Asn-322 or simultaneous mutation of the other four asparagine residues caused a loss of cytoprotection by FGFR4. None of the glycomutants altered the migration of cancer cells. Finally, mutation of Asn-112 caused a partial localization of FGFR4 to the Golgi. Overall, preventing glycosylation at individual residues reduced the cell survival function of FGFR4 and receptor glycosylation may regulate access to an extracellular protease or proteolytic susceptibility of FGFR4.

Analysis of mutations in cutaneous squamous cell carcinoma reveals novel genes and mutations associated with patient-specific characteristics and metastasis: a systematic review.

Cutaneous squamous cell carcinoma (SCC) causes approximately 1,000,000 cases and 9000 deaths each year in the United States. While individual tumor sequencing studies have discovered driver mutations in SCC, there has yet to be a review and subsequent analysis synthesizing current studies. To conduct a comprehensive synthesis and analysis of SCC sequencing studies with individual patient-level data, a comprehensive literature search was performed. Statistical analyses were performed to identify trends. Studies meeting inclusion criteria included a total of 279 patients (189 localized SCCs, 90 metastatic SCCs). Several mutations were correlated with demographic characteristics (TP53, MLL4, BRCA2, COL4A1). TP53, TERT, SPEN, MLL3, and NOTCH2 mutations were significantly more likely to be found in metastatic versus localized SCCs even after the Bonferroni correction for multiple comparisons. Silent mutations were found more in localized SCCs than metastatic SCCs, and nonsense mutations were found more in metastatic SCCs than localized SCCs (p = 0.0003 and p = 0.04, respectively). Additional mutations were identified that have not yet been explored in SCC including AHNAK2, LRP1B, TRIO, MDN1, COL4A2, SVIL, VPS13C, DST, DMD, and DYSF. Overall, novel mutations were identified and differences between mutation patterns in localized and metastatic SCCs were found. These findings may have clinical applications.

What's Eating You? Culex Mosquitoes and West Nile Virus.

West Nile virus (WNV) commonly presents cutaneously as a maculopapular rash on the trunk and extremities that most often appears around the time of defervescence and may serve as a positive prognostic indicator. Several laboratory tests can aid in diagnosis of WNV, including an IgM enzyme-linked immunosorbent assay (ELISA), but an antibody response may not be detectable for up to 8 days after symptom onset. Taking a comprehensive history in any patient presenting with a generalized maculopapular rash, fever, nonspecific symptoms, or neurologic changes can aid the astute dermatologist in promptly recognizing the possibility of WNV.

Basal Cell Carcinoma Gene Mutations Differ Between Asian, Hispanic, and Caucasian Patients: A Pilot Study.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy worldwide. While most BCCs are treated surgically, advanced BCCs are often treated with gene-targeted therapies. While there has been a lot of research in BCC from Caucasian patients, research is lacking in patients with skin of color. OBJECTIVE: To identify potential variations in BCC gene mutations between Asian, Hispanic, and Caucasian patients. METHODS: A cohort study was performed from 2015 to 2017 with 23 patients treated for BCC at an urban academic hospital. Gene mutations were assessed using a targeted mutation panel for 76 cancer-associated genes from formalin-fixed paraffin-embedded (FFPE) samples. RESULTS: Groups studied comprised Asian (n=5), Hispanic (n=10), and Caucasian (n=8) patients. The Hispanic cohort had the highest number of mutations per patient on average (3.4 versus 2.8 for both Caucasian and Asian cohorts). GATA3 mutations were more prevalent in Hispanic patients (P=0.02, single factor ANOVA). ARID1A and PTEN mutations co-occurred in the Hispanic cohort (P<0.05). The most common mutation in the Asian cohort was TP53 (2/5). The Caucasian cohort had the highest percent of UVB mutations (68.4%). CONCLUSIONS: This study shows potential differences in the prevalence of somatic gene mutations for BCC patients of different races and ethnicities, which could inform the underlying pathogenesis, impact the efficacy of therapies in specific populations, and may also help identify novel therapeutic targets. J Drugs Dermatol. 20(5): doi:10.36849/JDD.5884.

What Is New in Occupational Allergic Contact Dermatitis in the Year of the COVID Pandemic?

