A facial lentiginous nevus with atypical clinical features in a child: The importance of in vivo reflectance confocal microscopic findings.

A 14-year-old girl presented with a facial-pigmented lesion suspicious of melanoma clinically and dermoscopically. In vivo, reflectance confocal microscopy (RCM) findings excluded melanoma by revealing typical epidermal honeycomb and cobblestone patterns. Well-defined follicular contours were seen at the dermal-epidermal junction; there were no elongated, "medusa head-like" follicular protrusions or folliculotropism, which are classical findings seen in lentigo maligna. With this report, we aim to demonstrate the significance of utilizing RCM technology in difficult to diagnose lentiginous pigmented lesions.

Agminated Eruptive Melanocytic Nevi and Nail Changes Following Toxic Epidermal Necrolysis in a Pediatric Patient: A Case Report and Systematic Review of the Literature.

Eruptive melanocytic nevi (EMN) have been reported in the setting of immunosuppression, chemotherapy, and bullous skin disease, including less commonly, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This case report presents a 4-year-old girl who developed agminated EMN and nail changes after TEN. A systematic review of the literature supports clinically appropriate follow-up of EMN, as there is no reports of malignancy in EMN following SJS/TEN, nor reports of pediatric melanoma arising within EMN of any etiology. Further study of the possible correlation of nail changes with the development of EMN and better characterization of the dermoscopic features of EMN could improve monitoring and care of these patients.

Vitamin D status in children with congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are rare, pigmented birthmarks that can predispose patients to melanoma of the central nervous system and skin. Data from non-CMN melanoma cohorts suggest that vitamin D levels may be connected to outcome, prompting this study of 25-hydroxyvitamin D levels in plasma samples from 40 children with CMN. While 27% were insufficient and 13% deficient, this was representative of European populations, and UK supplementation guidelines are already in place. Our data support routine vitamin D supplementation for all CMN patients during winter months, without routine serum measurement.

Epidermal nevi and epidermolytic hyperkeratosis: A review of cases, highlighting indications for biopsy and genetics referral.

Epidermal nevi are common benign cutaneous hamartomas that may rarely demonstrate histopathologic evidence of epidermolytic hyperkeratosis (EHK), representing cutaneous mosaicism for pathogenic keratin variants. Rarely, individuals with linear epidermal nevi transmit to their children the inherited form of EHK, also known as epidermolytic ichthyosis, characterized by generalized erythema, blistering, and scaling at birth evolving to widespread hyperkeratosis. We present an updated review of reported cases of linear epidermal nevi with EHK exhibiting transmission of epidermolytic ichthyosis to guide important considerations in the care of individuals with epidermal nevi. Clinical characteristics of linear epidermal nevi do not reliably predict the presence of EHK. All reported cases of transmission to offspring have occurred in individuals with linear epidermal nevi involving more than one anatomic area suggesting increased reproductive risk with involvement of two or more anatomic sites. Therefore, genetics consultation is recommended for these individuals with biopsy-confirmed EHK. For individuals with smaller areas of epidermal nevus involvement, the implications are less well known, though genetics consultation may still be considered for those interested in further discussion of general reproductive risk.

Application of dermoscopy and reflectance confocal microscopy in vivo in the evaluation of nevi in children.

BACKGROUND: Melanocytic nevi are frequently observed in the pediatric population. While newly acquired nevi can appear during childhood, congenital nevi can continue to grow and clinically change, making patient caregivers concerned. Reflectance confocal microscopy (RCM) in vivo is a noninvasive tool that might enhance the diagnostic accuracy of dermoscopy, reducing the rate of unnecessary surgical procedures. This study aimed to assess the utility of RCM in increasing the diagnostic accuracy of pediatric melanocytic nevi that show pigmentation changes or grow rapidly. METHODS: Pediatric patients who presented between January 2022 and February 2023 in a single institution with rapidly growing melanocytic nevi or nevi that presented changes in the pigmentation were included in the study. All nevi were evaluated by means of dermoscopy and RCM. RESULTS: Forty-two patients with a total of 42 melanocytic nevi were included. Most lesions showed a honeycombed pattern (n = 21, 50%). On RCM, only 3 of 42 nevi presented atypical cells within the epidermis (7.1%). Evaluation of the dermoepidermal junction (DEJ) revealed the predominance of the meshwork pattern (n = 22, 52.4%). Notably, features considered significant for atypical melanocytic nevi included 9 nevi with scant atypical melanocytes (21.4%) and 3 nevi with nonedge papillae (7.1%). None of the studied lesions required biopsy among this cohort. CONCLUSIONS: Most rapidly growing and clinically changing nevi rarely exhibit single atypical cells in the DEJ. The RCM served as a valuable adjunct to dermoscopy, allowing reassurance in the evaluation of these lesions.

