Malignant Melanoma Arising in a Prolific Nevus Sebaceus With Colonization of Trichoblastoma.

ABSTRACT: Nevus sebaceus (NS) is a cutaneous hamartoma typically found on the head and neck, with a prevalence of 0.3% in newborns. Most NS are quiescent; however, benign and malignant lesions have been reported to arise within these nevi. Malignant transformation is not common but mainly includes basal cell carcinoma and squamous cell carcinoma. Malignant melanoma arising in NS is exceedingly rare, with only 2 previously documented cases. In this article, we report the first case of malignant melanoma arising in a NS in a 68-year-old man in the United States.

Clinicopathologic and Dermoscopic Features of 20 Cases of Spark's Nevus, a Dermoscopic Simulator of Melanoma.

ABSTRACT: Spark's nevus is a particular type of melanocytic nevus, with histology that shows features of both Spitz and Clark nevus. Detailed dermoscopic features in a series of Spark nevi have not been described yet. We performed a monocentric retrospective observational study on 20 lesions of Spark nevus excised from 19 patients (M:F = 10:9; mean age: 37,6 years), reviewed by 5 experts in dermoscopy and 2 dermatopathologists. A histologic review confirmed that Spark nevi were mostly symmetric (80%), well circumscribed (100%), mainly compound (65%) melanocytic lesions with either epithelioid (55%) or spitzoid (45%) cell morphology and bridging of the nests (100%). Spark nevi were more frequently found on the trunk (85%) in patients with a history of sunburns in childhood (84%), with skin phototype III (79%), and with high nevus count (>100 nevi, 7 patients (36%)). On dermoscopy, we observed different general patterns: multicomponent (40%), reticular-globular-homogeneous (15%), globular homogeneous (15%), reticular (15%), reticular-globular (5%), homogeneous (5%), and globular (5%). Spark nevi showed frequently dermoscopic asymmetry (63%), brown color (90%) with areas of central hyperpigmentation (41%) and peripheral hypopigmentation (28%), atypical pigment network (48%), irregular globules (42%), irregular dots (31%), irregular blotches (16%), blue-whitish veil (13%), peripheral island (25%), irregular hyperpigmented areas (12%), and regression (33%). BRAF mutation was present in 7 of the 10 analyzed cases (70%); all these cases presented a history of evolution. In conclusion, Spark nevi occur on the trunk of young adults with high nevus count and history of sunburns; dermoscopic features are protean, often atypical and suspicious of melanoma.

The Complex Interplay between Nevi and Melanoma: Risk Factors and Precursors.

One effort to combat the rising incidence of malignant melanoma is focused on early detection by the clinical and dermoscopic screening of melanocytic nevi. However, the interaction between nevi, which are congenital or acquired benign melanocytic proliferations, and melanoma is still enigmatic. On the one hand, the majority of melanomas are thought to form de novo, as only a third of primary melanomas are associated with a histologically identifiable nevus precursor. On the other hand, an increased number of melanocytic nevi is a strong risk factor for developing melanoma, including melanomas that do not derive from nevi. The formation of nevi is modulated by diverse factors, including pigmentation, genetic risk factors, and environmental sun exposure. While the molecular alterations that occur during the progression of a nevus to melanoma have been well characterized, many unanswered questions remain surrounding the process of nevus to melanoma evolution. In this review, we discuss clinical, histological, molecular, and genetic factors that influence nevus formation and progression to melanoma.

Melanoma During Pregnancy as a Complicated Medical Problem.

Importance: Pregnancy-associated melanomas (PAMs)-this is how melanomas identified during the childbearing years or up to 1 year after birth have been defined, accounting for one third of women in whom it is diagnosed. The exact epidemiology of melanoma is difficult to determine. However, its incidence is undoubtedly increasing, most likely related to the increasing age of mothers. Objective: The purpose of this study was to review the prognosis, diagnosis, and treatment; the effect of melanoma on pregnancy; and the effect of pregnancy on melanoma and melanocytic lesions. Evidence Acquisition: An extensive manual search of major electronic databases was conducted in January 2022. The following literature review provides comprehensive coverage of PAMs. Results: Any new nevus detected during pregnancy and changes in the nevus regarding color, diameter, symmetry, or lesion border require medical evaluation. New therapies for malignant melanoma, such as immunotherapy and targeted therapy, have improved overall survival and progression-free survival, but their use is often contraindicated in pregnant patients. Melanoma is considered to be the neoplasm most commonly involving the fetus and placenta. Conclusions: There are reports where immunotherapy and targeted therapy used in the patient were not associated with serious consequences for the fetus, being a therapeutic option for the patient. The described cases of pregnancy outcome during modern melanoma treatment are extremely important and may allow to shape the optimal therapeutic regimen in pregnant women with melanoma. Relevance: Education of pregnant women in the context of observation of skin lesions as well as maintenance of oncological vigilance by physicians seem to be an important element in limiting difficult decisions related to therapy of more advanced disease. Further large-scale studies using modern treatment in pregnant women with melanoma are needed.

