The process of melanosome transfer has fascinated pigment cell biologists for decades. Whole-organelle transfer is a unique property of melanocytes, suggesting that the biologic underpinnings of the ...process reflect melanocyte- and keratinocyte-specific proteins and pathways. Although several mechanisms of melanosome transfer are likely to occur in the skin, Ando et al. focused on a new mechanism of melanosome transfer that involves release of melanosome-containing globules, similar to shedding vesicles into the extracellular space, followed by uptake by keratinocytes. This model adds further complexity to the process of melanosome transfer in the skin.
Telomerase is frequently expressed in cancer and contributes to carcinogenesis. Two recent publications report the identification of a set of recurrent mutations in melanoma in the promoter of the ...telomerase reverse transcriptase gene (TERT) that appears to be the result of mutagenesis from ultraviolet (UV) radiation. Both groups reported that the mutations increase the transcription of TERT. This prompted our search for similar mutations in two other UV-related skin cancers, basal cell carcinoma, and squamous cell carcinoma. We found that the activating TERT promoter mutations reported in melanoma are also frequent in squamous cell carcinoma (50%) and basal cell carcinoma, the latter including both sporadic tumors (78%) and tumors from patients with nevoid basal cell carcinoma syndrome (68%). These mutations were found in only 1 of 11 Bowen's disease (squamous cell carcinoma in situ) specimens, and in none of 15 non-malignant skin specimens and 57 blood specimens. The mutations were frequently homozygous or hemizygous, with little or no normal signal at the mutated positions. These data suggest that TERT promoter mutations are the most frequent putative oncogenic mutations in cutaneous cancer.
Semaphorins are secreted and membrane-bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilin receptors. We recently reported that Plexin ...B1, the Semaphorin 4D (Sema4D) receptor, is a tumor-suppressor protein for melanoma, which functions, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report, we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to UV irradiation, and that it stimulates proliferation and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, partly through downregulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand, hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Sema4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met-dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly downregulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF-dependent effects on melanocytes, including melanocyte migration.
Although B cells account for a significant proportion of the lymphocytic infiltrate in discoid lupus erythematosus (DLE), their contribution to pathogenesis is unknown. In this study, we compare the ...immune landscape of 17 subjects with DLE with that of 21 subjects with subacute cutaneous lupus erythematosus using transcriptomic and histologic analyses of lesional skin. A few of the subjects (3 of 17 subjects with DLE, and 5 of 21 subjects with subacute cutaneous lupus erythematosus) had concomitant systemic lupus erythematosus. Using a modified Autoimmune Profiling Panel (NanoString Technologies, Seatle, WA), we show that B-cell‒specific genes, including canonical pan‒B cell markers CD19 (P = 0.0060), MS4A1 (CD20) (P = 0.0047), and CD79a (P = 0.0201), are among the most upregulated genes in DLE. Numerous other genes encoding B-cell‒associated proteins, including Igs, BAFF receptors, and FCRL family members, are similarly enriched. Relative cell type scoring reveals that among various inflammatory cell types, only B cells are more prevalent in DLE. Digital whole-image slide analysis of immunohistochemistry for B cells (CD20) and T cells (CD3) supports our gene expression findings of a disproportionately greater B-cell infiltrate in DLE lesions. Overall, this study identifies a B-cell‒predominant signature unique to DLE and highlights the importance of studying the role of cutaneous B cells in DLE pathogenesis.
Background Pigmented epithelioid melanocytoma (PEM) is an uncommon, recently described entity with unknown biologic behavior. There is a high rate of regional metastases, but limited evidence of ...distant metastases or disease-related death. Objective We sought to report our series of patients given a diagnosis of PEM at our institution and provide mutational analysis of genes commonly implicated in melanoma in 2 cases. Methods The pathology database was queried for cases of PEM diagnosed at the University of Rochester. Charts were reviewed for follow-up information. Mutational analysis of melanoma-associated genes was performed on 2 cases. Results Nine cases of PEM were retrieved in a 10-year retrospective review. Five patients underwent sentinel lymph node biopsy with 3 of 5 having a positive sentinel lymph node. All 9 patients are alive and disease-free with average follow-up of 38.75 months. Two tumors were tested for common melanoma-associated mutations, and were negative, except for a telomerase reverse transcriptase promoter deletion detected in 1 sample. The deletion has not been associated with melanoma, and therefore its biologic significance is unclear. Limitations Small sample size, retrospective nature, and single institution experience are limitations. Conclusions PEM appears to have an indolent behavior. However, currently the evidence is too limited to provide insight into its true biologic potential.
