Mosaic RASopathies concept: different skin lesions, same systemic manifestations?

BACKGROUND: Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in HRAS, KRAS, and less frequently, NRAS and BRAF may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders. METHODS: In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic HRAS variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in HRAS, KRAS, NRAS or BRAF. RESULTS: Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. KRAS pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in HRAS are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica. CONCLUSION: This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic RAS and BRAF pathogenic variants and may help improve their follow-up.

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.

Cutaneous Horn Presentation in Porokeratotic Eccrine Ostial and Dermal Duct Nevus. A Brief Review and Case Report.

ABSTRACT: Porokeratotic eccrine ostial and dermal duct nevus is a rare adnexal hamartoma characterized by the presence of a cornoid lamella exclusively overlying eccrine acrosyringia. Different clinical presentations have been reported in the literature. Here, we report a case of a 6-year-old girl diagnosed with porokeratotic eccrine ostial and dermal duct nevus confirmed by histopathologic study. Atypical lesions are described as whitish, warty-looking neoformations located in the anterolateral region of the right hip (cutaneous horn).

Rate of Benign and Malignant Secondary Tumors Associated With Nevus Sebaceous: A Systematic Review and Meta-Analysis.

BACKGROUND: Nevus sebaceous (NS) is a rare congenital skin lesion affecting approximately 0.3% of all newborns. Although benign, NS lesions can harbor malignant secondary tumors. The published rate of development of these malignant tumors varies. This meta-analysis aimed to identify the rate of malignant and benign secondary neoplasms occurring in NS. METHODS: A literature search was conducted using PubMed, Embase, and Web of Science from inception to April 2023. Eligible studies reported incidence or risk of secondary neoplasms in patients with NS. Two independent reviewers screened studies, extracted data, and assessed the quality of included studies. The primary outcome was the pooled incidence of secondary neoplasms. Studies with sample sizes greater than 50 patients were eligible for meta-analysis using the random-effects model. RESULTS: Twenty-eight studies were identified, 22 of which were eligible for meta-analysis. The overall rate of secondary neoplasms was 12.8% (95% confidence interval [Cl], 9.2%-17.6%). The rates of development of malignant and benign tumors were 2.4% (95% CI, 1.4%-4.1%) and 10.3% (95% CI, 7.5%-13.9%), respectively. The rate of development of basal cell carcinoma was 1.7% (95% CI, 0.9%-3.2%), whereas the rate of the development of syringocystadenoma papilliferum was 3.6% (95% CI, 2.5%-5.3%) and that if trichoblastoma was 2.6% (95% CI, 1.7%-3.8%). CONCLUSIONS: Although the rate of development of malignant tumors within a primary NS lesion is low, it is not negligible. Prophylactic early excision remains a viable approach to prevent secondary malignant neoplasms, address cosmetic and functional complications, and preempt the need for complex reconstruction in the future. We propose that resection of NS lesions in childhood remains a reasonable first-line option in the appropriate patient keeping in mind that it may leave an undesirable scar.

Thickness of melanocytes in giant congenital melanocytic nevus for complete surgical excision: clinicopathological evaluation of 117 lesions according to the area and size.

BACKGROUND: Giant congenital melanocytic nevi (GCMN) are usually defined as nevi that exceed 20 cm in maximal diameter or 15% of the total body surface area. There have been reports of life-long malignant change risks arising from GCMN, leading to surgical excision of GCMN. This study aims to evaluate the thickness of melanocytes based on clinical factors in order to provide objective information for the complete resection of the lesion. METHODS: Overall, 75 patients diagnosed with GCMN between 2000 and 2021 were included, and their clinical records were collected retrospectively. 117 pathologic slides obtained during excision were reviewed to measure nevus thickness. Clinical factors were assessed with a generalized estimated equation model for association with nevus thickness. RESULTS: The thickness of nevus was significantly associated with the location and size. Nevus thickness was more superficial in the distal extremity than in the head and trunk (P = 0.003 [head]; P < 0.001 [trunk]; P = 0.091 [Proximal extremity]). Nevi sized 60 cm or more were significantly deeper than those measuring 20-29.9 cm (P = 0.035). An interaction between size and location existed (P < 0.001). Trunk and distal extremity lesions consistently exhibited uniform thickness regardless of lesion size, whereas head and proximal extremity lesions showed variations in thickness based on lesion size. CONCLUSION: GCMNs have differences in thickness according to location and size. Therefore, it is necessary to devise an approach optimized for each patient to treat GCMN. In the study, it was emphasized that the thickness of GCMN is correlated with clinical factors, specifically the location and size of the nevus. Consequently, these findings underscore the need for individualized treatment plans for effective surgical intervention.

