Abstract
Cutaneous melanoma is a common cancer in Australia and New Zealand, Europe, and North America, and its incidence is still increasing in many regions. Ultraviolet (UV) radiation exposure (for example, through excessive sunlight exposure) remains the primary risk factor for melanoma; however, public awareness campaigns have led to a marked reduction in mortality. In addition to genetic damage from UV radiation, specific genetic alterations have been linked to melanoma. The stage of the tumour at the time of diagnosis is of greater importance for melanoma prognosis than in almost any other cancer. Context-dependent genetic mutations that attenuate tumour-suppressive mechanisms or activate growth-promoting signalling pathways are crucial factors in the development of cutaneous melanoma. In addition to external factors such as UV radiation, the tumour microenvironment can contribute to melanoma progression, invasion and metastasis. Cutaneous melanoma treatment has improved considerably over the past decade with the discovery and development of immune checkpoint inhibitors and therapy targeting BRAF and MEK. Over the next decade, several priorities are likely to influence melanoma research and management, including the continued advance of precision medicine methods to identify the most suitable patients for the most effective treatment, with the aim of improving clinical outcomes.
Access through your institution
Buy or subscribe
This is a preview of subscription content, access via your institution
Access options
Access through your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Learn more
Subscribe to this journal
Receive 1 digital issues and online access to articles
$119.00 per year
only $119.00 per issue
Learn more
Buy this article
Purchase on SpringerLink
Instant access to full article PDF
Buy now
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Log in
Learn about institutional subscriptions
Read our FAQs
Contact customer support
Fig. 1: Disease progression in melanoma.
Fig. 2: Global epidemiology of melanoma.
Fig. 3: Molecular mechanisms in melanoma pathogenesis.
Fig. 4: The role of the TME in melanoma.
Fig. 5: Clinical and dermoscopic images of primary cutaneous melanomas.
Fig. 6: Clinical and dermoscopic images of primary cutaneous melanomas in patients with darker skin tones.
Fig. 7: Digital monitoring of melanoma.
References
Centeno, P. P., Pavet, V. & Marais, R. The journey from melanocytes to melanoma. Nat. Rev. Cancer 23, 372–390 (2023). This review provides a comprehensive overview of the transformation process from normal melanocytes to malignant melanoma cells.
ArticleCASPubMedGoogle Scholar
Arnold, M. et al. Global burden of cutaneous melanoma in 2020 and projections to 2040. JAMA Dermatol. 158, 495–503 (2022). This study provides a comprehensive analysis of melanoma incidence and mortality worldwide, emphasizing the need for effective prevention, early detection and treatment strategies to mitigate this growing burden.
ArticlePubMedPubMed CentralGoogle Scholar
Tas, F. & Erturk, K. Major histotypes in skin melanoma: nodular and acral lentiginous melanomas are poor prognostic factors for relapse and survival. Am. J. Dermatopathol. 44, 799–805 (2022).
ArticlePubMedGoogle Scholar
Green, A. C., Wallingford, S. C. & McBride, P. Childhood exposure to ultraviolet radiation and harmful skin effects: epidemiological evidence. Prog. Biophys. Mol. Biol. 107, 349–355 (2011).
ArticlePubMedPubMed CentralGoogle Scholar
Noonan, F. P., Dudek, J., Merlino, G. & De Fabo, E. C. Animal models of melanoma: an HGF/SF transgenic mouse model may facilitate experimental access to UV initiating events. Pigment. Cell Res. 16, 16–25 (2003).
ArticleCASPubMedGoogle Scholar
Visser, M., van der Stoep, N. & Gruis, N. Progress report on the major clinical advances in patient-oriented research into familial melanoma (2013–2018). Fam. Cancer 18, 267–271 (2019).
ArticlePubMedGoogle Scholar
Ribeiro Moura Brasil Arnaut, J. et al. Molecular landscape of hereditary melanoma. Crit. Rev. Oncol. Hematol. 164, 103425 (2021).
ArticlePubMedGoogle Scholar
Otero, C. et al. Dermoscopic, confocal and histopathologic characteristics of small-diameter melanomas (minimelanoma): a cross sectional study. Australas. J. Dermatol. 62, e256–e261 (2021).
