PD-L1 and LAG-3 expression in advanced cutaneous squamous cell carcinomas.

BACKGROUND: Expression of programmed death ligand 1 (PD-L1) by cutaneous squamous cell carcinomas has been shown to correlate with advanced disease and risk of metastasis. Lymphocyte activation gene 3 (LAG-3, or CD223) is an inhibitory receptor that interacts with the PD-L1 axis, which has been shown to be a marker of immune exhaustion and a potential immunotherapy target. However, the role of LAG-3 in cutaneous squamous cell carcinoma has not been established. METHODS: We reviewed 18 cases of locally advanced and/or metastatic cutaneous squamous cell carcinomas and assessed for PD-L1 expression, presence or absence of tumor-infiltrating lymphocytes (TILs), and expression of LAG-3 by TILs. RESULTS: PD-L1 expression was present in 11 of 13 locally advanced primary tumors and 5 of 5 metastases. TILs were present in all 18 tumors, of which 14 cases were positive for LAG-3 expression. In positive cases, LAG-3 was expressed on average by 32% of TILs. CONCLUSIONS: Advanced cutaneous squamous cell carcinomas frequently express PD-L1 and are associated with an inflammatory response. LAG-3 expression by TILs was identified in a majority of cases. Our findings suggest that LAG-3 positive tumor-associated inflammatory cells may play a role in the development of advanced disease and offer another potential target for drug therapy.

Identification of a Robust Methylation Classifier for Cutaneous Melanoma Diagnosis.

Early diagnosis improves melanoma survival, yet the histopathological diagnosis of cutaneous primary melanoma can be challenging, even for expert dermatopathologists. Analysis of epigenetic alterations, such as DNA methylation, that occur in melanoma can aid in its early diagnosis. Using a genome-wide methylation screening, we assessed CpG methylation in a diverse set of 89 primary invasive melanomas, 73 nevi, and 41 melanocytic proliferations of uncertain malignant potential, classified based on interobserver review by dermatopathologists. Melanomas and nevi were split into training and validation sets. Predictive modeling in the training set using ElasticNet identified a 40-CpG classifier distinguishing 60 melanomas from 48 nevi. High diagnostic accuracy (area under the receiver operator characteristic curve = 0.996, sensitivity = 96.6%, and specificity = 100.0%) was independently confirmed in the validation set (29 melanomas, 25 nevi) and other published sample sets. The 40-CpG melanoma classifier included homeobox transcription factors and genes with roles in stem cell pluripotency or the nervous system. Application of the 40-CpG melanoma classifier to the diagnostically uncertain samples assigned melanoma or nevus status, potentially offering a diagnostic tool to assist dermatopathologists. In summary, the robust, accurate 40-CpG melanoma classifier offers a promising assay for improving primary melanoma diagnosis.

Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis.

Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.

Longitudinal Antibiotic Susceptibility Profiles of Staphylococcus aureus Cutaneous Infections in a Pediatric Outpatient Population.

This longitudinal update on Staphylococcus aureus prevalence and antibiotic resistance patterns surveyd 291 cultures from 188 patients in a pediatric outpatient dermatology clinic with suspected skin and soft tissue infections. The prevalence of methicillin-resistant Staphylococcus aureus remained stable at 24%. Staphylococcus aureus resistance to tetracyclines modestly but demonstrably increased in the interval since 2009.

PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression in primary cutaneous squamous cell carcinoma has not been described. METHODS: We reviewed immunohistochemical stained sections of 40 primary and five metastatic cutaneous squamous cell carcinomas using antibody to PD-L1 and classified the staining pattern according to the DAKO tumor proportion score method. We compared the staining results with microscopic staging parameters associated with risk of metastasis including tumor diameter, histologic grade, tumor thickness and perineural invasion. RESULTS: PD-L1 expression was present in 4 of 20 low risk tumors (20%), all of which showed low expression. PD-L1 expression was present in 14 of 20 high risk tumors (70%), 12 of which showed low expression and 2 of which showed high expression, 5 of 5 metastases (100%), with three showing low expression and two showing high expression. CONCLUSIONS: This survey documents PD-L1 expression in cutaneous squamous cell carcinoma and shows a positive correlation between the degree PD-L1 expression and pathologic findings related to risk of metastasis including large diameter, higher histological grade and tumor thickness.

Systemic therapy of childhood atopic dermatitis.

Atopic dermatitis (AD) is a common childhood inflammatory disease that, in a small percentage of cases, can become severe enough to require potent systemic treatment. Many trials have been conducted with systemic agents for the treatment of severe pediatric AD; we review the evidence here. Although corticosteroids are widely used in practice, they are not generally recommended as a systemic treatment option for AD in children. Most patients experience a relatively rapid and robust response to cyclosporine. Treating children with cyclosporine long term is troubling; however, azathioprine, mycophenolate mofetil, and methotrexate are all reasonable alternatives for maintenance therapy in recalcitrant cases. Several additional options are available for the most refractory cases, including interferon-γ, intravenous immunoglobulin, and various biologics. Phototherapy is another modality that can be effective in treating severe AD. Ultimately the choice of agent is individualized. Systemic therapy options are associated with potentially severe adverse effects and require careful monitoring. Nonsystemic approaches toward prevention of flares and long-term control of atopic dermatitis in pediatric patients should be continued in conjunction with systemic therapy. In the future, more targeted systemic treatments hold the potential for effective control of disease with fewer side effects than broadly immunosuppressive agents.

DNA methylation profiles in primary cutaneous melanomas are associated with clinically significant pathologic features.

DNA methylation studies have elucidated a methylation signature distinguishing primary melanomas from benign nevi and provided new insights about genes that may be important in melanoma development. However, it is unclear whether methylation differences among primary melanomas are related to tumor pathologic features with known clinical significance. We utilized the Illumina GoldenGate Cancer Panel array to investigate the methylation profiles of 47 primary cutaneous melanomas. Arraywide methylation patterns revealed a positive association of methylation with Breslow thickness and mutated BRAF, a negative association with mitotic rate, and a weak association with ulceration. Hierarchical clustering on CpG sites exhibiting the most variable methylation (n = 235) divided the melanoma samples into three clusters, including a highly methylated cluster that was positively associated with Breslow thickness and an intermediately methylated cluster associated with Breslow thickness and mitotic rate. Our findings provide support for the existence of methylation-defined subsets in melanomas with increased methylation associated with Breslow thickness.