PURPOSE OF REVIEW: This article aims to summarize some recent trends in occupational allergic contact dermatitis (ACD), including dermatitis related to pandemic-level personal protective equipment in healthcare workers, hazards patients may experience when working from home, and occupational perspectives on the recent American Contact Dermatitis Society (ACDS) allergens of the year and ACDS Core Allergen Series updates. RECENT FINDINGS: Recent ACDS Allergens of the Year may be particularly relevant to healthcare workers, including isobornyl acrylate, which is present in glucose sensors and propylene glycol present in hand cleansers and disinfectants. Lavender, limonene, and linalool, all of which are new additions to the ACDS Core Allergen Series, have been reported as causes for occupational ACD in massage therapists and aromatherapists. Isothiazolinone allergy continues to rise in both consumer and occupational settings. Finally, the COVID-19 pandemic has resulted in a wave of occupational ACD in healthcare workers to personal protective equipment, and revealed new potential allergens for individuals working from home. Occupational allergic contact dermatitis continues to exert a significant occupational disease burden. Remaining aware of the current trends in allergens may allow for earlier recognition, diagnosis, and treatment, subsequently helping our patients to work in healthier and safer environments.

The Correlation Between Immunohistochemistry Findings and Metastasis in Squamous Cell Carcinoma: A Review.

BACKGROUND: Cutaneous squamous cell carcinoma (SCC) is the second most common type of skin cancer. Only 2% to 5% of SCCs metastasize; however, those do carry a poor prognosis. Immunohistochemistry (IHC) is widely used by pathologists to characterize skin cancers and provide clinically useful information. OBJECTIVE: To evaluate the potential prognostic associations between IHC findings and metastasis in SCC. METHODS: Searches were conducted in MEDLINE via PubMed for articles published between 1999 and 2019. Search criteria included key words "immunohistochemistry" and "cutaneous squamous cell carcinoma." Six hundred and fifty-three articles were returned and screened, which ultimately left 31 for inclusion in our manuscript. RESULTS: Thirty-one articles analyzed in this review included a discussion of the expression of a particular IHC marker and the associated risk of metastasis and/or clinical utility of IHC markers in SCC, especially metastatic SCC. Markers that had several or more studies supporting clinical utility were E-cadherin, podoplanin, CD8+ T cells, PD-L1, epidermal growth factor receptor, and Cyclin D1. CONCLUSION: Immunohistochemistry profiling of SCC may be useful in select cases when providing a prognosis remains challenging and in identification of potential therapeutic targets for high-risk or metastatic tumors.

Next-generation sequencing identifies novel single nucleotide polymorphisms in high-risk cutaneous squamous cell carcinoma: A pilot study.

BACKGROUND: Cutaneous squamous cell carcinoma (SCC) causes 1 million cases in the United States annually. There are germline single nucleotide polymorphisms (SNPs) that result in an increased risk of SCC and altered response to therapy. PREMISE: There may be biologically relevant SNPs not detected using traditional GWAS studies. HYPOTHESIS: There are clinically and biologically relevant SNPs in high-risk SCC that may only be appreciated with next-generation sequencing. HOW TO TEST HYPOTHESIS: We performed next-generation sequencing (NGS) on primary SCCs using a targeted mutation panel with 76 cancer-associated genes. We analysed the presence of SNPs in a cohort of 20 high-risk SCCs compared to the American population (AP) (dbSNP). RELEVANCE AND PERSPECTIVES: Missense rs3822214 was present in significantly more SCC cases versus the AP. While the remainder is synonymous SNPs, there is growing evidence suggesting clinical relevance of these variants. A larger cohort to validate these findings would be useful.

Targeted next-generation sequencing of matched localized and metastatic primary high-risk SCCs identifies driver and co-occurring mutations and novel therapeutic targets.

BACKGROUND: Cutaneous squamous cell carcinoma (SCC) is the second most common type of skin cancer and is responsible for over one million cases annually. While only 3-5 % of SCCs metastasize, those that do are associated with significant morbidity and mortality. Using gene mutations to help predict metastasis and select therapeutics is still being explored. OBJECTIVE: To present novel data from targeted sequencing of 20 case-matched localized and metastatic high-risk SCCs. METHODS: A cancer-associated gene panel of 76 genes was run from formalin-fixed paraffin-embedded samples of 20 case-matched localized (10) and metastatic (10) high-risk SCCs (Vela Diagnostics). RESULTS: Using spatial clustering analysis, primary driver mutations were identified asEGFR in localized SCC and CDH1 in metastatic SCC. ERBB4 and STK11 were found to be significant co-occurring mutations in localized SCC. Pathway analyses showed the RTK/RAS, TP53, TGF-b, NOTCH1, PI3K, and cell cycle pathways to be highly relevant in all high-risk SCCs with the Wnt pathway enhanced in metastatic SCC only. CONCLUSIONS: This study compared gene mutations between localized and metastatic SCC with the intent of identifying key differences and new potential targeted treatment options. To our knowledge, the co-occurrence ofERBB4 and STK11 mutations has not been previously reported. Targeted inhibition of CDH1 and the Wnt pathway should be further explored in metastatic SCC.