ArticlePubMedGoogle Scholar
Pupelli, G. et al. Small-diameter melanocytic lesions: morphological analysis by means of in vivo confocal microscopy. Br. J. Dermatol. 168, 1027–1033 (2013).
ArticleCASPubMedGoogle Scholar
Megaris, A. et al. Dermoscopy features of melanomas with a diameter up to 5 mm (micromelanomas): a retrospective study. J. Am. Acad. Dermatol. 83, 1160–1161 (2020).
ArticlePubMedGoogle Scholar
Garbe, C. et al. European consensus-based interdisciplinary guideline for melanoma. Part 1: diagnostics – update 2024. Eur. J. Cancer 215, 115152 (2025).
ArticlePubMedGoogle Scholar
Garbe, C. et al. European consensus-based interdisciplinary guideline for melanoma. Part 2: treatment – update 2024. Eur. J. Cancer 215, 115153 (2025). Together with Part 1 of this guideline (Garbe et al. (2025)), this publication provides the latest diagnostic and therapy guidelines in Europe that are valid until the end of 2026.
ArticlePubMedGoogle Scholar
Lin, X. et al. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol. Cancer 23, 108 (2024).
ArticlePubMedPubMed CentralGoogle Scholar
McLaughlin, C. C. et al. Incidence of noncutaneous melanomas in the U.S. Cancer 103, 1000–1007 (2005).
ArticlePubMedGoogle Scholar
International Agency for Research on Cancer. Data Visualization Tools for Exploring the Global Cancer Burden in 2022. Cancer Todaygco.iarc.who.int/today (2024).
Brunsgaard, E. K., Wu, Y. P. & Grossman, D. Melanoma in skin of color: part I. Epidemiology and clinical presentation. J. Am. Acad. Dermatol. 89, 445–456 (2023). This paper highlights the importance of skin of colour (SOC) in the diagnosis of melanoma and focuses on the epidemiology and clinical presentation of melanoma in individuals with SOC.
ArticlePubMedGoogle Scholar
Garbe, C. et al. Epidemiology of cutaneous melanoma and keratinocyte cancer in white populations 1943-2036. Eur. J. Cancer 152, 18–25 (2021).
ArticlePubMedGoogle Scholar
International Agency for Research on Cancer. Comparable Cancer Statistics for Denmark, Finland, Iceland, Norway, Sweden, the Faroe Islands, and Greenland. NORDCANnordcan.iarc.fr/ (2023).
De Pinto, G. et al. Global trends in cutaneous malignant melanoma incidence and mortality. Melanoma Res. https://doi.org/10.1097/CMR.0000000000000959 (2024).
Erdmann, F. et al. International trends in the incidence of malignant melanoma 1953–2008 – are recent generations at higher or lower risk? Int. J. Cancer 132, 385–400 (2013).
ArticleCASPubMedGoogle Scholar
Keim, U. et al. Cutaneous melanoma attributable to UVR exposure in Denmark and Germany. Eur. J. Cancer 159, 98–104 (2021).
ArticlePubMedGoogle Scholar
Welch, H. G., Mazer, B. L. & Adamson, A. S. The rapid rise in cutaneous melanoma diagnoses. N. Engl. J. Med. 384, 72–79 (2021).
ArticlePubMedGoogle Scholar
International Agency for Research on Cancer. Trends in Cancer Incidence and Mortality Rates. Cancer Over Timegco.iarc.fr/overtime/en (2024).
Boer, F. L. et al. Trends in incidence and survival of 1496 patients with mucosal melanoma in The Netherlands (1990-2019). Cancers 15, 1541 (2023).
ArticlePubMedPubMed CentralGoogle Scholar
Cui, C. et al. An evidence-based staging system for mucosal melanoma: a proposal. Ann. Surg. Oncol. 29, 5221–5234 (2022).
ArticlePubMedGoogle Scholar
Leeneman, B. et al. Stage-specific trends in incidence and survival of cutaneous melanoma in the Netherlands (2003-2018): a nationwide population-based study. Eur. J. Cancer 154, 111–119 (2021).
ArticlePubMedGoogle Scholar
Eisemann, N. et al. Longer survival from melanoma in Germany. Dtsch. Arztebl Int. 121, 45–51 (2024).
