Topical therapy for regression and melanoma prevention of congenital giant nevi.

Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.

Abnormal metabolism in melanocytes participates in the activation of dendritic cell in halo nevus.

A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation.

Subungual melanoma: molecular analysis of 31 cases from early stage to invasive melanoma.

AIMS: The distinction between the benign subungual melanocytic lesions and an early lesion of subungual melanoma (SUM) remains a diagnostic challenge. We evaluated the routine diagnostic utility of array Comparative Genomic Hybridization (aCGH) to detect whole-genome copy number variations (CNV) as well as targeted next-generation sequencing (NGS) in SUM. METHODS AND RESULTS: This retrospective study included 20 cases of in situ SUM and 11 cases of invasive SUM. Analysis by aCGH detected common oncogene amplifications in all but one case of invasive SUM (n = 10) and in all cases of in situ SUM with a melanocyte count (MC) >45/mm (n = 4 true positive) and the average number of CNV was 8.5. Thirteen remaining cases of in situ SUM gave false negative results (n = 13), owing to a lack of sufficient melanocytes to analyse (median MC of 35.35; range: 10.16-39.5). Molecular analysis failed in four cases (three in situ SUM and one invasive SUM) due to insufficient amounts of DNA. Across the whole cohort, the sensitivity of aCGH was 52%, but when adjusting the cutoff to MC >45/mm, the sensitivity was 93%. Targeted NGS was less informative than aCGH analyses in our series of SUM. CONCLUSION: To distinguish malignant from benign lesions, especially in situ SUM versus atypical lentiginous melanocytic proliferations, aCGH analysis should be performed when the MC is above 45 melanocytes per linear millimetre. This pangenomic method can detect oncogene amplifications, as well as a number of CNV >3, which strongly support the diagnosis of malignancy.

Medulloblastoma and other neoplasms in patients with heterozygous germline SUFU variants: A scoping review.

In 2002, heterozygous suppressor of fused variants (SUFU+/-) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB). Other neoplasms associated with pathologic germline SUFU+/- variants have also been described among patients with basal cell nevus syndrome (BCNS; BCNS is also known as Gorlin syndrome, nevoid basal cell carcinoma [BCC] syndrome or Gorlin-Goltz syndrome; OMIM 109400), an autosomal-dominant cancer predisposition syndrome. The phenotype of patients with germline SUFU+/- variants is very poorly characterized due to a paucity of large studies with long-term follow-up. As such, there is a clinical need to better characterize the spectrum of neoplasms among patients with germline SUFU+/- variants so that clinicians can provide accurate counseling and optimize tumor surveillance strategies. The objective of this study is to perform a scoping review to map the evidence on the rate of medulloblastoma and to describe the spectrum of other neoplasms among patients with germline SUFU+/- variants. A review of all published literature in PubMed (MEDLINE), EMBASE, Cochrane, and Web of Science were searched from the beginning of each respective database until October 9, 2021. Studies of pediatric and adult patients with a confirmed germline SUFU+/- variant who were evaluated for the presence of any neoplasm (benign or malignant) were included. There were 176 patients (N = 30 studies) identified with a confirmed germline SUFU+/- variant who met inclusion criteria. Data were extracted from two cohort studies, two case-control studies, 18 case series, and eight case reports. The median age at diagnosis of a germline SUFU+/- variant was 4.5 years where 44.4% identified as female and 13.4% of variants were de novo. There were 34 different neoplasms (benign and malignant) documented among patients with confirmed germline SUFU+/- variants, and the most common were medulloblastoma (N = 59 patients), BCC (N = 21 patients), and meningioma (N = 19 patients). The median age at medulloblastoma diagnosis was 1.42 years (range 0.083-3; interquartile range 1.2). When data were available for these three most frequent neoplasms (N = 95 patients), 31 patients (32.6%) had neither MB, BCC nor meningioma; 51 patients (53.7%) had one of medulloblastoma or BCC or meningioma; eight patients (8.4%) had two of medulloblastoma or BCC or meningioma, and five patients (5.3%) had medulloblastoma and BCC and meningioma. This is the first study to synthesize the data on the frequency and spectrum of neoplasms specifically among patients with a confirmed germline SUFU+/- variant. This scoping review is a necessary step forward in optimizing evidence-based tumor surveillance strategies for medulloblastoma and estimating the risk of other neoplasms that could impact patient outcomes.