Reduction of overfitting on the highly imbalanced ISIC-2019 skin dataset using deep learning frameworks.

BACKGROUND: With the rapid growth of Deep Neural Networks (DNN) and Computer-Aided Diagnosis (CAD), more significant works have been analysed for cancer related diseases. Skin cancer is the most hazardous type of cancer that cannot be diagnosed in the early stages. OBJECTIVE: The diagnosis of skin cancer is becoming a challenge to dermatologists as an abnormal lesion looks like an ordinary nevus at the initial stages. Therefore, early identification of lesions (origin of skin cancer) is essential and helpful for treating skin cancer patients effectively. The enormous development of automated skin cancer diagnosis systems significantly supports dermatologists. METHODS: This paper performs a classification of skin cancer by utilising various deep-learning frameworks after resolving the class Imbalance problem in the ISIC-2019 dataset. A fine-tuned ResNet-50 model is used to evaluate the performance of original data, augmented data, and after by adding the focal loss. Focal loss is the best technique to solve overfitting problems by assigning weights to hard misclassified images. RESULTS: Finally, augmented data with focal loss is given a good classification performance with 98.85% accuracy, 95.52% precision, and 95.93% recall. Matthews Correlation coefficient (MCC) is the best metric to evaluate the quality of multi-class images. It has given outstanding performance by using augmented data and focal loss.

Neonatal cutaneous melanoma with cutaneous metastasis: a case report and review of literature.

Malignant melanoma, a rare skin cancer in children, primarily affects individuals over 10 years old. Giant congenital nevi, found in about 1% of newborns, increases the risk. However, the development of melanoma from a pre-existing giant congenital nevus diagnosed during the neonatal period is exceptionally rare. We present a case of congenital melanoma in a newborn, where nodules grew on an existing nevus on the baby's back. Literature on managing such cases was reviewed. This case highlights the importance of considering malignant transformation in congenital nevi and the challenges in their management. Due to limited reported cases over 80 years, conclusive findings on survival and treatment options are difficult to provide. Clinicians should report outcomes to develop a management algorithm for neonatal melanoma. Further studies are needed to enhance understanding of causes and treatment for patients with congenital giant hairy nevi and associated melanoma.

Inflammatory linear verrucous epidermal nevus in groin and labia with claudication: Successfully treated with photodynamic therapy.

SIGNIFICANCE: Inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon type of epidermal nevus and is refractory to therapy. We report the effectiveness of photodynamic therapy (PDT) for treating ILVEN with claudication in a young girl. ADDITIONAL CONTRIBUTIONS: We thank the patient for granting permission to publish this information. APPROACH: Aminolaevulinic Acid Hydrochloride (ALA) photodynamic therapy (PDT) was applied six times in 1-month interval. RESULTS: Most lesions and pruritus have subsided markedly, with mild scarring and a marked reduction in claudication. CONCLUSIONS: ALA PDT might be an effective and promising treatment for ILVEN in the future.

PRAME Expression in Melanocytic Proliferations in Special Sites.

The subset of nevi occurring at special sites (eg, acral skin, anogeni-tal region, breast, ear, flexural surfaces) have normal histologic variations that preclude the use of routinely used diagnostic criteria for malignancy. Suggested criteria for differentiating malignant special-site lesions from benign lesions have been described, but there is an unmet need for a validated test aiding in the delineation of benign and malignant lesions at special sites. Preferentially expressed antigen of melanoma (PRAME) expression has been characterized as a relatively specific marker of melanoma, but not within the specific population of special-site lesions. This study aimed to determine if PRAME may serve as a specific marker of melanoma within the population of special-sites lesions.

BioMEL: a translational research biobank of melanocytic lesions and melanoma.

INTRODUCTION: Diagnosing invasive cutaneous melanoma (CM) can be challenging due to subjectivity in distinguishing equivocal nevi, melanoma in situ and thin CMs. The underlying molecular mechanisms of progression from nevus to melanoma must be better understood. Identifying biomarkers for treatment response, diagnostics and prognostics is crucial. Using biomedical data from biobanks and population-based healthcare data, translational research can improve patient care by implementing evidence-based findings. The BioMEL biobank is a prospective, multicentre, large-scale biomedical database on equivocal nevi and all stages of primary melanoma to metastases. Its purpose is to serve as a translational resource, enabling researchers to uncover objective molecular, genotypic, phenotypic and structural differences in nevi and all stages of melanoma. The main objective is to leverage BioMEL to significantly improve diagnostics, prognostics and therapy outcomes of patients with melanoma. METHODS AND ANALYSIS: The BioMEL biobank contains biological samples, epidemiological information and medical data from adult patients who receive routine care for melanoma. BioMEL is focused on primary and metastatic melanoma, but equivocal pigmented lesions such as clinically atypical nevi and melanoma in situ are also included. BioMEL data are gathered by questionnaires, blood sampling, tumour imaging, tissue sampling, medical records and histopathological reports. ETHICS AND DISSEMINATION: The BioMEL biobank project is approved by the national Swedish Ethical Review Authority (Dnr. 2013/101, 2013/339, 2020/00469, 2021/01432 and 2022/02421-02). The datasets generated are not publicly available due to regulations related to the ethical review authority. TRIAL REGISTRATION NUMBER: NCT05446155.