PubMedPubMed CentralGoogle Scholar
Smith, A. J., Lambert, P. C. & Rutherford, M. J. Understanding the impact of sex and stage differences on melanoma cancer patient survival: a SEER-based study. Br. J. Cancer 124, 671–677 (2021).
ArticlePubMedGoogle Scholar
Di Carlo, V. et al. Sex differences in survival from melanoma of the skin: the role of age, anatomic location and stage at diagnosis: a CONCORD-3 study in 59 countries. Eur. J. Cancer 217, 115213 (2025).
ArticlePubMedGoogle Scholar
Crocetti, E. et al. Survival of patients with skin melanoma in Europe increases further: results of the EUROCARE-5 study. Eur. J. Cancer 51, 2179–2190 (2015).
ArticlePubMedGoogle Scholar
Conforti, C. & Zalaudek, I. Epidemiology and risk factors of melanoma: a review. Dermatol. Pract. Concept. 11, e2021161S (2021).
ArticlePubMedPubMed CentralGoogle Scholar
Stanienda-Sokol, K. et al. Primary locations of malignant melanoma lesions depending on patients’ gender and age. Asian Pac. J. Cancer Prev. 18, 3081–3086 (2017).
PubMedPubMed CentralGoogle Scholar
Raimondi, S., Suppa, M. & Gandini, S. Melanoma epidemiology and sun exposure. Acta Derm. Venereol. 100, adv00136 (2020).
ArticleCASPubMedGoogle Scholar
Campillo, P. et al. International incidence of melanoma in heart transplant recipients: a meta-analysis. Melanoma Res. 35, 24–30 (2025).
ArticlePubMedGoogle Scholar
Landi, M. T. et al. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility. Nat. Genet. 52, 494–504 (2020).
ArticleCASPubMedPubMed CentralGoogle Scholar
Goldstein, A. M. et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 66, 9818–9828 (2006).
ArticleCASPubMedGoogle Scholar
Goldstein, A. M. et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J. Med. Genet. 44, 99–106 (2007).
ArticleCASPubMedGoogle Scholar
Wiesner, T. et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat. Genet. 43, 1018–1021 (2011).
ArticleCASPubMedPubMed CentralGoogle Scholar
O’Shea, S. J. et al. A population-based analysis of germline BAP1 mutations in melanoma. Hum. Mol. Genet. 26, 717–728 (2017).
PubMedPubMed CentralGoogle Scholar
Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013). This paper identified a disease-segregating germline mutation in the TERT promoter in a family predisposed to melanoma and found additional TERT promoter mutations in a high percentage of sporadic melanomas and melanoma cell lines.
ArticleCASPubMedGoogle Scholar
Robles-Espinoza, C. D., del Castillo Velasco-Herrera, M., Hayward, N. K. & Adams, D. J. Telomere-regulating genes and the telomere interactome in familial cancers. Mol. Cancer Res. 13, 211–222 (2015).
ArticleCASPubMedGoogle Scholar
Shi, J. et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat. Genet. 46, 482–486 (2014).
ArticleCASPubMedPubMed CentralGoogle Scholar
Aoude, L. G. et al. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J. Natl Cancer Inst. 107, dju408 (2015).
ArticlePubMedGoogle Scholar
Potrony, M. et al. Update in genetic susceptibility in melanoma. Ann. Transl. Med. 3, 210 (2015).
PubMedPubMed CentralGoogle Scholar
Gumaste, P. V. et al. Skin cancer risk in BRCA1/2 mutation carriers. Br. J. Dermatol. 172, 1498–1506 (2015).
ArticleCASPubMedPubMed CentralGoogle Scholar
Ward, K. A., Lazovich, D. & Hordinsky, M. K. Germline melanoma susceptibility and prognostic genes: a review of the literature. J. Am. Acad. Dermatol. 67, 1055–1067 (2012).
ArticlePubMedGoogle Scholar
Eggermont, A. M., Spatz, A. & Robert, C. Cutaneous melanoma. Lancet 383, 816–827 (2014).
ArticleCASPubMedGoogle Scholar
Hawryluk, E. B. & Tsao, H. Melanoma: clinical features and genomic insights. Cold Spring Harb. Perspect. Med. 4, a015388 (2014).