Noonan syndrome-like disorder: Case report and review of the literature.

Of patients with a Noonan syndrome phenotype, only about 1% are found to be related to pathological variants in CBL, also known as Noonan syndrome-like disorder (NSLD). We present a case of a 4-year-old boy diagnosed with NSLD, presenting with multiple melanocytic nevi and superficial neurofibromas. A literature review identified common cutaneous findings of NSLD, for example, café-au-lait macules (22%), juvenile xanthogranuloma (16%), and thin hair (10%). As there are no documented cases of neurofibromas associated with NSLD, and only a single report of multiple melanocytic nevi, inclusion of these features in the phenotype may be warranted and mitigate the necessity for future biopsies in other children.

Dermoscopy aids in differentiating café-au-lait macules from congenital melanocytic nevi in patients with darker skin phototypes.

Dermoscopy aids in the diagnosis and management of pigmented growths and disorders of pigmentation in children. However, there is limited literature on the dermoscopic appearance of café-au-lait macules (CALMs) and congenital melanocytic nevi in patients with dark skin. We report two cases of young children with dark skin and many hyperpigmented patches in whom dermoscopy was utilized to accurately diagnose CALMs and facilitate testing for neurofibromatosis.

Parent experiences during delivery, postpartum, and adoption of children with congenital melanocytic nevi.

BACKGROUND/AIMS: Congenital melanocytic nevi (CMN) are often unexpected discoveries at time of childbirth or adoption. Understanding how parents/guardians cope with these visible birthmarks can help clinicians better care for children and their families. Using qualitative methods, we sought to categorize early family responses to CMN and identify approaches to better engage with parents early in their child's life. METHODS: Semi-structured interviews were conducted within a broader study on shared decision making for families with children with CMN. Discussions included information on birth and early life experiences. Data was dual-coded, inductively and deductively, and analyzed with the Parker and Endler framework exploring emotion-, task-, and avoidance-oriented coping. RESULTS: Fifteen parents of 13 children were interviewed. Parents described all three categories of coping. Emotions ranged from guilt, to neutrality, to positive responses seeing their child's CMN. Stress was lower in families with prior knowledge of CMN. Dermatology referral provided an opportunity for learning, but also triggered worry for some families. CONCLUSIONS: Parents process and react to the diagnosis of CMN with a range of emotions and coping styles. Dermatologists can utilize open-ended questions to understand family emotions and provide families with tailored knowledge and resources. Early discussion of the diagnosis and family education are important support tools.

Assessment of RAS-RAF-MAPK Pathway Mutation Status in Healthy Skin, Benign Nevi, and Cutaneous Melanomas: Pilot Study Using Droplet Digital PCR.

In the present study, we employed the ddPCR and IHC techniques to assess the prevalence and roles of RAS and RAF mutations in a small batch of melanoma (n = 22), benign moles (n = 15), and normal skin samples (n = 15). Mutational screening revealed the coexistence of BRAF and NRAS mutations in melanomas and nevi and the occurrence of NRAS G12/G13 variants in healthy skin. All investigated nevi had driver mutations in the BRAF or NRAS genes and elevated p16 protein expression, indicating cell cycle arrest despite an increased mutational burden. BRAF V600 mutations were identified in 54% of melanomas, and NRAS G12/G13 mutations in 50%. The BRAF mutations were associated with the Breslow index (BI) (p = 0.029) and TIL infiltration (p = 0.027), whereas the NRAS mutations correlated with the BI (p = 0.01) and the mitotic index (p = 0.04). Here, we demonstrate that the "young" ddPCR technology is as effective as a CE-IVD marked real-time PCR method for detecting BRAF V600 hotspot mutations in tumor biopsies and recommend it for extended use in clinical settings. Moreover, ddPCR was able to detect low-frequency hotspot mutations, such as NRAS G12/G13, in our tissue specimens, which makes it a promising tool for investigating the mutational landscape of sun-damaged skin, benign nevi, and melanomas in more extensive clinical studies.