Optical coherence tomography-measured blood vessel characteristics of port-wine birthmarks by depth: A cross-sectional study.

BACKGROUND: Port-Wine Birthmarks (PWB) are congenital capillary malformations requiring multiple treatments. Optical coherence tomography (OCT), a noninvasive imaging technique, characterizes vessels in cutaneous vascular lesions, including PWBs. OBJECTIVE: To assess variability in blood vessel characteristics within and between individual PWBs. METHODS: OCT was used to measure blood vessel density (%) and modal vessel diameter (micrometers) at increments of 0.05 mm from the skin surface to a depth of 0.50 mm at several adjacent spots of single PWBs in this cross-sectional study. Average ratios of vessel density and diameter in affected to control skin were obtained for each PWB by averaging data for all spots within a lesion. Statistical analysis was performed with a linear mixed effects model using SPSS software (IBM Corporation). RESULTS: There was great variability in vessel density and diameter within and between PWBs. Depths where average ratios of vessel density were consistently greater in affected to control skin were shallow, between 0.15 mm and 0.2 mm deep from the skin surface. LIMITATIONS: Small sample size and device's inability to measure diameters smaller than 20 micrometers. CONCLUSION: There is variability in vessel density and diameter within and between PWBs. Individualized treatment planning guided by OCT mapping should be studied further.

Melanoma in Pediatric and Young Adult Patients.

PURPOSE OF REVIEW: Melanoma in younger individuals has different clinical presentations, histologic characteristics and prognosis from older patients. This review summarizes key differences and important new insights into pediatric and young adult melanoma, as well as recent evolutions in treatment. RECENT FINDINGS: Molecular techniques have improved the classification of melanocytic neoplasms, and are especially useful in the workup of the diagnostically challenging lesions frequent in this age group. Molecular evaluation highlights differences between melanoma and atypical lesions with Spitz-like morphology, and should routinely be incorporated for diagnosing and classifying Spitzoid melanocytic to guide prognostication and treatment. Once diagnosed, the management of bona fide melanoma in children and young adults is largely similar to older patients, while the optimal management of lesions such as atypical Spitz tumors remains uncertain. Increased awareness of the presentation and diagnostic characteristics of melanoma in young individuals will allow earlier detection, and improved diagnostic techniques will allow optimum management without over- or under-treatment.

Giant congenital fibroblastic connective tissue nevus associated with vascular anomalies.

We described an unusual combination of fibroblastic connective nevus (FCTN) already present at birth with underlying vascular anomalies. Overall, the lesion appeared as a large purplish-brown mass in the groin region up to the third of the right thigh, with partial spontaneous regression during the first three months of life. The FCTN observed exhibited several unusual characteristics: it was congenital, large in size, and located in the lower limbs. Finally, it represented the first case described in which an FCTN arose in association with vascular anomalies.

Nevus lipomatosus superficialis: A series of six cases.

Nevus lipomatosus still imposes diagnostic, categorization, and etiologic challenges. Even though an intradermal adipose tissue is a histopathologic prerequisite, the lesions are clinically divided into classic multiple forms and a solitary variant, which some consider a separate so-called lipofibroma clinicopathologic entity. This further complicates the true prevalence, classification and etiopathogenesis of nevus lipomatosus. Case reports and series studies have reflected either consistent or variable and sometimes conflicting clinicopathologic findings. A few have reported electron microscopic findings. Immunohistochemistry is lacking. We report two multiple and four solitary forms of nevus lipomatosus in six patients, highlighting their salient histopathologic features and immunohistochemical profile. Both forms showed intradermal groups of perivascular S100+ lipogenic and CD34+ mesenchymal cells intermixed with scattered CD1a+ and FXIIIa+ dendrocytes, CD3 lymphocytic and CD117 mast cells in a fibromyxoid milieu. Epidermal nevoid and comedonal follicular alterations, attenuated dermal connective tissue and adnexal structures were variably present in both forms. We compared our findings with seven series of studies reporting classic and solitary forms. Both forms showed similar histopathologic findings, comparable clinicopathologic features, predominantly pelvic, and shoulder girdle distribution patterns in bimodal age onsets. Even though some lipomatous skin lesions clinically and histopathologically overlap with nevus lipomatosus, certain findings are helpful distinguishing features. Small intradermal islands of lipocytic fibroplasia have characteristic perivascular milieu that may function as a niche of preadipose CD34 mesenchymal stem cells. They are most likely represented in the dermis of the pelvic and shoulder areas in certain individuals prone to maintain these embryonic reservoirs, which are clinically manifested at different ages. Some may have unifocal or multifocal residues reflecting multiple and solitary forms.