Dermatologic reactions are among the most common adverse events of antiprogrammed cell death‐1 (anti‐PD‐1) monoclonal antibodies agents and include maculopapular rash, psoriasiform rash, lichenoid ...eruptions, autoimmune bullous disorders, and vitiligo. Here, we present a case of a 12‐year‐old African American male with metastatic spitzoid melanoma treated with nivolumab who developed a mild lichenoid eruption that progressed to a severe case of lichen planus pemphigoides (LPP). Management was complex given the patient's age and history and included hospitalization for intravenous steroids, an intensive topical steroid regimen, methotrexate, and discontinuation of nivolumab. This case illustrates a rare but dramatic progression from a mild LP‐like eruption to severe bullous lichenoid eruption, most consistent with LPP, as well as the diagnostic and treatment challenges in the setting of a pediatric patient on nivolumab.
Background. Granuloma annulare (GA) is a common, benign, idiopathic inflammatory dermatosis. Aside from case reports and small studies, there are limited data about the characteristics of GA in ...children. Objective. This study aimed to better characterize the epidemiologic and clinical features, triggering factors, disease associations, and outcomes of GA in the pediatric population. Methods. We conducted a retrospective study of 73 pediatric patients diagnosed with GA at the University of Rochester Medical Center over a 7-year period. Results. The most common subtype was localized GA (71.2%, n = 52), followed by subcutaneous (also known as “deep GA”; 16.4%, n = 12) and generalized (12.3%, n = 9) subtypes. Over 90% of patients had idiopathic GA, with the remaining patients reporting viral infection or trauma as triggers. Half of the patients studied had comorbid conditions, most frequently atopic dermatitis (17.8%, n = 13), obesity (9.59%, n = 7), asthma (6.85%, n = 5), and allergic rhinitis (6.85%, n = 5). The median duration of the disease was 11.00 months (interquartile range (IQR) 15.75 months); generalized GA had the shortest duration (median 10.00 months, IQR 15.50 months), while subcutaneous GA had the longest duration (median 12.00 months and IQR 29.00 months). Although recurrence rates for subcutaneous and generalized GA were high at 45.5% and 33.3%, respectively, most patients achieved clearance or improvement with treatment. Conclusion. Most cases of GA in our study were idiopathic, with no clear differences between GA subtypes and associated comorbidities. Topical steroids were the most prescribed treatment with mixed efficacy.
Current staging systems for cutaneous squamous cell carcinoma (cSCC) incorporate histologic grade. There are no universally agreed on criteria to define differentiation for cSCC.
To determine the ...interrater and intrarater reliability among dermatopathologists and Mohs surgeons in grading histological differentiation for cSCC.
One hundred thirty-one archived slides were selected. Three dermatopathologists and 3 Mohs surgeons graded the tumors in a blinded manner (Round 1). In an attempt to improve concordance, all 6 participants were then asked to regrade the tumors based on a devised quantitative grading scale (Round 2).
For Round 1, overall κ was 0.56 corresponding to a weak agreement. κ for well, moderate, and poorly differentiated tumors was 0.68, 0.39, and 0.59, respectively, corresponding to moderate, minimal, and weak concordance. For Round 2 of the study, overall κ was 0.60, with κ = 0.75, 0.46, and 0.61 for well, moderate, and poorly differentiated tumors, respectively. Overall intrarater reliability was 0.70 (κ = 0.70, 0.77, 0.68, 0.71, 0.56, and 0.75), corresponding to a moderate concordance.
Overall concordance for cSCC histologic grading is weak to moderate among the experimental group. Substantial differences in concordance exist among histological degrees of differentiation, with lowest agreement in moderately differentiated tumors.
Recombinant proteins are widely used in biomedical sciences, and in pharmaceutical research. Through genetic recombination, specific DNA sequences are engineered and inserted into a biological host. ...Once inside the host, the DNA is transcribed and translated into the target protein and is ready to be purified. Here, we describe the transfection, purification, and visualization of Fc-tagged SEMA4D (semaphorin 4D) recombinant protein.
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