Recent-Onset Melanoma and the Implications of the Excessive Use of Tanning Devices-Case Report and Review of the Literature.

Introduction: Melanoma, a malignant tumor arising from uncontrolled melanocytic proliferation, commonly found in the skin but capable of affecting extracutaneous sites, ranks fifth among diagnosed oncological entities and is a significant cause of cancer deaths, constituting over 80% of skin cancer mortality. Genetic factors and ultraviolet radiation (UVR) exposure, from both natural and artificial sources, are the primary risk factors. Case Presentation: We reported the case of a 25-year-old female with numerous pigmented nevi and notable changes attributed to extensive indoor tanning sessions. Dermatological examinations and dermoscopic evaluations revealed atypical features in two pigmented nevi, leading to surgical excision. Histopathological and immunohistochemical analyses confirmed a compound nevus in one lesion and superficial spreading melanoma in the other, emphasizing the importance of vigilant follow-up and the correct use of immunohistochemistry. Discussion: Indoor tanning significantly elevates the cutaneous melanoma risk, with initiation before age 35 amplifying the risk by up to 75%, especially in young women. The risk escalates with cumulative sessions, particularly exceeding 480, and individuals undergoing over 30 sessions face a 32% higher risk. UVR induces DNA damage, genetic mutations, and immunosuppression, contributing to oncogenesis. Genetic factors, like the PTCHD2 gene, may influence the tanning dependency. Legislation targeting minors has been enacted globally but only with partial efficacy. Tanning accelerators, though associated with minor side effects, correlate with high-risk behaviors. The case underscores the urgency of addressing indoor tanning risks, emphasizing targeted awareness efforts and legislative improvements. Conclusions: In conclusion, the reported case highlights the increased risk of cutaneous melanoma linked to indoor tanning, particularly among young women and specific sociodemographic groups. Despite legislative measures, challenges persist, suggesting the potential efficacy of online campaigns involving relatable influencers to raise awareness and discourage artificial tanning.

Study of Risk Factors for the Presence of Interdigital Nevi of the Feet. / Estudio de los factores de riesgo de la presencia de los nevus interdigitales de los pies.

BACKGROUND AND OBJECTIVES: No studies focused on counting the interdigital acquired melanocytic nevi (AMN) of the foot (IDNf) have ever been conducted. Therefore, our objective was to study the relationship between the presence of IDNf and the total number of AMN in the feet and the rest of the body, the racial phenotypic characteristics, and other risk factors for melanoma. MATERIAL AND METHODS: We conducted a cross-sectional observational study with 255 patients ≥18 years old who attended our Dermatology Unit from September 2020 through February 2021, and included all AMN ≥1mm from the feet and ≥2mm from the rest of the bod. The association between the variables was studied using univariate and multivariate logistic regression models. RESULTS: The presence of IDNf was significantly and independently associated with the presence of plantar AMN and body counts ≥50 AMN. However, no significant differences were observed regarding sex, age, personal history of melanoma, presence of nevi on the dorsum of the foot, history of sunburn or UV rays, or racial phenotypic characteristics. CONCLUSIONS: The presence of IDNf is associated with a higher count of plantar nevi and total AMN in the body, meaning that interdigital spaces of the foot-anatomical expansions of the sole and other possibly genetic causes-could be responsible for the number of AMN found in this location, as these regions are not photoexposed.

Spectrum of Melanocytic Tumors Harboring BRAF Gene Fusions: 58 Cases With Histomorphologic and Genetic Correlations.

