Risk factors and outcomes of melanoma in children and adolescents: A retrospective multicenter study.

BACKGROUND: Pediatric melanoma presents with distinct clinical features compared to adult disease. OBJECTIVE: Characterize risk factors and negative outcomes in pediatric melanoma. METHODS: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers. RESULTS: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls. LIMITATIONS: Retrospective nature, cohort size, control selection, and potential referral bias. CONCLUSION: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma.

A retrospective multicenter study of fatal pediatric melanoma.

BACKGROUND: Pediatric melanoma is rare and diagnostically challenging. OBJECTIVE: To characterize clinical and histopathologic features of fatal pediatric melanomas. METHODS: Multicenter retrospective study of fatal melanoma cases in patients younger than 20 years diagnosed between 1994 and 2017. RESULTS: Of 38 cases of fatal pediatric melanoma identified, 57% presented in white patients and 19% in Hispanic patients. The average age at diagnosis was 12.7 years (range, 0.0-19.9 y), and the average age at death was 15.6 years (range, 1.2-26.2 y). Among cases with known identifiable subtypes, 50% were nodular (8/16), 31% were superficial spreading (5/16), and 19% were spitzoid melanoma (3/16). One fourth (10/38) of melanomas arose in association with congenital melanocytic nevi. LIMITATIONS: Retrospective nature, cohort size, and potential referral bias. CONCLUSIONS: Pediatric melanoma can be fatal in diverse clinical presentations, including a striking prevalence of Hispanic patients compared to adult disease, and with a range of clinical subtypes, although no fatal cases of spitzoid melanoma were diagnosed during childhood.

Clinical and dermoscopic features of cutaneous BAP1-inactivated melanocytic tumors: Results of a multicenter case-control study by the International Dermoscopy Society.

BACKGROUND: Multiple BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) have been associated with a familial cancer syndrome involving germline mutations in BAP1. OBJECTIVES: We sought to describe the clinical and dermoscopic features of BIMTs. METHODS: This was a retrospective, multicenter, case-control study. Participating centers contributed clinical data, dermoscopic images, and histopathologic data of biopsy-proven BIMTs. We compared the dermoscopic features between BIMTs and control patients. RESULTS: The dataset consisted of 48 BIMTs from 31 patients (22 women; median age 37 years) and 80 control patients. Eleven patients had a BAP1 germline mutation. Clinically, most BIMTs presented as pink, dome-shaped papules (n = 24). Dermoscopically, we identified 5 patterns: structureless pink-to-tan with irregular eccentric dots/globules (n = 14, 29.8%); structureless pink-to-tan with peripheral vessels (n = 10, 21.3%); structureless pink-to-tan (n = 7, 14.9%); a network with raised, structureless, pink-to-tan areas (n = 7, 14.9%); and globular pattern (n = 4, 8.5%). The structureless with eccentric dots/globules pattern and network with raised structureless areas pattern were only identified in BIMT and were more common in patients with BAP1 germline mutations (P < .0001 and P = .001, respectively). LIMITATIONS: Limitations included our small sample size, retrospective design, the absence of germline genetic testing in all patients, and inclusion bias toward more atypical-looking BIMTs. CONCLUSIONS: Dome-shaped papules with pink-to-tan structureless areas and peripheral irregular dots/globules or network should raise the clinical suspicion for BIMT.

Nevi and lasers: Practical considerations.

Lasers are increasingly used for elective ablation of melanocytic nevi (MN). However, the associated risks of treating MN with lasers are debated and not well studied. Theoretical risks include inadvertently treating a melanoma mistaken for a nevus, the inability to remove all nevus cells and the possibility for residual cells to undergo malignant transformation, and the difficulty in clinically monitoring the remnant nevus for melanoma progression. Additional concerns include the morphological suitability of a lesion for laser removal and managing patients' expectations about the variable cosmetic outcomes. These potential issues have prompted us to outline some practical suggestions for clinicians and patients to consider when determining the suitability of a nevus for laser ablation. The choice to perform laser removal of a nevus is personal, both from the perspective of the treating physician and that of the person being treated. While acknowledging some uncertainty, we believe that these suggestions can help mitigate risk and improve patient outcomes. Lasers Surg. Med. 50:7-9, 2018. © 2017 Wiley Periodicals, Inc.

