-
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 -
Frontiers in Oncology 2022Spitz tumors represent a distinct subtype of melanocytic lesions with characteristic histopathologic features, some of which are overlapping with melanoma. More common... (Review)
Review
Spitz tumors represent a distinct subtype of melanocytic lesions with characteristic histopathologic features, some of which are overlapping with melanoma. More common in the pediatric and younger population, they can be clinically suspected by recognizing specific patterns on dermatoscopic examination, and several subtypes have been described. We now classify these lesions into benign Spitz nevi, intermediate lesions identified as "atypical Spitz tumors" (or Spitz melanocytoma) and malignant Spitz melanoma. More recently a large body of work has uncovered the molecular underpinning of Spitz tumors, including mutations in the HRAS gene and several gene fusions involving several protein kinases. Here we present an overarching view of our current knowledge and understanding of Spitz tumors, detailing clinical, histopathological and molecular features characteristic of these lesions.
PubMed: 35747831
DOI: 10.3389/fonc.2022.889223 -
Journal of the American Academy of... Oct 2020Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal... (Review)
Review
Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal antibodies that block cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein 1, or programmed cell death ligand 1 show improved and sustained responses in patients with cancer. However, these agents are associated with a plethora of adverse events, many manifesting in the skin. As the clinical application of cancer immunotherapies expands, understanding the clinical and histopathologic features of associated cutaneous toxicities becomes increasingly important to dermatologists, oncologists, and pathologists to ensure timely diagnosis and appropriate care. This review discusses cutaneous reactions to immune checkpoint inhibitors, focusing on histopathologic features.
Topics: Acantholysis; Alopecia; Drug Eruptions; Humans; Immune Checkpoint Inhibitors; Keratinocytes; Lichenoid Eruptions; Nevus, Pigmented; Panniculitis; Pemphigoid, Bullous; Pruritus; Psoriasis; Stevens-Johnson Syndrome; Vitiligo
PubMed: 32360716
DOI: 10.1016/j.jaad.2020.04.105 -
Frontiers in Oncology 2021The "multidimensional" World Health Organization (WHO) classification 2018 of melanocytic tumors encompasses nine melanoma pathways (seven of which for cutaneous... (Review)
Review
The "multidimensional" World Health Organization (WHO) classification 2018 of melanocytic tumors encompasses nine melanoma pathways (seven of which for cutaneous melanoma) according to a progression model in which morphologically intermediate melanocytic tumors are cosidered as simulators and/or precursors to melanoma. These "intermediates" can be subclassified into: i) a "classical" subgroup (superficial/thin compound: dysplastic nevus), which is placed within the morphologic and molecular progression spectrum of classical (Clark's and McGovern's) melanoma subtypes (superficial spreading and, possibly, nodular); and ii) a "non-classical" subgroup (thick compound/dermal: "melanocytomas") whose genetic pathways diverge from classical melanoma subtypes. Such a progression model is aimed at giving a conceptual framework for a histopathological classification; however, routine clinicopathological practice strongly suggests that most melanomas arise and that the vast majority of nevi are clinically stable or even involuting over time. Clinicopathological correlation can help identify some severely atypical but benign tumors (: sclerosing nevus with pseudomelanomatous features) as well as some deceptively bland melanomas (: lentiginous melanoma; nested melanoma), thereby addressing some ambiguous cases to a correct clinical management. The recently available adjuvant therapy regimens for melanoma raise the problem of a careful distinction between severely atypical (high grade) melanocytoma and "classical" melanoma: conventional morphology can guide an algorithmic approach based on an antibody panel (anti-mutated BRAF, BAP1, PRAME, ALK, TRKA, MET, HRAS-WT, ROS; beta catenin; R1alpha; p16; HMB45; Ki67), a first-line molecular study (identification of hot spot mutations of and ) and an advanced molecular study (sequencing of ; fusions studies of ); as a final step, next-generation sequencing can identify melanocytic tumors with rare genetic signatures and melanocytic tumors with a high tumor mutation burden which should be definitely ascribed to the category of classical melanoma with the respective therapeutic options.
PubMed: 34277420
DOI: 10.3389/fonc.2021.675296 -
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 -
Pediatric Dermatology Nov 2022Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of...
