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Pathology, Research and Practice Jul 2024BAP1-inactivated melanocytoma (BIM) is a novel subgroup of melanocytic neoplasm listed in the 5th edition of WHO classification of skin tumor. BIM is characterized by... (Review)
Review
BAP1-inactivated melanocytoma (BIM) is a novel subgroup of melanocytic neoplasm listed in the 5th edition of WHO classification of skin tumor. BIM is characterized by two molecular alterations, including a mitogenic driver mutation (usually BRAF gene) and the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, which encodes for BRCA1-associated protein (BAP1). The latter represents a nuclear-localized deubiquitinase involved in several cellular processes including cell cycle regulation, chromatin remodeling, DNA damage response, differentiation, senescence and cell death. BIMs are histologically characterized by a population of large epithelioid melanocytes with well-demarcated cytoplasmic borders and copious eosinophilic cytoplasm, demonstrating loss of BAP1 nuclear expression by immunohistochemistry. Recently, we have published a series of 50 cases, extending the morphological spectrum of the neoplasm and highlighting some new microscopic features. In the current article, we focus on some new histological features, attempting to explain and link them to certain mechanisms of tumor development, including senescence, endoreplication, endocycling, asymmetric cytokinesis, entosis and others. In light of the morphological and molecular findings observed in BIM, we postulated that this entity unmasks a fine mechanism of tumor in which both clonal/stochastic and hierarchical model can be unified.
Topics: Ubiquitin Thiolesterase; Humans; Tumor Suppressor Proteins; Melanoma; Skin Neoplasms; Nevus, Pigmented; Melanocytes; Biomarkers, Tumor; Mutation
PubMed: 38326181
DOI: 10.1016/j.prp.2024.155162 -
Neoplasia (New York, N.Y.) Sep 2023Cutaneous melanoma is the deadliest form of skin neoplasm and its high mortality rates could be averted by early accurate detection. While the detection of melanoma is...
Cutaneous melanoma is the deadliest form of skin neoplasm and its high mortality rates could be averted by early accurate detection. While the detection of melanoma is currently reliant upon melanin visualisation, research into melanosome biogenesis, as a key driver of pathogenesis, has not yielded technology that can reliably distinguish between atypical benign, amelanotic and melanotic lesions. The endosomal-lysosomal system has important regulatory roles in cancer cell biology, including a specific functional role in melanosome biogenesis. Herein, the involvement of the endosomal-lysosomal system in melanoma was examined by pooled secondary analysis of existing gene expression datasets. A set of differentially expressed endosomal-lysosomal genes was identified in melanoma, which were interconnected by biological function. To illustrate the protein expression of the dysregulated genes, immunohistochemistry was performed on samples from patients with cutaneous melanoma to reveal candidate markers. This study demonstrated the dysregulation of Syntenin-1, Sortilin and Rab25 may provide a differentiating feature between cutaneous melanoma and squamous cell carcinoma, while IGF2R may indicate malignant propensity in these skin cancers.
Topics: Humans; Melanoma; Skin Neoplasms; Carcinoma, Squamous Cell; Lysosomes; rab GTP-Binding Proteins; Melanoma, Cutaneous Malignant
PubMed: 37562257
DOI: 10.1016/j.neo.2023.100924 -
Advances in Therapy Aug 2023The incidence of cutaneous melanoma (CM) is increasing. CM is defined as melanoma in situ when limited within the epidermis and invasive when atypical melanocytes... (Review)
Review
The incidence of cutaneous melanoma (CM) is increasing. CM is defined as melanoma in situ when limited within the epidermis and invasive when atypical melanocytes progressively invade the dermis. Treatment of CM is challenging. On one hand, melanoma in situ does not require further treatment except for a limited secondary excision with reduced margins to minimize the risk of local recurrences; on the other, invasive melanoma requires a personalized approach based on tumor staging. Consequently, an association of surgical and medical treatments is often necessary for invasive forms of the disease. In this scenario, new knowledge on melanoma pathogenesis has led to the development of safe and effective treatments, and several drugs are currently under investigation. However, extensive knowledge is required to offer patients a tailored-tail approach. The aim of our article was to review current literature to provide an overview of treatment options for invasive melanoma, highlighting strategical approaches that can be used in patients with these forms of disease.