Comparative Quantitative Proteomic Analysis of Melanoma Subtypes, Nevus-Associated Melanoma, and Corresponding Nevi.

A substantial part of cutaneous malignant melanomas develops from benign nevi. However, the precise molecular events driving the transformation from benign to malignant melanoma are not well-understood. We used laser microdissection and mass spectrometry to analyze the proteomes of melanoma subtypes, including superficial spreading melanomas (n = 17), nodular melanomas (n = 17), and acral melanomas (n = 15). Furthermore, we compared the proteomes of nevi cells with those of melanoma cells within the same specimens (nevus-associated melanoma (n = 14)). In total, we quantified 7935 proteins. Despite the genomic and clinical differences of the melanoma subtypes, our analysis revealed relatively similar proteomes, except for the upregulation of proteins involved in immune activation in nodular melanomas versus acral melanomas. Examining nevus-associated melanoma versus nevi, we found 1725 differentially expressed proteins (false discovery rate < 0.05). Among these proteins were 140 that overlapped with cancer hallmarks, tumor suppressors, and regulators of metabolism and cell cycle. Pathway analysis indicated aberrant activation of the phosphoinositide 3-kinase-protein kinase B-mTOR pathways and the Hippo-YAP pathway. Using a classifier, we identified six proteins capable of distinguishing melanoma from nevi samples. Our study represents a comprehensive comparative analysis of the proteome in melanoma subtypes and associated nevi, offering insights into the biological behavior of these distinct entities.

Giant Cerebriform Nevus Lipomatosus Cutaneous- Superficialis with Diffuse Lipomatosis: An Unusual Presentation on the Neck.

A 25-year-old man presented with gradually increasing swelling of 15 years' duration on the left side of his neck. There had been occasional foul-smelling discharge from the swelling. Local examination revealed an 8 cm × 5 cm oblong-shaped, yellowish to skin-colored, soft, -cerebriform swelling. There were multiple open comedones (Figure 1a). The surrounding skin had small and soft skin-colored papules. On palpation, there was no ulceration, tenderness, induration, or bag of worms. A scar from the past surgery was visible. Systemic examina- tion was unremarkable. The differential diagnosis demonstrated plexiform neurofibroma and nevus lipomatosus cutaneous superficialis (NLCS; Figure 2).

Fusion between an Algorithm Based on the Characterization of Melanocytic Lesions' Asymmetry with an Ensemble of Convolutional Neural Networks for Melanoma Detection.

Melanoma is still a major health problem worldwide. Early diagnosis is the first step toward reducing its mortality, but it remains a challenge even for experienced dermatologists. Although computer-aided systems have been developed to help diagnosis, the lack of insight into their predictions is still a significant limitation toward acceptance by the medical community. To tackle this issue, we designed handcrafted expert features representing color asymmetry within the lesions, which are parts of the approach used by dermatologists in their daily practice. These features are given to an artificial neural network classifying between nevi and melanoma. We compare our results with an ensemble of 7 state-of-the-art convolutional neural networks and merge the 2 approaches by computing the average prediction. Our experiments are done on a subset of the International Skin Imaging Collaboration 2019 dataset (6296 nevi, 1361 melanomas). The artificial neural network based on asymmetry achieved an area under the curve of 0.873, sensitivity of 90%, and specificity of 67%; the convolutional neural network approach achieved an area under the curve of 0.938, sensitivity of 91%, and specificity of 82%; and the fusion of both approaches achieved an area under the curve of 0.942, sensitivity of 92%, and specificity of 82%. Merging the knowledge of dermatologists with convolutional neural networks showed high performance for melanoma detection, encouraging collaboration between computer science and medical fields.

Prenatal recognition of cerebriform sebaceous naevus.