ArticlePubMedPubMed CentralGoogle Scholar
Zanna, I. et al. Germline MC1R variants and frequency of somatic BRAF, NRAS, and TERT mutations in melanoma: literature review and meta-analysis. Mol. Carcinog. 60, 167–171 (2021).
ArticleCASPubMedGoogle Scholar
Fargnoli, M. C., Gandini, S., Peris, K., Maisonneuve, P. & Raimondi, S. MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis. Eur. J. Cancer 46, 1413–1420 (2010).
ArticleCASPubMedGoogle Scholar
Young, A. R. et al. Human melanocytes and keratinocytes exposed to UVB or UVA in vivo show comparable levels of thymine dimers. J. Invest. Dermatol. 111, 936–940 (1998).
ArticleCASPubMedGoogle Scholar
Fadadu, R. P. & Wei, M. L. Ultraviolet A radiation exposure and melanoma: a review. Melanoma Res. 32, 405–410 (2022).
ArticleCASPubMedGoogle Scholar
Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015). In cutaneous melanoma, this paper represents the initial TCGA data which described the landscape of genomic alterations in melanoma and is a landmark paper that serves as the starting point to all genomic analysis in melanoma.
ArticleGoogle Scholar
Krauthammer, M. et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat. Genet. 47, 996–1002 (2015).
ArticleCASPubMedPubMed CentralGoogle Scholar
Shain, A. H. et al. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nat. Genet. 47, 1194–1199 (2015).
ArticleCASPubMedPubMed CentralGoogle Scholar
Kollias, N., Sayre, R. M., Zeise, L. & Chedekel, M. R. Photoprotection by melanin. J. Photochem. Photobiol. B 9, 135–160 (1991).
ArticleCASPubMedGoogle Scholar
Raposo, G. & Marks, M. S. Melanosomes-dark organelles enlighten endosomal membrane transport. Nat. Rev. Mol. Cell Biol. 8, 786–797 (2007).
ArticleCASPubMedPubMed CentralGoogle Scholar
Scott, M. C. et al. Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation. J. Cell Sci. 115, 2349–2355 (2002).
ArticleCASPubMedGoogle Scholar
Cassidy, P. B., Abdel-Malek, Z. A. & Leachman, S. A. Beyond red hair and sunburns: uncovering the molecular mechanisms of MC1R signaling and repair of UV-induced DNA damage. J. Invest. Dermatol. 135, 2918–2921 (2015).
ArticleCASPubMedPubMed CentralGoogle Scholar
Curtin, J. A. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005).
ArticleCASPubMedGoogle Scholar
Bastian, B. C. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu. Rev. Pathol. 9, 239–271 (2014).
ArticleCASPubMedPubMed CentralGoogle Scholar
van Poppelen, N. M. et al. Genetics of ocular melanoma: insights into genetics, inheritance and testing. Int. J. Mol. Sci. 22, 336 (2020).
ArticlePubMedPubMed CentralGoogle Scholar
Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013).
ArticleCASPubMedPubMed CentralGoogle Scholar
Elder, D. E., Bastian, B. C., Cree, I. A., Massi, D. & Scolyer, R. A. The 2018 World Health Organization classification of cutaneous, mucosal, and uveal melanoma: detailed analysis of 9 distinct subtypes defined by their evolutionary pathway. Arch. Pathol. Lab. Med. 144, 500–522 (2020).
ArticleCASPubMedGoogle Scholar
Maldonado, J. L. et al. Determinants of BRAF mutations in primary melanomas. J. Natl Cancer Inst. 95, 1878–1890 (2003).
ArticleCASPubMedGoogle Scholar
Whiteman, D. C. et al. Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma. J. Natl Cancer Inst. 95, 806–812 (2003).
ArticlePubMedGoogle Scholar
Vredeveld, L. C. et al. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes. Dev. 26, 1055–1069 (2012).
ArticleCASPubMedPubMed CentralGoogle Scholar
Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).
ArticleCASPubMedGoogle Scholar
Kiuru, M. & Busam, K. J. The NF1 gene in tumor syndromes and melanoma. Lab. Invest. 97, 146–157 (2017).