Clinical implication of PRAME immunohistochemistry in differentiating melanoma in situ and dysplastic nevus in non-acral nevus-associated melanoma in situ: An institutional experience and meta-analysis.

INTRODUCTION: PReferentially expressed Antigen in MElanoma (PRAME) has shown utility in differentiating benign from malignant melanocytic neoplasms. In this study, we investigated the clinical significance of PRAME expression in dysplastic nevi (DN) and nevus-associated melanoma in situ (MIS). METHODS: We included 172 DN and 38 nevus-associated MIS from our institutional archive. PRAME positive expression was defined as nuclear staining in at least 75% of melanocytes. In addition, relevant studies from PubMed and Web of Science were incorporated into a meta-analysis using the random-effects model to assess PRAME expression in MIS and DN. RESULTS: Our institutional data revealed that 71.1% of nevus-associated MIS cases exhibited positive PRAME expression in the MIS components, whereas all DN components were negative for PRAME. 5.7% of cases diagnosed as DN in our cohort demonstrated diffuse positivity for PRAME. Notably, MIS associated with DN displaying epidermal and dermal components displayed a higher likelihood of PRAME positivity compared to those arising on a background of DN with solely epidermal (junctional) components (84% vs. 46%, p = 0.024). The meta-analysis indicated that the pooled PRAME positivity in MIS and DN was 54.5% and 1.9%, respectively. CONCLUSION: PRAME is a valuable immunohistochemical marker for differentiating MIS from DN, particularly in the context of nevus-associated MIS.

Asymptomatic CD34+ plaque on the scalp of a child.

Fibroblastic connective tissue nevus (FCTN) is a rare, benign dermal mesenchymal lesion of fibroblastic and myofibroblastic lineage. We report a case of a 2-year-old male who presented with an 18-month history of an erythematous, asymptomatic, unchanging dermal plaque on the right medial frontal scalp. A punch biopsy showed a disorderly, bland, dermal fibroblastic spindle cell proliferation extending to the superficial subcutis. It stained positive for CD34, and concern for dermatofibrosarcoma protuberans was raised. However, FISH was negative for PDGFB rearrangement, and the constellation of findings was most consistent with FCTN. This case underscores the importance of distinguishing CD34+ mesenchymal tumors for both dermatologists and dermatopathologists. As these represent a rather diverse group of lesions with different biological behaviors, a knowledge of the differential diagnosis of these entities is critical for proper patient management.

Immunohistochemical Expression of Lymphatic Endothelial Markers in Blue Rubber Bleb Nevus Syndrome.

INTRODUCTION: Blue rubber bleb nevus syndrome (BRBNS) is an uncommon vascular anomaly characterized by multifocal cutaneous, visceral, and other soft tissue or solid organ venous malformations. We observed that BRBNS lesions express immunohistochemical markers of lymphatic differentiation. METHODS: BRBNS histopathologic specimens assessed at our institution during the past 27 years were reviewed. Slides from 19 BRBNS lesions were selected from 14 patients (9 cutaneous, 9 gastrointestinal, and 1 hepatic). We recorded the involved anatomical compartments and presence/absence of thrombi or vascular smooth muscle. Immunohistochemical endothelial expression of PROX1 (nuclear) and D2-40 (membranous/cytoplasmic) was evaluated semi-quantitatively. RESULTS: Endothelial PROX1 immunopositivity was noted in all specimens; the majority (89.5%) demonstrated staining in more than 10% of cells. D2-40 immunopositivity was present in one-third (33%) of cutaneous lesions and only 1 gastrointestinal lesion. CONCLUSION: Endothelial cells in BRBNS almost always express 1 or more immunohistochemical markers of lymphatic differentiation.

Autopsy case of linear nevus sebaceous syndrome with KRAS (G12D) mutation.