Topics: Humans; Melanoma; Skin Neoplasms; Treatment Outcome; Neoplasm Staging; Melanoma, Cutaneous Malignant
PubMed: 37306810
DOI: 10.1007/s12325-023-02555-5 -
International Journal of Molecular... Jul 2020Inflammasomes represent a group of protein complexes that contribute to host defense against pathogens and repair processes upon the induction of inflammation. However,... (Review)
Review
Inflammasomes represent a group of protein complexes that contribute to host defense against pathogens and repair processes upon the induction of inflammation. However, aberrant and chronic inflammasome activation underlies the pathology of numerous common inflammatory diseases. Inflammasome assembly causes activation of the protease caspase-1 which in turn activates proinflammatory cytokines and induces a lytic type of cell death termed pyroptosis. Although NLRP1 (NACHT, leucine-rich repeat and pyrin domain containing 1) was the first inflammasome sensor, described almost 20 years ago, the molecular mechanisms underlying its activation and the resulting downstream events are incompletely understood. This is partially a consequence of the poor conservation of the NLRP1 pathway between human and mice. Moreover, recent evidence demonstrates a complex and multi-stage mechanism of NLRP1 inflammasome activation. In contrast to other inflammasome sensors, NLRP1 possesses protease activity required for proteolytic self-cleavage and activation mediated by the function-to-find domain (FIIND). CARD8 is a second FIIND protein and is expressed in humans but not in mice. In immune cells and AML (acute myeloid leukemia) cells, the anti-cancer drug talabostat induces CARD8 activation and causes caspase-1-dependent pyroptosis. In contrast, in human keratinocytes talabostat induces NLRP1 activation and massive proinflammatory cytokine activation. NLRP1 is regarded as the principal inflammasome sensor in human keratinocytes and UVB radiation induces its activation, which is believed to underlie the induction of sunburn. Moreover, gain-of-function mutations of cause inflammatory skin syndromes and a predisposition for the development of skin cancer. SNPs (single nucleotide polymorphisms) of are associated with several (auto)inflammatory diseases with a major skin phenotype, such as psoriasis or vitiligo. Here, we summarize knowledge about NLRP1 with emphasis on its role in human keratinocytes and skin. Due to its accessibility, pharmacological targeting of NLRP1 activation in epidermal keratinocytes represents a promising strategy for the treatment of the numerous patients suffering from NLRP1-dependent inflammatory skin conditions and cancer.
Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis Regulatory Proteins; CARD Signaling Adaptor Proteins; Humans; Inflammasomes; Inflammation; Keratinocytes; NLR Proteins; Neoplasm Proteins; Skin; Skin Neoplasms
PubMed: 32640751
DOI: 10.3390/ijms21134788 -
Cells Aug 2021Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival... (Review)
Review
Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.
Topics: Antineoplastic Agents; Chromatin Assembly and Disassembly; DNA Methylation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Humans; Melanoma; RNA, Untranslated; Skin Neoplasms
PubMed: 34440824
DOI: 10.3390/cells10082048 -
The Australasian Journal of Dermatology Feb 2023
Topics: Humans; Poroma; Dermoscopy; Skin Neoplasms; Sweat Gland Neoplasms; Diagnosis, Differential
PubMed: 36412254
DOI: 10.1111/ajd.13957 -
Current Oncology Reports Mar 2022Liquid biopsies, including circulating tumour DNA (ctDNA), can inform a variety of clinical questions. This review examines the potential role of ctDNA as a clinical... (Review)
Review
PURPOSE OF REVIEW
Liquid biopsies, including circulating tumour DNA (ctDNA), can inform a variety of clinical questions. This review examines the potential role of ctDNA as a clinical tool to inform clinical decision-making from early to late stage cutaneous melanoma.