Early contribution of germline and nevi genetic alterations to a rapidly-progressing cutaneous melanoma patient: a case report.

BACKGROUND: Cutaneous melanoma is the skin cancer with the highest mutational burden and metastatic rate. Early genetic alterations and biomarkers of distant progression are a point of interest. In addition to germline-susceptibility loci, almost 30% of melanomas arise from precursor benign nevi lesions, providing a source for malignant transformation. CASE PRESENTATION: Patient#009 developed a cutaneous melanoma over a nevus, followed by progression to regional and distant metastases in months, unresponsive to targeted therapy. To search for the genetic contribution to this rapid progression, a longitudinal analysis was performed through WES of germline, nevi, primary tumor, and a metastatic lymph node. Differential SNP/INDEL and CNV gene alterations, with functional impact on key pathways and cancer hallmarks in each step of evolution, were discerned. Tumor-associated nevus was, for the first time, split into two sections, distant and adjacent to the primary tumor, to study its heterogeneity. Shared SNP alterations, with stable allele fraction from germline to metastasis were detected, mainly affecting DNA repair genes and promoting genome instability. Early somatic alterations, shared by nevi and primary and metastatic tumors, included BRAFV600E and focal copy-loss of several genes, acquiring additional cancer hallmarks. Phylogenetic analyses revealed that these common somatic alterations would provide a "bridge", allowing progression from a benign to a malignant state. Distant and adjacent nevi were rich in alterations, presenting differential SNP and CNV alterations. Upon tumor transformation, a marked increase in CNV over SNP alterations was determined. Both the number of SNP and CNV-affected genes, including known driver genes, increased throughout progression, although TMB levels remained lower than expected for melanoma. Typical alterations in BRAFV600E tumors related to intrinsic resistance to targeted therapy were found, including BRAF amplification and loss of PTEN, CDKN2A/B, and TP53 surveillance genes. Finally, numerous metastatic alterations were detected, further promoting tumor progression. CONCLUSIONS: In this patient, longitudinal WES analysis revealed a sequential and cumulative pattern of genetic alterations, where germline and nevi somatic events contributed early to its rapid clinical progression. In this case report, we found tumor-associated nevi as genetically heterogeneous precursor entities, in which potential prognostic biomarkers should be studied prospectively.

What is an epidermal nevus?

An epidermal nevus is a common birthmark that causes the skin to be a different texture than the rest of the skin. It is often seen at birth or in early childhood.

Sublimation of Benign Conjunctival Nevi Using Plasma-Assisted Noninvasive Surgery: A Clinical Case Series.

Background: Conjunctival nevi (CN) are common benign ocular tumors. Given their low risk of malignancy, surgical removal of nevi is primarily requested by patients. Herein, we introduce Atmospheric Low-temperature Plasma (ALTP) as a novel noninvasive method for the removal of CN. Methods: A clinical case series was conducted from 2020 to 2021 at the Vision Health Ophthalmic Center in Tehran, Iran. CN in one of the eyes of seven patients was treated. In all patients, the benignity of CN was confirmed by ocular oncologists. The white handpiece of the Plexr device, which generates plasma with the lowest output, was used to apply plasma spots on the nevi. In addition, the Ocular Surface Disease Index (OSDI) questionnaire was completed by all patients before and six months after the treatment. Results: In all patients, the nevi outside the limbus area completely disappeared. The mean size of pre- and post-operative nevi was 3.89×11.7 and 0.54×1.69 mm, respectively. Results of the OSDI questionnaire showed significantly lower scores after the surgery in all patients. Conclusion: The ALTP method is a simple, cost-effective, and office-based surgery to remove CN safely and effectively.

Nevus apocrino puro: una entidad raramente sospechada / Pure apocrine nevus: a rarely suspected entity

Los nevus apocrinos puros son hamartomas de las unidades pilosebáceas caracterizadas por proliferaciones benignas de glándulas apocrinas maduras, la cual es una descripción microscópica realizada en los reportes de patología sin que se nombre el diagnóstico exacto. Considerando además, los diagnósticos diferenciales clínicos y la baja frecuencia de este diagnóstico, presentamos un caso clínico y una revisión del tema

Pure apocrine nevi are hamartomas of the pilosebaceous units characterized by benign proliferations of mature apocrine glands, which is a microscopic description made in pathology reports without the exact diagnosis being named. Considering the clinical differential diagnoses and its low frequency, we present a case report and a review of the literature on this topic

A Single-Institution Cohort Study With Nevi of Special Site: Recurrence, Progression to Melanoma, and Patterns of Management.