ArticleCASPubMedPubMed CentralGoogle Scholar
Davis, E. J., Johnson, D. B., Sosman, J. A. & Chandra, S. Melanoma: what do all the mutations mean? Cancer 124, 3490–3499 (2018).
ArticlePubMedGoogle Scholar
Hayes, T. K. et al. A functional landscape of resistance to MEK1/2 and CDK4/6 inhibition in NRAS-mutant melanoma. Cancer Res. 79, 2352–2366 (2019).
ArticleCASPubMedPubMed CentralGoogle Scholar
Holt, M. E. et al. My cancer genome: coevolution of precision oncology and a molecular oncology knowledgebase. JCO Clin. Cancer Inf. 5, 995–1004 (2021).
ArticleGoogle Scholar
Hodis, E. et al. A landscape of driver mutations in melanoma. Cell 150, 251–263 (2012). This paper shows that the range of driver mutations provides irrefutable genomic evidence for a direct mutagenic role of UV light in the pathogenesis of melanoma.
ArticleCASPubMedPubMed CentralGoogle Scholar
Hayward, N. K. et al. Whole-genome landscapes of major melanoma subtypes. Nature 545, 175–180 (2017). This paper builds on TCGA analysis but summarizes the landscape of genetic and genomic alterations in melanoma across non-aural cutaneous, acral cutaneous and mucosal melanoma, highlighting the differences in tumour mutational burden and copy number alterations across the subtypes.
ArticleCASPubMedGoogle Scholar
Moran, B., Silva, R., Perry, A. S. & Gallagher, W. M. Epigenetics of malignant melanoma. Semin. Cancer Biol. 51, 80–88 (2018).
ArticleCASPubMedGoogle Scholar
Conway, K. et al. Characterization of the CpG island hypermethylated phenotype subclass in primary melanomas. J. Invest. Dermatol. 142, 1869–1881.e10 (2022).
ArticleCASPubMedGoogle Scholar
Zhong, F. et al. Reshaping the tumour immune microenvironment in solid tumours via tumour cell and immune cell DNA methylation: from mechanisms to therapeutics. Br. J. Cancer 129, 24–37 (2023).
ArticleCASPubMedPubMed CentralGoogle Scholar
Trotta, A. P. et al. Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition. J. Biol. Chem. 292, 11727–11739 (2017).
ArticleCASPubMedPubMed CentralGoogle Scholar
Kimm, M. A. et al. Tumor-associated macrophages – implications for molecular oncology and imaging. Biomedicines 9, 374 (2021).
ArticleCASPubMedPubMed CentralGoogle Scholar
Pedri, D., Karras, P., Landeloos, E., Marine, J. C. & Rambow, F. Epithelial-to-mesenchymal-like transition events in melanoma. FEBS J. 289, 1352–1368 (2022).
ArticleCASPubMedGoogle Scholar
Hoek, K. S. et al. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment. Cell Res. 19, 290–302 (2006).
ArticleCASPubMedGoogle Scholar
Lim, S. Y., Pedersen, B. & Rizos, H. Protein-based classification of melanoma differentiation subtypes. Pigment. Cell Melanoma Res. 35, 471–473 (2022).
ArticleCASPubMedGoogle Scholar
Massi, D., Mihic-Probst, D., Schadendorf, D., Dummer, R. & Mandala, M. Dedifferentiated melanomas: morpho-phenotypic profile, genetic reprogramming and clinical implications. Cancer Treat. Rev. 88, 102060 (2020).
ArticleCASPubMedGoogle Scholar
Atkins, M. B. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105–2116 (1999).
ArticleCASPubMedGoogle Scholar
Kirkwood, J. M. et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J. Clin. Oncol. 14, 7–17 (1996).
ArticleCASPubMedGoogle Scholar
Vesely, M. D., Kershaw, M. H., Schreiber, R. D. & Smyth, M. J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235–271 (2011).
ArticleCASPubMedGoogle Scholar
Dunn, G. P., Old, L. J. & Schreiber, R. D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004).
ArticleCASPubMedGoogle Scholar
Lee, N., Zakka, L. R., Mihm, M. C. Jr. & Schatton, T. Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy. Pathology 48, 177–187 (2016).
ArticlePubMedGoogle Scholar
Ohue, Y. & Nishikawa, H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target. Cancer Sci. 110, 2080–2089 (2019).