We report a series of 58 melanocytic tumors that harbor an activating fusion of BRAF, a component of the mitogen-activated protein kinase (MAPK) signaling cascade. Cases were diagnosed as melanocytic nevus (n = 12, 21%), diagnostically ambiguous favor benign (n = 22, 38%), and diagnostically ambiguous concerning for melanoma (n = 12, 21%) or melanoma (n = 12, 21%). Three main histopathologic patterns were observed. The first pattern (buckshot fibrosis) was characterized by large, epithelioid melanocytes arrayed as single cells or "buckshot" within marked stromal desmoplasia. The second pattern (cords in whorled fibrosis) demonstrated polypoid growth with a whorled arrangement of cords and single melanocytes within desmoplasia. The third pattern (spindle-cell fascicles) showed fascicular growth of spindled melanocytes. Cytomorphologic features characteristic of Spitz nevi were observed in most cases (n = 50, 86%). Most of the cases (n = 54, or 93%) showed stromal desmoplasia. Histomorphology alone was not sufficient in distinguishing benign from malignant melanocytic tumors with BRAF fusion gene because the only histopathologic features more commonly associated with a diagnosis of malignancy included dermal mitoses (P = .046) and transepidermal elimination of melanocytes (P = .013). BRAF fusion kinases are targetable by kinase inhibitors and, thus, should be considered as relevant genetic alterations in the molecular workup of melanomas. Recognizing the 3 main histopathologic patterns of melanocytic tumors with BRAF fusion gene will aid in directing ancillary testing.

Detection of Circulating Tumor Cells in Patients with Small Choroidal Melanocytic Lesions.

PURPOSE: To determine the presence of circulating tumor cells (CTCs) in patients with indeterminate small choroidal melanocytic lesions (SCMLs). DESIGN: Retrospective case series. PARTICIPANTS: Forty-seven patients with choroidal melanocytic lesions 2.5 mm or less in tumor thickness and ≤ 10 mm in largest basal diameter (LBD). METHODS: Blood samples were analyzed for CTCs and the presence of monosomy-3 (M3) in CTCs. Tissue biopsy was performed in the patients who were CTC-positive (pCTC). MAIN OUTCOME MEASURES: Presence and M3 status of the CTCs with regard to the clinical characteristics and results from tissue biopsy. RESULTS: Median thickness of all (n = 47) lesions was 1.1 mm (range: 0.2-2.5 mm), and LBD was 5.6 mm (range: 2.0-10.0 mm). Circulating tumor cells were found in 25 patients (n = 25). This group was classified as pCTC and compared with the CTC-negative (nCTC) group consisting of 22 patients (n = 22). Median tumor dimensions in the pCTC versus the nCTC group were 1.6 mm (range: 0.6-2.5 mm) versus 0.5 mm (range: 0.2-2.5 mm) for thickness and 6.6 mm (range: 4.1-10.0 mm) versus 4.0 mm (range: 2.0-8.0 mm) for LBD, respectively. Both LBD and thickness were positively associated (P < 0.001) with the presence of CTC. Compared with the nCTC group, a higher percentage of the pCTC group exhibited LBD > 5 mm (36% vs. 88%), subretinal fluid (9.1% vs. 56%), orange pigment (4.5% vs. 60%), sonographic hollowness (9.1% vs. 60%), and the presence of multiple risk factors (0% vs. 68% for ≥3 factors) with P < 0.001 for all parameters. No significant difference was detected in the clinical parameters of the patients who had disomy-3 (D3) (n = 7) versus M3 (n = 17) in their CTC. The tissue biopsy confirmed the uveal melanoma (UM) in 22 of the 25 pCTC patients (88%), whereas no conclusive diagnosis could be determined in the remaining 3 cases because of insufficient or invalid material. CONCLUSIONS: We report compelling evidence for the potential of liquid biopsy as an additional tool to screen SCMLs for malignancy. These findings pave the way toward the implementation of liquid biopsy to detect small UM and monitor melanocytic lesions. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinical insights from an unusual Turner syndrome manifestation: Congenital cutis verticis gyrata.