RECENT FINDINGS
In pre-clinical studies, ctDNA has been shown to detect minimal residual disease and molecular relapse; predict and monitor response to therapy; and identify key resistance mechanisms. Here, we examine the potential utility of ctDNA and discuss its limitations for use in patients with melanoma. We present novel clinical trials, which are testing its value as a tool to augment clinical decision-making. Finally, we discuss the steps that are needed to ensure that ctDNA is used optimally in order to improve outcomes for patients with melanoma. Preclinical studies have shown that ctDNA has huge potential to provide real-time information about disease status in patients with melanoma. It is now time to test it rigorously within clinical trials to assess how it can be optimally used to benefit patients in the clinic.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Humans; Melanoma; Neoplasm Recurrence, Local; Skin Neoplasms
PubMed: 35133615
DOI: 10.1007/s11912-021-01151-6 -
Current Oncology (Toronto, Ont.) Jul 2023Non-melanoma skin cancer of the head and neck (NMSCHN) is one of the most common malignancies worldwide, and its incidence is growing at a significant rate. It has been... (Review)
Review
Non-melanoma skin cancer of the head and neck (NMSCHN) is one of the most common malignancies worldwide, and its incidence is growing at a significant rate. It has been found to be aggressive in its spread and has the capacity to metastasize to regional lymph nodes. Cutaneous squamous cell carcinoma (cSCC) has a considerably high mortality rate. It has remarkable characteristics: diameter >2 cm, depth >5 mm, high recurrence, perineural invasion, and locoregional metastases. Aggressive cSCC lesions most commonly metastasize to the parotid gland. Also, immunocompromised patients have a higher risk of developing this aggressive cancer along with the worst prognostic outcomes. It is very important to discuss and assess the risk factors, prognostic factors, and outcomes of patients with cSCC, which will give clinicians future directives for making modifications to their treatment plans. The successful treatment of aggressive cSCC of the head and neck includes early detection and diagnosis, surgery alone or adjuvant chemotherapy, and radiotherapy as required. Multimodal therapy options should be considered by clinicians for better outcomes of aggressive cSCC of the head and neck.
Topics: Humans; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Skin Neoplasms; Head and Neck Neoplasms; Neoplasm Staging
PubMed: 37504347
DOI: 10.3390/curroncol30070487 -
Cancer Cytopathology Jan 2022Malignant melanoma (MM) is a highly aggressive neoplasm with a growing worldwide incidence. It is not uncommon that the disease is already metastatic at the time of the... (Review)
Review
Malignant melanoma (MM) is a highly aggressive neoplasm with a growing worldwide incidence. It is not uncommon that the disease is already metastatic at the time of the first diagnosis. Regional lymph nodes and skin are the first and most common metastatic sites, followed by distant visceral sites (lungs, liver, and central nervous system) and bone. In this clinical setting, fine-needle aspiration (FNA) often represents the first diagnostic approach. FNA is a useful tool to obtain a rapid and accurate diagnosis, in conjunction with ancillary techniques and molecular analysis, as recommended by recent guidelines. The aim of this review was to describe the cytomorphology, immunocytochemical tools, and molecular tools used for the diagnosis of MM metastases on FNA.
Topics: Biopsy, Fine-Needle; Humans; Lymph Nodes; Lymphatic Metastasis; Melanoma; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 34310059
DOI: 10.1002/cncy.22488 -
Comptes Rendus Biologies Nov 2021Melanocytes are located in various parts of the human body, such as the skin and the eye. Their transformation leads to melanoma, an aggressive and deadly neoplasm.... (Review)
Review
Melanocytes are located in various parts of the human body, such as the skin and the eye. Their transformation leads to melanoma, an aggressive and deadly neoplasm. Cutaneous and uveal melanomas show different characteristics, including significant differences in genetic alterations, metastatic sites and therapeutic response. In recent decades, great efforts have been made to obtain a more comprehensive understanding of genetics, genomics and molecular changes, enabling the identification of key cellular processes and signaling pathways in melanomas. Major breakthroughs were realized in the treatment of metastatic cutaneous melanoma, but most patients relapse. Currently, there is no approved systemic treatment for metastatic uveal melanoma. Thus, these two different cancers are in therapeutic need to overcome treatment failure and improve patient prognosis. In this review we discuss on one hand the mutation of MITF, the master gene of melanocyte homeostasis, which we identified as a new melanoma predisposition gene in cutaneous melanoma, and on the other hand the recent findings of intratumor heterogeneity and characterization of cell sub-populations in primary uveal melanomas. These studies offer new tools for early detection and therapeutic targets.
Topics: Humans; Melanoma; Skin Neoplasms; Uveal Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 35786627
DOI: 10.5802/crbiol.63