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Journal of Cutaneous Pathology Jul 2020Nearly 15% of melanomas occur in patients with a family history and a subset of these patients have a germline mutation in a melanoma predisposing gene. CDKN2A mutations... (Comparative Study)
Comparative Study Review
Nearly 15% of melanomas occur in patients with a family history and a subset of these patients have a germline mutation in a melanoma predisposing gene. CDKN2A mutations are responsible for the majority of hereditary melanoma, but many other susceptibility genes have been discovered in recent years, including CDK4, TERT, ACD, TERF2IP, POT1, MITF, MC1R, and BAP1. Additionally, melanoma risk is increased in mixed cancer syndromes caused by mutations in PTEN, BRCA2, BRCA1, RB1, and TP53. While early onset, multiple tumors, and family cancer history remain the most valuable clinical clues for hereditary melanoma, characteristic epithelioid cytology of melanocytic tumors may suggest an underlying BAP1 mutation. Herein, we review the clinical and histopathologic characteristics of melanocytic tumors associated with these germline mutations and discuss the role of genetic counseling.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p16; Genes, p16; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Melanoma; Microphthalmia-Associated Transcription Factor; Middle Aged; Nevus, Pigmented; Phenotype; Receptor, Melanocortin, Type 1; Shelterin Complex; Telomerase; Telomere-Binding Proteins; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Young Adult
PubMed: 32249949
DOI: 10.1111/cup.13689 -
The American Journal of Surgical... Nov 2018PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen that was isolated by autologous T cells in a melanoma patient. While frequent PRAME... (Comparative Study)
Comparative Study
PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen that was isolated by autologous T cells in a melanoma patient. While frequent PRAME mRNA expression is well documented in cutaneous and ocular melanomas, little is known about PRAME protein expression in melanocytic tumors. In this study we examined the immunohistochemical expression of PRAME in 400 melanocytic tumors, including 155 primary and 100 metastatic melanomas, and 145 melanocytic nevi. Diffuse nuclear immunoreactivity for PRAME was found in 87% of metastatic and 83.2% of primary melanomas. Among melanoma subtypes, PRAME was diffusely expressed in 94.4% of acral melanomas, 92.5% of superficial spreading melanomas, 90% of nodular melanomas, 88.6% of lentigo maligna melanomas, and 35% of desmoplastic melanomas. When in situ and nondesmoplastic invasive melanoma components were present, PRAME expression was seen in both. Of the 140 cutaneous melanocytic nevi, 86.4% were completely negative for PRAME. Immunoreactivity for PRAME was seen, albeit usually only in a minor subpopulation of lesional melanocytes, in 13.6% of cutaneous nevi, including dysplastic nevi, common acquired nevi, traumatized/recurrent nevi, and Spitz nevi. Rare isolated junctional melanocytes with immunoreactivity for PRAME were also seen in solar lentigines and benign nonlesional skin. Our results suggest that immunohistochemical analysis for PRAME expression may be useful for diagnostic purposes to support a suspected diagnosis of melanoma. It may also be valuable for margin assessment of a known PRAME-positive melanoma, but its expression in nevi, solar lentigines, and benign nonlesional skin can represent a pitfall and merits further investigations to better assess the potential clinical utility of this marker.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Biomarkers, Tumor; Child; Female; Humans; Hutchinson's Melanotic Freckle; Immunohistochemistry; Male; Melanocytes; Melanoma; Middle Aged; Nevus, Pigmented; Reproducibility of Results; Skin Neoplasms; Young Adult
PubMed: 30045064
DOI: 10.1097/PAS.0000000000001134 -
Cell Jun 2022Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to...
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.
Topics: Animals; Heterografts; Humans; Melanoma; Mice; Neoplasm Transplantation; Nevus, Pigmented; Skin Neoplasms
PubMed: 35561684
DOI: 10.1016/j.cell.2022.04.025 -
Nature Communications Jun 2019Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here...
Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8 T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.
Topics: Adult; Aged; Aging; CD8-Positive T-Lymphocytes; Cellular Senescence; Cytokines; Dermis; Fibroblasts; Histocompatibility Antigens Class I; Humans; In Vitro Techniques; Killer Cells, Natural; NK Cell Lectin-Like Receptor Subfamily C; Nevus, Pigmented; Phenotype; RNA, Small Interfering; Signal Transduction; Skin; Young Adult; p38 Mitogen-Activated Protein Kinases; HLA-E Antigens
PubMed: 31160572
DOI: 10.1038/s41467-019-10335-5 -
The New England Journal of Medicine Nov 2015The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known.