Cerebriform sebaceous naevus (CSN) is a rare morphological sebaceous naevus variant and challenging to diagnose prenatally due to its flat, smooth and waxy appearance and lack of association with extracutaneous manifestations.A multigravida was referred to our tertiary obstetric unit at 24 weeks of gestation for evaluation of fetal auricular lesions. We were able to further characterise the lesions via serial obstetric ultrasound imaging with the aid of three-dimensional (3D) technology. Although the precise diagnosis prenatally was uncertain, the use of 3D technology allowed the reconstruction of the fetal cutaneous lesions for multidisciplinary assessment to facilitate the development of a neonatal management plan. The diagnosis of CSN was made postnatally on biopsy.

Risk factors of lentigo maligna as compared to other melanoma subtypes.

BACKGROUND: Lentigo maligna (LM) exhibits a particular epidemiological profile compared to other histopathologic subtypes of melanoma, with a propensity for the head and neck area and a higher mean age at diagnosis. Few small-scale studies have exclusively evaluated the risk factors for the development of LM. OBJECTIVE: This study aims to compare LM to other histological subtypes of melanoma for the prevalence of known melanoma risk factors, including pigmentary characteristics, history of occupational sun exposure, nevus count, and familial melanoma history. PATIENTS AND METHODS: We conducted a case-control study of 152 patients with LM and 784 patients with other melanoma subtypes (OM). The Mann-Whitney t-test and Pearson chi-squared test were used to detect differences between the two groups in continuous and categorical variables, respectively. Univariate and multivariate logistic regression models were then constructed to identify risk factors for developing LM compared to other melanoma subtypes. RESULTS: In multivariate logistic regression analysis, LM was positively associated with a lentigines count >50 and occupational sun exposure compared to OM (OR 2.10, 95% CI 1.35-3.29 and OR 2.18, 95% CI 1.33-3.57, respectively). In contrast, patients with an increased nevus count and fair or medium skin color were less likely to develop LM than OM (OR 0.93, P < 0.001, 95% CI 0.91-0.94, and OR 0.28, P < 0.001, 95% CI 0.17-0.46, respectively). In univariate analysis, LM exhibited a weaker association with all pigmentary traits than OM. No significant associations were found for atypical nevi count and family history. CONCLUSION: We found significant differences in the prevalence of known melanoma risk factors between LM and other melanoma subtypes, which supports the hypothesis of a distinct pathogenetic pathway of LM.

Mosaic GJB2 mutations in widespread porokeratotic adnexal ostial nevus: Report of two patients.

Porokeratotic adnexal ostial nevus (PAON) is a rare adnexal hamartoma characterized by keratotic papules following Blaschko's lines, typically located on the unilateral distal extremities. Cutaneous somatic GJB2 mutations have been linked to the pathogenesis of PAON. However, the genetic mechanism underlying bilateral or extended forms, which are less documented, remains unknown. In this study, we presented two cases of PAON with widespread cutaneous lesions and scalp involvement, and demonstrated the presence of GJB2 mosaic mutations in both patients. We further investigated the mosaic frequency in different tissues to gain insights into the mutation events contributing to the phenotype of widespread PAON. Our findings suggest that early postzygotic mutation causing mosaic GJB2 mutations may contribute to the widespread phenotype of PAON, thereby enriching the disease spectrum and mutation profile of PAON.

Correlation between super-high magnification (400x) dermoscopy and reflectance confocal microscopy for the diagnosis of melanosis and other pigmented genital lesions.

The clinical diagnosis of pigmented genital lesions is challenging. Reflectance confocal microscopy (RCM) is effective for diagnosis but is limited in its application due to elevated costs. A more affordable dermatoscope with a 400x magnification (D400) has recently been brought to market. The aim of our study was to compare these two imaging techniques for the analysis of pigmented genital tumours. An observational, prospective and mono-centric study was carried out from October 2017 to May 2019, in which clinical, dermatoscopic (20x and 400x) and RCM data from 207 pigmented genital lesions were collected. The images generated via D400 and RCM were analysed by three expert investigators. Similarities between the criteria observed using D400 and RCM were evaluated by each investigator. In total, 207 lesions were included: 183 melanosis, 19 nevi, one basal cell carcinoma (BCC), two condylomas and two melanomas in situ. Our series correlates well with data found in the literature especially for the distribution of different lesions, their topography, and their aspect using x20 dermatoscopy and RCM. Pattern and cell criteria defined using RCM largely paralleled those observed with D400 for all three investigators. Correlation between D400 and RCM was moderate to strong with regards to the identification of the ring pattern and clustered round cells, strong for dendritic and plump cells, and perfect for isolated round cells and spindle cells. D400 is an easy-to-use, cost-effective alternative for the analysis of pigmented genital lesions, particularly for melanosis.