Cutis verticis gyrata (CVG) is classified as primary or secondary according to the absence or presence of underlying soft tissue abnormalities. We report an infant with Turner syndrome (TS) who in addition presented with CVG on the scalp. The skin biopsy revealed a hamartoma-like lesion. We reviewed the clinical and histopathological findings of the 13 reported cases of congenital CVG in patients with TS, including ours. In 11 of them, CVG was localized on the skin of the scalp, mainly on the parietal region, and in two, on the forehead. Clinically, CVG had a flesh-colored aspect, with absent or sparse hair, and was not progressive. CVG was classified as primary in four patients who had skin biopsy and it was attributed to the intrauterine lymphedema of TS. However, histopathology in two of these patients identified dermal hamartoma as a secondary cause of CVG, and in three others, including ours, there were hamartomatous changes. Although further studies are required, previous findings support the proposal that some CVG may instead be dermal hamartomas. This report alerts clinicians to recognize CVG as a low-frequency manifestation of TS, but also to consider the possible co-occurrence of TS in all female infants with CVG.

Dysplastic nevus part I: Historical perspective, classification, and epidemiology.

Since the late 1970s, the diagnosis and management of dysplastic nevi have been areas fraught with controversy in the fields of dermatology and dermatopathology. Diagnostic uncertainty and lack of standardized nomenclature continue to propagate confusion among clinicians, dermatopathologists, and patients. In part I of this CME review article, we summarize the historical context that gave rise to the debate surrounding dysplastic nevi and review key features for diagnosis, classification, and management, as well as epidemiology. We discuss essentials of clinical criteria, dermoscopic features, histopathologic features, and the diagnostic utility of total body photography and reflectance confocal microscopy in evaluating dysplastic nevi, with emphasis on information available since the last comprehensive review a decade ago.

RNA analysis of tape strips to rule out melanoma in lesions clinically assessed as cutaneous malignant melanoma: A diagnostic study.

BACKGROUND: Distinguishing cutaneous malignant melanoma (CMM) from nevi can be clinically challenging. Suspicious lesions are therefore excised, resulting in many benign lesions being removed surgically to find 1 CMM. It has been proposed to use tape strip derived ribonucleic acid (RNA) to distinguish CMM from nevi. OBJECTIVE: To develop this technique further and validate if RNA profiles can rule out CMM in clinically suspicious lesions with 100% sensitivity. METHODS: Before surgical excision, 200 lesions clinically assessed as CMM were tape stripped. Expression levels of 11 genes on the tapes were investigated by RNA measurement and used in a rule-out test. RESULTS: Histopathology showed that 73 CMMs and 127 non-CMMs were included. Our test correctly identified all CMMs (100% sensitivity) based on the expression levels of 2 oncogenes, PRAME and KIT, relative to a housekeeping gene. Patient age and sample storage time were also significant. Simultaneously, our test correctly excluded CMM in 32% of non-CMM lesions (32% specificity). LIMITATIONS: Our sample contained a very high proportion of CMMs, perhaps due to inclusion during COVID-19 shutdown. Validation in a separate trial must be performed. CONCLUSION: Our results demonstrate that the technique can reduce removal of benign lesions by one-third without overlooking any CMMs.

Agminated presentation of fusion-driven melanocytic neoplasms.

BACKGROUND: The conventionally understood pathogenesis of agminated Spitz nevi includes a mosaic HRAS mutation followed by copy number gains in 11p. However, we have recently observed agminated presentations of fusion-driven melanocytic neoplasms. METHODS: We retrieved cases from our database of benign fusion-induced melanocytic neoplasms with an agminated presentation. Both the primary lesion and the secondary lesion were sequenced. TERT-promoter mutational testing and the melanoma fluorescence in situ hybridization assay were also performed. RESULTS: Three cases were included. Two had a PRKCA fusion (partners ATP2B4 and MPZL1) and one had a ZCCHC8::ROS1 fusion. None of the cases met morphologic or molecular criteria for malignancy. There was no evidence of tumor progression in secondary lesions. The same fusion was identified in the primary and secondary lesions. None of the patients developed evidence of nodal or systemic metastasis. CONCLUSIONS: We present accumulating evidence that fusion-driven melanocytic neoplasms can present with an agminated presentation. The differential diagnosis of an agminated presentation versus a locally recurrent or potentially locally metastatic tumor is critical, and accurate diagnosis has significant prognostic and therapeutic consequences for the patient. As with HRAS mutations, fusion-driven melanocytic tumors may have an agminated presentation.