BACKGROUND
Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of Blaschko. Two cases of ILVEN with CARD14 mutations and one case with a GJA1 mutation have been previously reported.
OBJECTIVE
To elucidate the genetic cause of a cohort of patients diagnosed based on clinical and histopathological evaluation with ILVEN.
METHODS
We recruited patients diagnosed with ILVEN based on clinical and histopathological criteria. Exome sequencing of affected skin with or without blood/saliva was performed and germline and somatic pathogenic variants were identified.
RESULTS
Five patients were enrolled. All had skin lesions from birth or early childhood. Two patients developed psoriasis vulgaris after the diagnosis of ILVEN. The first had a germline heterozygous CARD14 mutation and a post-zygotic hotspot mutation in KRT10. The histopathologic evaluation did not show epidermolytic hyperkeratosis. The second had a post-zygotic hotspot mutation in HRAS. Her ILVEN became itchy once psoriasis developed. One patient was re-diagnosed with linear porokeratosis based on a germline mutation in PMVK and a post-zygotic second-hit mutation. Two patients were re-diagnosed with congenital hemidysplasia with ichthyosiform nevus and limb defect nevus based on germline NSDHL mutations.
CONCLUSION
ILVEN is a clinical descriptor for a heterogenous group of mosaic inflammatory disorders. Genetic analysis has the potential to more precisely categorize ILVEN and permits pathogenesis-directed therapies in some cases.
Topics: Female; Humans; Child, Preschool; Nevus, Sebaceous of Jadassohn; Skin Neoplasms; Nevus; Nevus, Pigmented; Psoriasis; Skin Diseases; Guanylate Cyclase; Membrane Proteins; CARD Signaling Adaptor Proteins; 3-Hydroxysteroid Dehydrogenases
PubMed: 35853659
DOI: 10.1111/pde.15094 -
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 -
Current Ophthalmology Reports Dec 2023To provide an up-to-date review of the epidemiology, presentation, diagnosis, and treatment options for conjunctival nevi (CN).
PURPOSE OF REVIEW
To provide an up-to-date review of the epidemiology, presentation, diagnosis, and treatment options for conjunctival nevi (CN).
RECENT FINDINGS
Around 17.2%-42% of all conjunctival tumors have been found to be CN, which most frequently present in White individuals between the first to early third decade of life, with equal distribution between males and females. CN commonly occur in the interpalpebral bulbar conjunctiva with pigmentation ranging from amelanotic to dark. Diagnosis is typically made through slit lamp examination, visualized by a well circumscribed, variably elevated, variably pigmented, solitary lesion with clear cysts distributed throughout the pigment. In ambiguous cases, anterior segment optical coherence tomography (AS-OCT) can highlight the presence of sub-clinical cysts, whose presence points to a diagnosis of nevus. However, excisional biopsy with histopathology examination is the gold standard for identifying CN.
SUMMARY
CN are benign, variably pigmented lesions. They are the most common of the conjunctival melanocytic tumors. Due to the extremely low risk of transformation to malignant melanoma (MM), CN are usually managed with routine observation and photo documentation.
PubMed: 38390435
DOI: 10.1007/s40135-023-00315-w -
Actas Dermo-sifiliograficas May 2023The advent of molecular pathology has fueled unprecedented advances in the diagnosis and understanding of melanocytic tumors. These advances, however, have also... (Review)
Review
The advent of molecular pathology has fueled unprecedented advances in the diagnosis and understanding of melanocytic tumors. These advances, however, have also generated concepts that may be difficult to grasp for clinical practitioners, who are not always conversant with the array of genetic techniques employed in the laboratory. These same practitioners, however, are being increasingly called on to provide treatments that are often based on the latest molecular findings for melanocytic tumors. We review the most recent concepts in the pathway classification of melanocytic tumors, including intermediate lesions known as melanocytomas. We examine the genetic and molecular techniques used to study these tumors, look at where they overlap, and discuss their limitations and some of the most difficult-to-interpret results.
Topics: Humans; Melanoma; Skin Neoplasms; Nevus, Epithelioid and Spindle Cell; Syndrome
PubMed: 36649787
DOI: 10.1016/j.ad.2023.01.001