BACKGROUND
The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known.
METHODS
We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas.
RESULTS
Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed.
CONCLUSIONS
Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.).
Topics: DNA Copy Number Variations; Disease Progression; Evolution, Molecular; Humans; Melanoma; Mutation; Nevus, Pigmented; Point Mutation; Sequence Analysis, DNA; Skin Neoplasms; Ultraviolet Rays
PubMed: 26559571
DOI: 10.1056/NEJMoa1502583 -
Ugeskrift For Laeger Dec 2018Melanonychia is seen, when melanin is incorporated in the nail, which gives a band of dark discolouration of the nail. Nail discolouration is a common cause for patients...
Melanonychia is seen, when melanin is incorporated in the nail, which gives a band of dark discolouration of the nail. Nail discolouration is a common cause for patients to seek medical attention, and it is often benign. Melanonychia can be seen due to melanocytic proliferation (ungual naevi), benign hyperplasia (lentigo) and hypermelanosis (infections, traumas). However, subungual melanoma also commonly presents with melanonychia and is often overseen, leading to a worse prognosis. It is therefore important systematically to examine all nail discolourations to find the cause and rule out malignancy.
Topics: Humans; Melanoma; Nail Diseases; Nails; Nevus, Pigmented; Skin Neoplasms
PubMed: 30547873
DOI: No ID Found -
Pigment Cell & Melanoma Research Nov 2015Melanocytic nevi are a benign clonal proliferation of cells expressing the melanocytic phenotype, with heterogeneous clinical and molecular characteristics. In this... (Review)
Review
Melanocytic nevi are a benign clonal proliferation of cells expressing the melanocytic phenotype, with heterogeneous clinical and molecular characteristics. In this review, we discuss the genetics of nevi by salient nevi subtypes: congenital melanocytic nevi, acquired melanocytic nevi, blue nevi, and Spitz nevi. While the molecular etiology of nevi has been less thoroughly studied than melanoma, it is clear that nevi and melanoma share common driver mutations. Acquired melanocytic nevi harbor oncogenic mutations in BRAF, which is the predominant oncogene associated with melanoma. Congenital melanocytic nevi and blue nevi frequently harbor NRAS mutations and GNAQ mutations, respectively, while Spitz and atypical Spitz tumors often exhibit HRAS and kinase rearrangements. These initial 'driver' mutations are thought to trigger the establishment of benign nevi. After this initial phase of the cell proliferation, a senescence program is executed, causing termination of nevi growth. Only upon the emergence of additional tumorigenic alterations, which may provide an escape from oncogene-induced senescence, can malignant progression occur. Here, we review the current literature on the pathobiology and genetics of nevi in the hope that additional studies of nevi promise to inform our understanding of the transition from benign neoplasm to malignancy.
Topics: Carcinogenesis; Genetic Predisposition to Disease; Humans; Nevus, Pigmented; Skin Neoplasms
PubMed: 26300491
DOI: 10.1111/pcmr.12412 -
Tidsskrift For Den Norske Laegeforening... Jan 2021
Topics: Humans; Nevus, Pigmented; Skin Neoplasms
PubMed: 33433097
DOI: 10.4045/tidsskr.20.0605 -
The Indian Journal of Medical Research Sep 2022
Topics: Humans; Skin Neoplasms; Nevus, Pigmented
PubMed: 36453290
DOI: 10.4103/ijmr.IJMR_73_20 -
Polish Journal of Pathology : Official... 2019The distinction between atypical Spitz lesions, conventional melanocytic nevi including Spitz nevi, and malignant melanomas may be difficult in some cases or may even be... (Review)
Review
The distinction between atypical Spitz lesions, conventional melanocytic nevi including Spitz nevi, and malignant melanomas may be difficult in some cases or may even be impossible. The histological assessment of these lesions is necessary to ensure correct diagnosis and treatment. Nevertheless, pathologists may be subject to suboptimal concordance in the diagnosis of some atypical lesions. In literature, certain atypical lesions have been defined differently: the terms atypical and metastasising Spitz tumour, malignant Spitz nevus, borderline and intermediate melanocytic tumour, melanocytic tumour of uncertain malignant potential MELTUMP, and low-grade malignant melanoma have been introduced to designate this heterogeneous group of pathological entities and variants. This review focuses on some issues concerning the historical background, diagnostic state-of-the-art, evolution, and classification of these complicated lesions.
Topics: Diagnosis, Differential; Humans; Melanoma; Nevus, Epithelioid and Spindle Cell; Skin Neoplasms
PubMed: 31556548
DOI: 10.5114/pjp.2019.84459