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Italian Journal of Dermatology and... Jun 2021Despite the rapid recent advances in molecular analysis of tumors, which allow large-scale and high-resolution genomics, the "gold standard" for melanoma diagnosis... (Review)
Review
Despite the rapid recent advances in molecular analysis of tumors, which allow large-scale and high-resolution genomics, the "gold standard" for melanoma diagnosis continues to be histopathology, in conjunction with clinical characteristics and sometimes with important support of immunohistochemistry. Observations, where postulated that cutaneous melanomas may arise through two distinct pathways, discoveries such as that BRAF mutations were mostly common in melanomas on sun-exposed skin with little solar elastosis and seminal works for melanoma progression and evolution set the groundwork for the new WHO Classification of Melanoma: a classification of melanoma that not only encompasses histologic but also clinical, epidemiologic, and genetic characteristics. The melanomas were divided into those etiologically related to sun exposure and those that are not, based on their mutational signatures, anatomic site, and epidemiology. On the basis of degree of associated solar elastosis melanomas on the sun exposed skin were further divided by the histopathologic degree of cumulative solar damage (CSD) of the surrounding skin, into low and high CSD. On the low-CSD group of melanomas are included superficial spreading melanomas, while the high-CSD melanomas encompasses lentigo maligna and desmoplastic melanomas. The "non-CSD" classification includes acral melanomas, some melanomas in congenital nevi, melanomas in blue nevi, Spitz melanomas, mucosal melanomas, and uveal melanomas. Nodular and nevoid melanoma may occur in any pathway. A group of intermediate tumors termed melanocytoma is proposed for tumors that in addition to mutations that activate the MAPK pathway, harbor multiple driver mutations, and they are either low-grade or high-grade, to indicate that they may carry a higher risk of malignant transformation. In this review a summary of the most recent WHO classification of melanoma is provided. A short analysis of essential histopathologic prognostic parameters is also provided. The new classification of melanoma discriminates distinct types of melanoma based on their clinicopathologic, and genomic characteristics. Undoubtedly, melanoma research will continue to evolve as new clinical, pathological, molecular data accumulates. The challenge of the forthcoming years is to better characterize the intermediate category of melanocytic lesions.
Topics: Humans; Hutchinson's Melanotic Freckle; Melanoma; Prognosis; Skin Neoplasms; Uveal Neoplasms
PubMed: 33982546
DOI: 10.23736/S2784-8671.21.06958-3 -
Cells Sep 2021Melanoma develops as a result of several genetic alterations, with UV radiation often acting as a mutagenic risk factor. Deep knowledge of the molecular signaling... (Review)
Review
Melanoma develops as a result of several genetic alterations, with UV radiation often acting as a mutagenic risk factor. Deep knowledge of the molecular signaling pathways of different types of melanoma allows better characterization and provides tools for the development of therapies based on the intervention of signals promoted by these cascades. The latest World Health Organization classification acknowledged the specific genetic drivers leading to melanoma and classifies melanocytic lesions into nine distinct categories according to the associate cumulative sun damage (CSD), which correlates with the molecular alterations of tumors. The largest groups are melanomas associated with low-CSD or superficial spreading melanomas, characterized by frequent presentation of the V600 mutation. High-CSD melanomas include lentigo maligna type and desmoplastic melanomas, which often have a high mutation burden and can harbor , non-V600E, or mutations. Non-CSD-associated melanomas encompass acral and mucosal melanomas that usually do not show , , or mutations (triple wild-type), but in a subset may have or mutations. To improve survival, these driver alterations can be treated with targeted therapy achieving significant antitumor activity. In recent years, relevant improvement in the prognosis and survival of patients with melanoma has been achieved, since the introduction of / tyrosine kinase inhibitors and immune checkpoint inhibitors. In this review, we describe the current knowledge of molecular pathways and discuss current and potential therapeutic targets in melanoma, focusing on their clinical relevance of development.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Genetic Predisposition to Disease; Humans; Immune Checkpoint Inhibitors; Melanoma; Molecular Targeted Therapy; Mutation; Phenotype; Protein Kinase Inhibitors; Skin Neoplasms; Treatment Outcome
PubMed: 34571969
DOI: 10.3390/cells10092320 -
Cancer Aug 2016Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United... (Review)
Review
Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.