SVEP1 plays a crucial role in epidermal differentiation.

SVEP1 is a recently identified multidomain cell adhesion protein, homologous to the mouse polydom protein, which has been shown to mediate cell-cell adhesion in an integrin-dependent manner in osteogenic cells. In this study, we characterized SVEP1 function in the epidermis. SVEP1 was found by qRT-PCR to be ubiquitously expressed in human tissues, including the skin. Confocal microscopy revealed that SVEP1 is normally mostly expressed in the cytoplasm of basal and suprabasal epidermal cells. Downregulation of SVEP1 expression in primary keratinocytes resulted in decreased expression of major epidermal differentiation markers. Similarly, SVEP1 downregulation was associated with disturbed differentiation and marked epidermal acanthosis in three-dimensional skin equivalents. In contrast, the dispase assay failed to demonstrate significant differences in adhesion between keratinocytes expressing normal vs low levels of SVEP1. Homozygous Svep1 knockout mice were embryonic lethal. Thus, to assess the importance of SVEP1 for normal skin homoeostasis in vivo, we downregulated SVEP1 in zebrafish embryos with a Svep1-specific splice morpholino. Scanning electron microscopy revealed a rugged epidermis with perturbed microridge formation in the centre of the keratinocytes of morphant larvae. Transmission electron microscopy analysis demonstrated abnormal epidermal cell-cell adhesion with disadhesion between cells in Svep1-deficient morphant larvae compared to controls. In summary, our results indicate that SVEP1 plays a critical role during epidermal differentiation.

Dermoscopic Photographs Impact Confidence and Management of Remotely Triaged Skin Lesions.

Introduction: Improving remote triage is crucial given expansions in tele-dermatology and with limited in-person care during COVID-19. In addition to clinical pictures, dermoscopic images may provide utility for triage. Objectives: To determine if dermoscopic images enhance confidence, triage accuracy, and triage prioritization for tele-dermatology. Methods: In this preliminary parallel convergent mixed-methods study, a cohort of dermatologists and residents assessed skin lesions using clinical and dermoscopic images. For each case, participants viewed a clinical image and determined diagnostic category, management, urgency, and decision-making confidence. They subsequently viewed the associated dermoscopy and answered the same questions. A moderated focus group discussion followed to explore perceptions on the role of dermoscopy in tele-dermatology. Results: Dermoscopy improved recognition of malignancies by 23% and significantly reduced triage urgency measures for non-malignant lesions. Participants endorsed specific utilities of tele-dermoscopy, such as for evaluating pigmented lesions, with limitations including poor image quality. Conclusions: Dermoscopic images may be useful when remotely triaging skin lesions. Standardized imaging protocols are needed.

Enhancing Skin Cancer Diagnosis with Dermoscopy.

Dermoscopy increases the sensitivity for skin cancer detection, decreases the number of benign lesions biopsied for each malignant diagnosis, and enables the diagnosis of thinner melanomas compared with naked eye examination. Multiple meta-analyses have identified that dermoscopy improves the diagnostic accuracy for melanoma when compared with naked eye examination. In addition, studies have established that dermoscopy can aid in the detection of keratinocyte carcinomas. Dermoscopy triage algorithms have been developed to help novices decide when a biopsy or a referral is most appropriate. In this article, the authors illustrate the dermoscopic features that assist in identifying melanoma and keratinocyte carcinomas.

Triage amalgamated dermoscopic algorithm (TADA) for skin cancer screening.