ABSTRACT: Nevi of specialized sites (NOSS) occur on the scalp, ears, flexural, acral, and genital areas and display atypical clinical and histologic features. We assessed NOSS recurrence and progression to melanoma, management patterns, and associations between histologic features and treatment recommendations. We queried all histologic diagnoses of NOSS (n = 275) from 2012 to 2017 from a large U.S. academic medical center with reference dermatopathology laboratory and matched these to clinical records. A blinded panel of dermatopathologists re-evaluated lesions, catalogued histologic findings, and gave management recommendation. Associations with dermatopathologist decision and concordance between new and original recommendations were assessed. Of 117 cases with follow-up, 2 locally recurred (1.46%) and none eventuated in melanoma. Clinical features were not associated with original treatment recommendations. After histopathologic review, large melanocytes [odds ratio ratio (ORR) = 8.00, 95% CI, 1.35-47.4] and junctional mitotic figures (ORR = 65.0, 6.5-650) predicted excision recommendation. Likewise, accumulation of many (>9) high-risk features was associated with excision recommendation. Panel review changed treatment recommendation in 27% of cases. Fair concordance existed between original and panel recommendations (κ = 0.29, 0.15-0.44). The low rate of recurrence and lack of melanoma occurrence suggest that despite an atypical clinical and histopathologic appearance, these nevi have limited potential for malignant transformation. Histopathologic findings seem to be principal drivers behind the recommendation for excision in this analysis. Variability existed in treatment recommendations; the panel's consensus recommendation tended to downgrade treatment. This highlights the importance of further outcomes-based studies to identify true high-risk features and refine management guidelines.

Etiological identification of recurrent male fatality due to a novel NSDHL gene mutation using trio whole-exome sequencing: A rare case report and literature review.

BACKGROUND: Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant, lethal male disorder caused by mutations to the NSDHL (NAD(P)H steroid dehydrogenase-like protein) gene. It primarily exhibits strictly unilateral congenital hemidysplasia with ichthyosiform erythroderma and ipsilateral limb defects in female individuals. METHODS: A Chinese couple suffering from recurrent spontaneous abortion in male fetuses was enrolled in this study. Chromosomal microarray analysis and whole-exome sequencing were performed for genetic etiological diagnosis. RESULTS: A 33-year-old pregnant woman with recurrent spontaneous abortion was experiencing her third pregnancy with a male embryo. In this pregnancy, a miscarriage occurred at a gestational age of 10+6  weeks with no copy number variants. However, a novel mutation c.790-6C>T in the NSDHL gene was observed in the fetus through whole-exome sequencing (WES). Parental verification indicated that the NSDHL gene variant was inherited from the mother. Additionally, the variant in the NSDHL gene was absent in her subsequent pregnancy with a female fetus. CONCLUSION: In this study, we detected c.790-6C>T, a novel variant in the NSDHL gene that results in recurrent miscarriage in males. Our study may broaden the scope of research on the NSDHL gene in CHILD syndrome and strengthens the application value of WES for the genetic etiological identification of recurrent miscarriage.

Regular use of vitamin D supplement is associated with fewer melanoma cases compared to non-use: a cross-sectional study in 498 adult subjects at risk of skin cancers.

There are conflicting results on the role of vitamin D system in cutaneous carcinogenesis. Therefore, it was investigated whether the use of oral vitamin D supplements associates with photoaging, actinic keratoses, pigment cell nevi, and skin cancers. In this cross-sectional study, 498 adults (aged 21-79 years, 253 males, 245 females, 96 with immunosuppression) subjects at risk of any type of skin cancer were examined, and possible confounding factors were evaluated. The subjects were divided into three groups based on their self-reported use of oral vitamin D supplements: non-use, occasional use, or regular use. The serum level of 25-hydroxyvitamin-D3 was analyzed in 260 subjects. In 402 immunocompetent subjects, vitamin D use did not associate with photoaging, actinic keratoses, nevi, basal, and squamous cell carcinoma. In contrast, there were lower percentages of subjects with a history of past or present melanoma (32/177, 18.1% versus 32/99, 32.3%, P = 0.021) or any type of skin cancer (110/177, 62.1% versus 74/99, 74.7%, P = 0.027) among regular users compared to non-users. In the logistic regression analysis, the odds ratio for melanoma was 0.447 ( P = 0.016, 95% confidence interval, 0.231-0.862) among regular users. Furthermore, the investigator-estimated risk class of skin cancers was significantly lower among regular users. Serum 25-hydroxyvitamin-D3 did not show marked associations with skin-related parameters. The results on 96 immunosuppressed subjects were somewhat similar, although the number of subjects was low. In conclusion, regular use of vitamin D associates with fewer melanoma cases, when compared to non-use, but the causality between them is obscure.

Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression.

Human melanocytic nevi (moles) result from a brief period of clonal expansion of melanocytes. As a cellular defensive mechanism against oncogene-induced hyperplasia, nevus-resident melanocytes enter a senescent state of stable cell cycle arrest. Senescent melanocytes can persist for months in mice and years in humans with a risk to escape the senescent state and progress to melanoma. The mechanisms providing prolonged survival of senescent melanocytes remain poorly understood. Here, we show that senescent melanocytes in culture and in nevi express high level of the anti-apoptotic BCL-2 family member BCL-W but remain insensitive to the pan-BCL-2 inhibitor ABT-263. We demonstrate that resistance to ABT-263 is driven by mTOR-mediated enhanced translation of another anti-apoptotic member, MCL-1. Strikingly, the combination of ABT-263 and MCL-1 inhibitors results in synthetic lethality to senescent melanocytes, and its topical application sufficient to eliminate nevi in male mice. These data highlight the important role of redundant anti-apoptotic mechanisms for the survival advantage of senescent melanocytes, and the proof-of-concept for a non-invasive combination therapy for nevi removal.

Histopathological and Immunohistochemical Features of Small to Big Satellite Nevus Uncover the Nevogenesis of Large/Giant Congenital Melanocytic Nevus.

The nevogenesis of large/giant congenital melanocytic nevus (lgCMN) is a complex biological process including several integral prenatal stages. Limited by ethical concerns, the debate of whether lgCMN develops from the epidermis to the dermis or in the opposite direction remains controversial. With the present study of the accompanying satellite nevi, we tend to support that lgCMN develops from epidermis to dermis. The satellite nevi were divided into 3 groups: big (diameter >10 mm), medium (>5 mm but ≤10 mm), and small (≤5 mm). Hematoxylin and eosin and immunohistochemical staining (SOX10, Ki67, and p16) were performed to compare the nevocyte infiltration depth as well as the positively stained rates among these satellite nevi. Compared to big satellite nevi, less deeply the nevocytes infiltrated the dermis, as well as more cells expressed SOX10 and Ki67 in the epidermis and fewer cells expressed p16 in the dermis of small satellite nevi. Additionally, two specimens were obtained from each of 4 patients who underwent serial resections of lgCMN at an average interval of 1.75 years to examine the histopathological changes. In the present study, satellite nevi of different sizes represent different stages of lgCMN from early to late, deepening our comprehension of the sequential stages of lgCMN nevogenesis. Initially, abnormal nevocytes seeded, proliferated, and spread along the epidermis. At rete ridges that protrude from the papillary dermis within the epidermis, some nevocytes formed nests and gradually penetrated into the dermis. Eventually, the nevocytes infiltrated the dermis and entered a homeostatic state. This study provides new evidence supporting the theory of epidermal-to-dermal nevogenesis in lgCMN.

White Sponge Nevus Caused by Keratin 4 Gene Mutation: A Case Report.

White sponge nevus (WSN) is a rare autosomal dominant disease with a family history, often caused by mutations of the keratin 4 (K4) and keratin 13 (K13) genes in patients. It is characterized by frequently occurred white corrugated folds in the bilateral buccal mucosa with soft texture. On histopathological examination, hyperkeratosis of epithelial cells, edema, and vacuolar changes in the spinous cells are observed in the lesions, despite a normal layer of basal cells. WSN should be differentiated from other oral white spot diseases, mainly oral lichen planus, oral candidiasis, oral white edema, and Heck's disease, to reduce misdiagnosis and unnecessary treatment. At present, there is no specific treatment method. The purpose of this study was to report the clinical data of four WSN patients of the same family with the K4 gene mutation. The occurrence of WSN in a pair of monozygotic twins with very similar clinical presentations was identified for the first time. The gene sequencing results showed that there was a heterozygous deletion (C. 438_440delCAA) in exon 1 of the K4 gene, resulting in an aspartic acid loss in both the proband and his father. Finally, the etiology, pathogenesis, pathological manifestations, clinical manifestations, diagnosis, differential diagnosis, and related treatment methods are discussed to provide a reference for clinical treatment of the disease.