Follicular colonization in melanocytic nevi and melanoma: A literature review.

The lentiginous spread of melanocytes into the hair follicle can be observed in a number of benign melanocytic neoplasms such as in nevi but also in sun-induced melanocytic hyperplasia and melanoma. The follicular colonization by melanocytes in melanoma is classified into three distinct patterns: primary follicular melanoma, melanoma with folliculotropism, and invasive melanoma arising from melanoma in situ with folliculotropism. The role of follicular colonization in melanoma pathologic staging is still a matter of debate though the description of the latter has been recommended by the International Collaboration on Cancer Reporting. In this review, we will discuss the role of follicular colonization in melanoma and melanocytic nevi as well as the facts and controversies regarding this topic.

PRAME-negativity in sclerosing nevi with pseudomelanomatous features supports classification as an indolent lesion.

BACKGROUND: Some dysplastic nevi, termed sclerosing nevi with pseudomelanomatous features, may have florid fibroplasia associated with features that cause melanoma to be a prominent consideration in the differential diagnosis. PRAME (PReferentially expressed Antigen in MElanoma) immunohistochemistry (IHC) has been shown to be a useful marker in the distinction of melanoma and nevus. PRAME expression in such sclerosing nevi with pseudomelanomatous features has not been evaluated to our knowledge. METHODS: Thirty-two sclerosing nevi with pseudomelanomatous features were stained with PRAME IHC, with positive labeling defined as staining of >75% of the cytomorphologically atypical lesional cells. RESULTS: All 32 cases had variable cytologic atypia, bridging of elongated rete, fibroplasia, and a vertically oriented trizonal appearance. Some cases (23/32) had centrally located flattening of the rete ridge pattern bilaterally flanked by fibroplasia associated with elongated rete. PRAME labeling was negative (<1% labeling) in 28/32 cases. Four cases, also interpreted as having negative labeling with PRAME, showed only weak nuclear positivity of <50% of the melanocytes within the pseudomelanomatous foci. p16 staining was positive in 28/28 lesions. CONCLUSIONS: Rare sclerosing nevi with pseudomelanomatous features (4/32; ~13%) had weak PRAME labeling of 25%-50% of atypical foci. Twenty-eight of 32 lesions had virtually no labeling with PRAME. PRAME results support classifying sclerosing nevi with pseudomelanomatous features as indolent lesions.

The Natural Evolution of Nevi with Peripheral Globules.

BACKGROUND: Peripheral globules (PG) in melanocytic lesions represent a concerning dermoscopic feature since they might be present in growing nevi and melanomas. Their natural evolution has not been fully elucidated, and an age-based management approach has been recommended. OBJECTIVES: The aim of this study was to calculate the growth rate of lesions with PG and investigate possible association with age, sex, location, and the global dermoscopic pattern. METHODS: We retrospectively selected the lesions of interest from a cohort of Caucasian patients who underwent sequential digital dermoscopy monitoring. Lesions with PG distributed at 75% or more of their circumference with available follow-up images or histopathologic report were included. The surface area was automatically calculated with the help of an incorporated tool used in the acquisition of the images. The images were also evaluated by independent investigators for the presence of pre-defined criteria. Growth-curve models were used to assess the growth rate. The outcome variable was the area of nevi in mm2, and scatterplots with Lowess curves were used to present the mean change of nevi during follow-up. RESULTS: A total of 208 lesions from 98 patients with a median age of 36 years (range 15-75) were included. The median follow-up time was 18 months (range 4-48). The mean growth rate for all nevi was 0.16 mm2/month (95% CI, 0.14-0.18, p < 0.001), ranging from -0.29 to 0.61 mm2/month. The growth rate was higher in nevi with a homogeneous dermoscopic pattern (p < 0.001). The number of peripheral globules during follow-up varied from increasing to complete disappearance. None of the lesions developed any melanoma-specific structure at follow-up. CONCLUSION: Nevi with PG grew at a mean rate of 0.16 mm2/month, and the growth rate was independent of age, gender, or anatomic location. Nevi with homogeneous pattern demonstrated the highest growth rate in our cohort. None of the monitored nevi with PG developed melanoma-specific criteria at follow-up.