IMPORTANCE: Dermoscopic triage algorithms have been shown to improve beginners' abilities for identifying pigmented skin lesions requiring biopsy. OBJECTIVE: To estimate the diagnostic accuracy of the Triage Amalgamated Dermoscopic Algorithm (TADA) for pigmented and nonpigmented skin cancers. Secondarily, to compare TADAs performance to those of existing triage algorithms for the identification of pigmented skin cancers. DESIGN: Cross-sectional, observational, reader study that took place at a beginner and intermediate level dermoscopy course. PARTICIPANTS: Two hundred medical professionals of various specialties attended the course and 120 voluntarily joined the study (60% participation rate). EXPOSURES: After receiving basic dermoscopy training, participants evaluated 50 polarized, dermoscopic images of pigmented (22 benign, 18 malignant) and nonpigmented (1 benign, 9 malignant) skin lesions using TADA. Pigmented lesions were also evaluated using the Three-Point Checklist and AC Rule. With TADA, participants first determined if a lesion was an unequivocal angioma, dermatofibroma, or seborrheic keratosis, which would exclude it from further evaluation. All other lesions were assessed for architectural disorder, starburst pattern, blue-black or gray color, shiny white structures, negative network, ulcer/erosion, or vessels. Any one feature indicated suspicion for malignancy. RESULTS: Most participants were dermatologists (n=64, 53.3%) or primary care physicians (n=41, 34.2%), and many lacked previous dermoscopy training (n=52, 43.3%). TADA's sensitivity and specificity for all skin cancers was 94.6% (95% CI=93.4-95.7%) and 72.5% (95% CI=70.1-74.7%), respectively. For pigmented skin cancers, the sensitivity and specificity were 94.0% (95% CI=92.9-95.0%) and 75.5% (95% CI=73.8-77.2%). This compared to 71.9% (95%CI=69.8-73.9%) and 81.4% (95%CI=79.7-83.0%) for the Three-Point Checklist and 88.6% (95%CI=87.1-89.9%) and 78.7% (95%CI=76.9-80.3%) for the AC Rule. CONCLUSIONS: These results suggest that TADA compares favorably to existing triage algorithms and might be a useful triage tool with high sensitivity and specificity for pigmented and nonpigmented skin cancers. Further studies are needed to validate these preliminary observations.

Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis.

Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.

Early diagnosis of genital mucosal melanoma: how good are our dermoscopic criteria?

BACKGROUND: There are limited studies on the dermoscopic features of mucosal melanoma, particularly early-stage lesions. Described criteria include the presence of blue, gray, or white colors, with a reported sensitivity of 100%. It is unclear if these features will aid in the detection of early mucosal melanoma or improve diagnostic accuracy compared to naked-eye examination alone. CASE: An Asian female in her fifties was referred for evaluation of an asymptomatic, irregularly pigmented patch of the clitoral hood and labia minora of unknown duration. Her past medical history was notable for Stage IV non-small cell lung cancer. She denied a personal or family history of skin cancer. Dermoscopic evaluation of the vulvar lesion revealed heterogeneous brown and black pigmentation mostly composed of thick lines. There were no other colors or structures present. As the differential diagnosis included vulvar melanosis and mucosal melanoma, the patient was recommended to undergo biopsy, which was delayed due to complications from her underlying lung cancer. Repeat dermoscopic imaging performed three months later revealed significant changes concerning for melanoma, including increase in size, asymmetric darkening, and the appearance of structureless areas and central blue and pink colors. Histopathological examination of a biopsy and subsequent resection confirmed the diagnosis of melanoma in situ. CONCLUSION: Previously described dermoscopic features for mucosal melanoma may not have high sensitivity for early melanomas. Additional studies are needed to define the dermoscopic characteristics of mucosal melanomas that aid in early detection. Health care providers should have a low threshold for biopsy of mucosal lesions that show any clinical or dermoscopic features of melanoma, especially in older women.

Biologically distinct subsets of nevi.

Melanocytic nevi (MN) encompass a range of benign tumors with varying microscopic and macroscopic features. Their development is a multifactorial process under genetic and environmental influences. The clinical importance of MN lies in distinguishing them from melanoma and in recognizing their associations with melanoma risk and cancer syndromes. Historically, the distinction between the different types of MN, as well as between MN and melanoma, was based on clinical history, gross morphology, and histopathological features. While histopathology with clinical correlation remains the gold standard for differentiating and diagnosing melanocytic lesions, in some cases, this may not be possible. The use of dermoscopy has allowed for the assessment of subsurface skin structures and has contributed to the clinical evaluation and classification of MN. Genetic profiling, while still in its early stages, has the greatest potential to refine the classification of MN by clarifying their developmental processes, biological behaviors, and relationships to melanoma. Here we review the most salient clinical, dermoscopic, histopathological, and genetic features of different MN subgroups.