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous syndrome associated with systemic complications that involve multiple organs, including the skin, central nervous system, eyes, and skeleton. LNSS is considered to be caused by mosaic RAS gene mutation. In this report, we present an autopsy case of LNSS in a Japanese boy. The affected neonate had hydrops fetalis and was born at 28 weeks and 4 days of gestation, weighing 2104 g. He had bilateral inverted eyelids, verrucous linear nevus separated along Blaschko's line, myocardial hypertrophy, and pharyngeal constriction, and underwent intensive treatment in NICU for arrhythmia, hydrocephalus, and respiratory distress. The hydrocephalus progressed gradually and he died at the age of 181 days, 12 days after a sudden cardiac arrest and recovery. KRAS G12D mutation was found in a skin biopsy specimen but not in blood cells, suggesting a postzygotic mosaicism. Autopsy revealed novel pathological findings related to LNSS, including intracranial lipomatous hamartoma and mesenteric lymphangioma, in addition to previously reported findings such as multicystic dysplastic kidney. There was the limited expression of mutated KRAS protein in kidneys.

18F-FDG PET/CT findings in nevoid basal cell carcinoma syndrome: a systematic review and a new case report.

BACKGROUND: To demonstrate and analyze the 18F-FDG positron emission tomography/computed tomography (PET/CT) findings in this rare nevoid basal cell carcinoma syndrome (NBCCS). CASE PRESENTATION: A 71-year-old woman with the left invasive breast cancer was treated with hormone therapy for six months and underwent the 18F-FDG PET/CT examination for efficacy evaluation. 18F-FDG PET/CT revealed the improvement after treatment and other unexpected findings, including multiple nodules on the skin with 18F-FDG uptake, bone expansion of cystic lesions in the bilateral ribs, ectopic calcifications and dilated right ureter. She had no known family history. Then, the patient underwent surgical excision of the all skin nodules and the postoperative pathology were multiple basal cell carcinomas. Finally, the comprehensive diagnosis of NBCCS was made. The patient was still in follow-up. Additionally, we have summarized the reported cases (n = 3) with 18F-FDG PET/CT from the literature. CONCLUSIONS: It is important to recognize this syndrome on 18F-FDG PET/CT because of different diagnoses and therapeutic consequences.

Picosecond alexandrite laser treatment of nevus of Ota in children.

BACKGROUND: The picosecond alexandrite laser has been safely and effectively used to treat the nevus of Ota in adults. However, limited data are available for children. OBJECTIVE: To investigate the efficacy, safety, and correlative influencing factors of a 755nm picosecond alexandrite laser in the treatment of nevus of Ota in children. METHODS: We retrospectively analyzed Chinese children with nevus of Ota who received a 755nm picosecond alexandrite laser treatment in a tertiary dermatological hospital. RESULT: A total of 305 pediatric patients received an average of two treatments achieving an average of 79% pigment clearance. After the first treatment, 22 patients achieved complete clearance (95%-100%), and 72 patients achieved excellent response (75%-94%), with an average initial efficacy of 63% lesion clearance. Treatment at an early age achieved better initial efficacy (0- to 12-month group >1- to 6-year group, 6- to 12-year group). And 0- to 12-month group achieved better final efficacy. More treatment sessions also increased the final efficacy. Both initial efficacy and final efficacy were better when treating a darker lesion. The incidence of complications was 12.1%, with 10.8% being post-inflammatory hyperpigmentation and 1.3% being hypopigmentation. The rate of recurrence was 6.6%. LIMITATION: Retrospective study. CONCLUSION: A 755nm picosecond alexandrite laser is safe and effective in treating nevus of Ota in children. Younger to initiate treatment, darker lesions, and more treatments are positively associated with better pigmentation clearance.

Erbium: YAG laser treatment efficacy and association with histologic features for giant congenital melanocytic nevi management.