Topics: Chromosome Aberrations; Combined Modality Therapy; Early Detection of Cancer; Genetic Predisposition to Disease; Genetic Testing; Humans; Melanoma; Mutation; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Research; Treatment Outcome; Uveal Neoplasms
PubMed: 26991400
DOI: 10.1002/cncr.29727 -
International Journal of Molecular... Nov 2020Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in... (Review)
Review
Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is "curable" at this stage. However, after metastasis, it is difficult to treat and the five-year survival is only 25%. In recent years, a better understanding of the etiology of melanoma and its progression has made it possible for the development of targeted therapeutics, such as vemurafenib and immunotherapies, to treat advanced melanomas. In this review, we focus on the molecular mechanisms that mediate melanoma development and progression, with a special focus on the immune evasion strategies utilized by melanomas, to evade host immune surveillances. The proposed mechanism of action and the roles of immunotherapeutic agents, ipilimumab, nivolumab, pembrolizumab, and atezolizumab, adoptive T- cell therapy plus T-VEC in the treatment of advanced melanoma are discussed. In this review, we implore that a better understanding of the steps that mediate melanoma onset and progression, immune evasion strategies exploited by these tumor cells, and the identification of biomarkers to predict treatment response are critical in the design of improved strategies to improve clinical outcomes for patients with this deadly disease.
Topics: Humans; Immune Evasion; Immunotherapy; Melanoma; Risk Factors; Skin Neoplasms; Tumor Microenvironment
PubMed: 33256089
DOI: 10.3390/ijms21238984 -
Seminars in Cancer Biology Dec 2019Cutaneous melanoma is the most common skin cancer with an incidence that has been rapidly increasing in the past decades. Melanomas are among the most immunogenic tumors... (Review)
Review
Cutaneous melanoma is the most common skin cancer with an incidence that has been rapidly increasing in the past decades. Melanomas are among the most immunogenic tumors and, as such, have the greatest potential to respond favorably to immunotherapy. However, like many cancers, melanomas acquire various suppressive mechanisms, which generally act in concert, to escape innate and adaptive immune detection and destruction. Intense research into the cellular and molecular events associated with melanomagenesis, which ultimately lead to immune suppression, has resulted in the discovery of new therapeutic targets and synergistic combinations of immunotherapy, targeted therapy and chemotherapy. Tremendous effort to determine efficacy of single and combination therapies in pre-clinical and clinical phase I-III trials has led to FDA-approval of several immunotherapeutic agents that could potentially be beneficial for aggressive, highly refractory, advanced and metastatic melanomas. The increasing availability of approved combination therapies for melanoma and more rapid assessment of patient tumors has increased the feasibility of personalized treatment to overcome patient and tumor heterogeneity and to achieve greater clinical benefit. Here, we review the evolution of the immune system during melanomagenesis, mechanisms exploited by melanoma to suppress anti-tumor immunity and methods that have been developed to restore immunity. We emphasize that an effective therapeutic strategy will require coordinate activation of tumor-specific immunity as well as increased recognition and accessibility of melanoma cells in primary tumors and distal metastases. This review integrates available knowledge on melanoma-specific immunity, molecular signaling pathways and molecular targeting strategies that could be utilized to envision therapeutics with broader application and greater efficacy for early stage and advanced metastatic melanoma.
Topics: Animals; Biomarkers; Cell Communication; Cytokines; Energy Metabolism; Humans; Immune System; Immunity; Melanoma; Signal Transduction; Tumor Escape; Tumor Microenvironment
PubMed: 31404607
DOI: 10.1016/j.semcancer.2019.08.002 -
International Journal of Molecular... May 2022Similar to other malignancies, TCGA network efforts identified the detailed genomic picture of skin melanoma, laying down the basis of molecular classification. On the... (Review)
Review
Similar to other malignancies, TCGA network efforts identified the detailed genomic picture of skin melanoma, laying down the basis of molecular classification. On the other hand, genome-wide association studies discovered the genetic background of the hereditary melanomas and the susceptibility genes. These genetic studies helped to fine-tune the differential diagnostics of malignant melanocytic lesions, using either FISH tests or the myPath gene expression signature. Although the original genomic studies on skin melanoma were mostly based on primary tumors, data started to accumulate on the genetic diversity of the progressing disease. The prognostication of skin melanoma is still based on staging but can be completed with gene expression analysis (DecisionDx). Meanwhile, this genetic knowledge base of skin melanoma did not turn to the expected wide array of target therapies, except the BRAF inhibitors. The major breakthrough of melanoma therapy was the introduction of immune checkpoint inhibitors, which showed outstanding efficacy in skin melanoma, probably due to their high immunogenicity. Unfortunately, beyond , mutations and tumor mutation burden, no clinically validated predictive markers exist in melanoma, although several promising biomarkers have been described, such as the expression of immune-related genes or mutations in the IFN-signaling pathway. After the initial success of either target or immunotherapies, sooner or later, relapses occur in the majority of patients, due to various induced genetic alterations, the diagnosis of which could be developed to novel predictive genetic markers.