The Effects of Lavender Essential Oil on Wound Healing: A Review of the Current Evidence.

Background: The commercialization of essential oils has expanded their presence in the United States, and emerging studies demonstrate that they may have a place in Western medicine. One oil with a significant body of evidence is lavender essential oil, which may have benefits in wound healing. Objectives: This review aims to present the scientific literature on therapeutic lavender essential oil with the goal of expanding the current repertoire of cost-effective wound healing options available to physicians and patients. Methods: A review was conducted according to PRISMA guidelines in PubMed, Cochrane Library, and Embase from June 2018 through March 2019 to identify articles related to lavender essential oil in the context of wound healing. Results: This search yielded 36 unique studies, 20 of which remained after screening. This review utilizes human clinical trials (n = 7), animal trials (n = 5), in vitro studies (n = 2), and previously conducted reviews (n = 6). Overall, these studies demonstrated a faster rate of wound healing, increased expression of collagen, and enhanced activity of proteins involved in the tissue remodeling process in wounds treated with lavender essential oil. Conclusions: The current body of literature suggests a potential therapeutic benefit of lavender essential oil in wound healing. However, standardization of the chemical composition and additional high-quality human clinical trials are needed to further evaluate the safety and efficacy of lavender essential oil in clinical practice.

The proportion of male and female editors in women's health journals: A critical analysis and review of the sex gap.

BACKGROUND: Historically, women have been underrepresented in leadership positions in medicine. The reasons for this are multifactorial. In recent years, women's representation in medicine has improved. However, inequities in the proportion of men and women in medical leadership remain, especially with regard to editorial journal boards. OBJECTIVE: This study aimed to explore current trends of women in leadership positions on journal editorial boards. METHODS: A comprehensive search for women's health journals was performed in collaboration with university librarians in February 2019 using EMBASE, Scopus, SciFinder, and MEDLINE records for journals with relevance to women's health. Each journal was e-mailed to verify the accuracy of the journal editorial boards listed on their respective webpages. Five categories, as well as the totals for each journal, were analyzed for the proportion of women versus men: editor-in-chief, associate editor, deputy editor, and section editor, and other. RESULTS: Women comprised the minority of positions on women's health editorial boards. Of the total 1440 board members included, 602 members (42%) were women and 838 members (58%) were men. Women occupied 54 of 132 editor-in-chief positions (41%), 257 of 596 associate editor positions (43%), 13 of 42 deputy editor positions (30%), 46 of 120 section editor positions (38%), and 232 of 549 other editor positions (42%). CONCLUSION: Although the sex gap in leadership in medicine is improving, it is still present. Our findings suggest that women are underrepresented as editors at most levels in women's health journals centered on topics such as reproductive health, obstetrics and gynecology, perinatology, gynecological oncology, and breastfeeding. With sponsorship/mentorship for women, flexible scheduling, and considerate thought in leadership appointment, this sex gap will continue to improve.

Representation of women as editors in dermatology journals: A comprehensive review.

BACKGROUND: Despite a substantial increase in the number of women matriculating into medical school, a gender gap still exists with respect to academic leadership positions. This gap is apparent in the field of dermatology, particularly in the composition of dermatology journal editorial boards. To address this gap, we must first acknowledge its existence, examine potential reasons for its existence, and propose strategies to narrow the gap. OBJECTIVE: Our objective is to determine the representation of women as editors in dermatology journals. METHODS: A comprehensive search was performed for dermatology journals indexed in Medline, Journal Citation Reports, Scopus, and Embase in August, September, and October 2018. The editorial board of each journal was analyzed for the number and percentage of male and female editors in four different positions. We verified the accuracy of editorial boards listed on publisher websites by emailing administrative personnel. We also recorded the number of years from terminal degree for editorial board members of the 10 journals with the highest impact factors using SCImago Journal Rankings. RESULTS: Women occupied 18% of editor-in-chief positions, 36% of deputy editor roles, 22% of overall editorial board positions, and 22% of other board roles. The average number of years since terminal degree was not statistically different between women and men, with women averaging 30.2 years and men averaging 28.0 years since completion of terminal degree (p = .27). CONCLUSIONS: Our findings suggest that women are underrepresented as editors at all levels in dermatology journals. This supports prior findings reporting a minority of women in academic leadership roles. Thus, although women have made major advancements in the medical field over the past century, there remains room for progress with regard to equal representation in academic leadership roles, including editorial positions, professorships, and department chair roles.