BACKGROUND: Limited research exists on laser treatment of giant congenital melanocytic nevus (GCMN). OBJECTIVE: We sought to elucidate the efficacy of the Erbium: YAG laser on GCMN and the histologic factors associated with a positive clinical response. METHODS AND MATERIALS: Between 2019 and 2022, we enrolled 30 medium-to-giant CMN patients who underwent Er: YAG laser treatment. All patients received biopsies before and after laser treatments. Clinical efficacy outcomes were evaluated by the investigator's global assessment (IGA), 5-point scale of depigmentation, and Vancouver Scar Scale (VSS) scores at least 6 months after treatment. RESULTS: Of the 30 cases, 18 (60.0%) showed improvement (IGA score ≥3). Eight (26.7%) patients showed repigmentation. Eight (26.7%) patients developed hypertrophic scars. The average IGA, depigmentation, and VSS scores were 2.93, 3.57, and 3.20. The IGA score was higher (3.24 ± 1.18 vs. 2.22 ± 0.97, p = 0.031) and a lower repigmentation rate (14.3% vs. 55.6%, p = 0.032) was observed in the cases with Grenz zone. The IGA score was higher (3.33 ± 1.24 vs. 2.13 ± 0.89, p = 0.023) and the repigmentation rate was lower (11.1% vs. 50.0%, p = 0.034) also in the cases with the melanocytes nests with aggregation of melanin. Lesions with superficial ablation resulted in less hypertrophic scar formation than those with deep ablation (5.9% vs. 53.8%, p < 0.05). CONCLUSION: The Er: YAG laser demonstrated effective clinical results for GCMNs. The grenz zone and the melanocytes nests with aggregation of melanin are promising predictors of laser efficacy.

Topical everolimus therapy for epidermal nevi associated with woolly hair nevus in a patient with a mosaic HRAS mutation.

A patient with woolly hair nevus syndrome, presented with epidermal facial nevi by the age of 12 years. Despite transient improvement with topical 1% sirolimus cream, the facial nevus grew larger. The patient was then treated with topical 1% everolimus cream resulting in a reduction in the size of the nevus. This case highlights a novel use of topical 1% everolimus cream, which previously has not been used to treat epidermal nevi.

Follicular Becker's nevi: A case series and review of literature.

The follicular variant of Becker's nevus is an under-reported entity. We present the rare occurrence of follicular Becker's nevus in 7 patients, confirmed through dermoscopy and histopathological examination. Dermoscopy shows perifollicular hypopigmentation surrounded by a well-defined net-like pigmentation corresponding clinically to the presence of folliculocentric macules. Histology shows prominent basal and suprabasal melanization surrounding the follicle, corresponding to well-defined net-like pigmentation seen on dermoscopy. However, the melanization does not extend along the entire length of the follicular epithelium leading to perifollicular hypopigmentation on dermoscopy. Though biopsy is confirmatory, it is not usually necessary.

Corymbiform cutaneous disorders in pediatric dermatology: Exploring this pattern of presentation beyond secondary syphilis.

"Corymbiform" is a term found in medical literature as early as 1876 to describe a central larger lesion with smaller surrounding lesions, leading to the appearance of an irregular border. While the term in current medical literature most often describes a possible morphology of secondary syphilis, the authors have noted this pattern presenting in other cutaneous conditions. We present a commentary on the corymbiform pattern in dermatology including a series of photographs of cutaneous disorders presenting in a corymbiform morphology in pediatric patients. While the term corymbiform is not commonly used in the present-day dermatologic literature, increased recognition and use of this term may aid in the recognition of various dermatologic diagnoses presenting in a less common morphology and may also lend to increased fluidity of dermatologic descriptions in the literature.

Plexiform neurofibroma masquerading as a giant congenital melanocytic nevus.

A 4-month-old male presented for a large, hypertrichotic brown patch on the upper back with several scattered 0.5-1.5 cm, round to oval, brown macules and patches on the trunk and extremities. The lesion was initially diagnosed as a giant congenital melanocytic nevus based on clinical exam and histopathology with immunohistochemical stains. The patient was later diagnosed with neurofibromatosis type 1, and the lesion on the back developed a "bag of worms" texture consistent with a plexiform neurofibroma and found to harbor a pathogenic variant in the NF1 gene. This case highlights the diagnostic challenge of differentiating these lesions and their overlapping clinical and histopathological features.

Significant improvement of a nevus spilus-type congenital melanocytic nevus with oral selumetinib.

Giant congenital melanocytic nevi (GCMN) can be cosmetically significant and can lead to melanoma. There is no standard pharmacologic treatment for GCMN. We present the case of an 8-year-old female with kaposiform lymphangiomatosis caused by an NRAS mutation whose nevus spilus-type GCMN improved on oral selumetinib.