Topics: Genome-Wide Association Study; Humans; Melanoma; Pathology, Molecular; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 35628196
DOI: 10.3390/ijms23105384 -
American Journal of Clinical Dermatology Nov 2018This review presents the main challenges encountered when diagnosing unusual variants of malignant melanoma with the aim of raising awareness to allow application of the... (Review)
Review
This review presents the main challenges encountered when diagnosing unusual variants of malignant melanoma with the aim of raising awareness to allow application of the most appropriate treatment strategies. Although these melanomas are often rare, their misdiagnosis potentially jeopardizes patients' health and survival, and has medicolegal implications. The clinical and histologic presentations of melanoma vary greatly, and assessment of uncommon melanomas can be difficult for practitioners because of their scarcity and resemblance to other dermatologic entities. The most problematic melanoma types are desmoplastic melanoma, polypoid melanoma, primary dermal melanoma, verrucous malignant melanoma, pigmented epithelioid melanocytoma, mucosal melanoma, follicular melanoma and melanoma with non-melanocytic differentiation. The two most difficult-to-diagnose subtypes of melanoma are the nevoid and the amelanotic melanomas. Some specific attributes of these variants can be more easily recognized with digital dermatoscopy, facilitating early detection and possibly avoiding invasive procedures. Key cases with the most notable clinical, dermatoscopic, and histopathologic features are presented, highlighting the practical issues of making an accurate diagnosis and choosing the best therapy.
Topics: Clinical Decision-Making; Dermoscopy; Diagnosis, Differential; Disease Progression; Humans; Melanoma; Microscopy, Confocal; Prognosis; Skin; Skin Neoplasms; Survival Rate
PubMed: 30374898
DOI: 10.1007/s40257-018-0373-6 -
Archives of Pathology & Laboratory... Apr 2020There have been major advances in the understanding of melanoma since the last revision of the World Health Organization (WHO) classification in 2006. (Review)
Review
The 2018 World Health Organization Classification of Cutaneous, Mucosal, and Uveal Melanoma: Detailed Analysis of 9 Distinct Subtypes Defined by Their Evolutionary Pathway.
CONTEXT.—
There have been major advances in the understanding of melanoma since the last revision of the World Health Organization (WHO) classification in 2006.
OBJECTIVE.—
To discuss development of the 9 distinct types of melanoma and distinguishing them by their epidemiology, clinical and histologic morphology, and genomic characteristics. Each melanoma subtype is placed at the end of an evolutionary pathway that is rooted in its respective precursor, wherever appropriate and feasible, based on currently known data. Each precursor has a variable risk of progression culminating in its fully evolved, invasive melanoma.
DATA SOURCES.—
This review is based on the "Melanocytic Tumours" section of the 4th edition of the , published in 2018.
CONCLUSIONS.—
Melanomas were divided into those etiologically related to sun exposure and those that are not, as determined by their mutational signatures, anatomic site, and epidemiology. Melanomas on the sun-exposed skin were further divided by the histopathologic degree of cumulative solar damage (CSD) of the surrounding skin, into low and high CSD, on the basis of degree of associated solar elastosis. Low-CSD melanomas include superficial spreading melanomas and high-CSD melanomas incorporate lentigo maligna and desmoplastic melanomas. The "nonsolar" category includes acral melanomas, some melanomas in congenital nevi, melanomas in blue nevi, Spitz melanomas, mucosal melanomas, and uveal melanomas. The general term is proposed to encompass "intermediate" tumors that have an increased (though still low) probability of disease progression to melanoma.
Topics: Humans; Melanoma; Mucous Membrane; Skin Neoplasms; Uveal Neoplasms; World Health Organization; Melanoma, Cutaneous Malignant
PubMed: 32057276
DOI: 10.5858/arpa.2019-0561-RA -
Archives of Pathology & Laboratory... Oct 2001The rapidly developing fields of melanoma research are revolutionizing the current concepts on melanoma etiology and pathogenesis and are introducing newer diagnostic... (Review)
Review
CONTEXT
The rapidly developing fields of melanoma research are revolutionizing the current concepts on melanoma etiology and pathogenesis and are introducing newer diagnostic techniques and potential therapeutic approaches.
OBJECTIVES
To present the most current concepts on the etiology and pathogenesis of melanoma and to introduce the recent diagnostic techniques and the potential therapeutic approaches.
METHODS
Data sources were reports on melanoma published in the English language literature and observations made using specimens available at Harvard University, Johns Hopkins Medical Center, Albany Medical College, Loyola University Medical Center, and University of Tennessee Health Science Center.
RESULTS
Studies on melanoma containing chromosomal or genetic evaluation were selected for further analysis. Current clinical and pathologic categories with the reported genetic abnormalities were related to the latest information on pigment biology. The data extracted were used to develop a conceptual framework on the pathogenesis of melanoma; the generated model was then evaluated and used to suggest potential therapeutic approaches.
CONCLUSIONS
(1) Melanoma is not genetically homogeneous, and the existing differences between the pathologic categories, particularly in areas such as type of growth phase (radial vs vertical growth), total vertical dimension, ulceration of primary tumor, and metastatic process, have profound prognostic and therapeutic implications. (2) Chromosomal aberrations and gene mutations are found in sporadic and familial melanomas; among the most important are those affecting the 9p21, which contains the p16 locus, a site known to be critical for normal progression of the cell cycle. Aberrant p16 expression is associated with more aggressive behavior. (3) Melanoma cells possess a remarkable repertoire of biosynthetic capacities represented by the production of hormones, growth factors, and their receptors that may sustain and accelerate tumor development and progression. For example, expression of the tumoral products alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone is regulated in vitro by ultraviolet light, a known carcinogen. (4) Melanomas differ from other tumors in their intrinsic capability to express melanogenic enzymes with the corresponding structural proteins to actually synthesize melanin. Melanogenesis-related proteins are rapidly entering the clinical arena, being used not only as diagnostic markers, but also as potential targets for melanoma therapy.
Topics: Chromosome Aberrations; Chromosome Disorders; Disease Susceptibility; Female; Genetic Predisposition to Disease; Growth Substances; Humans; Immunotherapy; Male; Melanins; Melanoma; Neoplasm Metastasis
PubMed: 11570904
DOI: 10.5858/2001-125-1295-MM -
Frontiers in Immunology 2021Acral and mucosal melanomas are extremely rare in Caucasians; however, they are the predominant melanoma subtypes in Asians and other non-Caucasian populations. Acral... (Review)
Review
Acral and mucosal melanomas are extremely rare in Caucasians; however, they are the predominant melanoma subtypes in Asians and other non-Caucasian populations. Acral and mucosal melanomas share many clinicopathological features, including aggressive phenotypes, similar genetic landscapes, and grim prognoses. In spite of advances in melanoma management, patients with acral and mucosal melanomas show limited benefit from current therapies. The rarity of these subtypes of melanoma is a significant factor contributing to the poor understanding of these pathological subtypes and the lack of effective interventions. Furthermore, the mechanisms contributing to disparities between different types of melanoma remain largely unclear. Herein, we comprehensively review current knowledge on the clinicopathological characteristics and mutational landscapes of acral and mucosal melanomas, as well as providing an overview of current therapies for patients with these aggressive melanoma subtypes, focusing on available immunotherapeutic interventions. We also discuss pathological differences between different melanoma subtypes and summarize current knowledge on melanoma disparities between Asians and Caucasians. Finally, we discuss emerging immunotherapeutic strategies for the treatment of acral and mucosal melanomas, focusing on combination therapies with immune checkpoint inhibitors. Unraveling the unique features of acral and mucosal melanomas is key for their early diagnosis and for the development of effective therapies.
Topics: Animals; Combined Modality Therapy; Disease Management; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Immunotherapy; Melanoma; Mucous Membrane; Mutation; Skin Neoplasms; Tumor Microenvironment
PubMed: 34149718
DOI: 10.3389/fimmu.2021.680407