ArticleCASPubMedPubMed CentralGoogle Scholar
Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).
ArticleCASPubMedGoogle Scholar
Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).
ArticleCASPubMedGoogle Scholar
Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).
ArticleCASPubMedPubMed CentralGoogle Scholar
Jerby-Arnon, L. et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984–997.e24 (2018). Together with Cabrita et al. (2020) and Petitprez et al. (2020), this paper demonstrates that tertiary lymphoid structures play a pivotal role in the immune microenvironment of melanoma, as evidenced by the expression of distinct T cell phenotypes.
ArticleCASPubMedPubMed CentralGoogle Scholar
Hsieh, W. C. et al. Spatial multi-omics analyses of the tumor immune microenvironment. J. Biomed. Sci. 29, 96 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Giesen, C. et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat. Methods 11, 417–422 (2014).
ArticleCASPubMedGoogle Scholar
Bravo, A. I. et al. HEV-associated dendritic cells are observed in metastatic tumor-draining lymph nodes of cutaneous melanoma patients with longer distant metastasis-free survival after adjuvant immunotherapy. Front. Immunol. 14, 1231734 (2023).
ArticleCASPubMedPubMed CentralGoogle Scholar
Tsujikawa, T. et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep. 19, 203–217 (2017).
ArticleCASPubMedPubMed CentralGoogle Scholar
Ugolini, F., Pasqualini, E., Simi, S., Baroni, G. & Massi, D. Bright-field multiplex immunohistochemistry assay for tumor microenvironment evaluation in melanoma tissues. Cancers 14, 3682 (2022).
ArticleCASPubMedPubMed CentralGoogle Scholar
Sun, Z., Nyberg, R., Wu, Y., Bernard, B. & Redmond, W. L. Developing an enhanced 7-color multiplex IHC protocol to dissect immune infiltration in human cancers. PLoS ONE 16, e0247238 (2021).
ArticleCASPubMedPubMed CentralGoogle Scholar
De Logu, F. et al. Spatial proximity and relative distribution of tumor-infiltrating lymphocytes and macrophages predict survival in melanoma. Lab. Invest. 103, 100259 (2023).
ArticlePubMedGoogle Scholar
Fridman, W. H., Pages, F., Sautes-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).
ArticleCASPubMedGoogle Scholar
Yaseen, Z. et al. Validation of an accurate automated multiplex immunofluorescence method for immuno-profiling melanoma. Front. Mol. Biosci. 9, 810858 (2022).
ArticleCASPubMedPubMed CentralGoogle Scholar
Massi, D. et al. The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors. J. Immunother. Cancer 7, 308 (2019).
ArticlePubMedPubMed CentralGoogle Scholar
Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).
ArticleCASPubMedPubMed CentralGoogle Scholar
Gajewski, T. F. The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin. Oncol. 42, 663–671 (2015).
ArticlePubMedPubMed CentralGoogle Scholar
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017). This review summarizes the steps in the cancer immunity cycle and highlights key targets for cancer immunotherapy.
ArticleCASPubMedGoogle Scholar
Indini, A. et al. Targeting inflamed and non-inflamed melanomas: biological background and clinical challenges. Semin. Cancer Biol. 86, 477–490 (2022).
ArticleCASPubMedGoogle Scholar
Kittler, H., Pehamberger, H., Wolff, K. & Binder, M. Diagnostic accuracy of dermoscopy. Lancet Oncol. 3, 159–165 (2002).
ArticleCASPubMedGoogle Scholar
Argenziano, G. et al. Dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. J. Clin. Oncol. 24, 1877–1882 (2006).
ArticlePubMedGoogle Scholar
Serra-Garcia, L. et al. Dermoscopy training course improves podiatrists’ accuracy in diagnosing lesions suggestive of acral melanoma: a cross-sectional study. Australas. J. Dermatol. 63, e44–e48 (2022).
ArticlePubMedGoogle Scholar
Garbe, C. et al. European consensus-based interdisciplinary guideline for melanoma. Part 1: diagnostics - update 2019. Eur. J. Cancer 126, 141–158 (2020).
ArticleCASPubMedGoogle Scholar
Dinnes, J. et al. Dermoscopy, with and without visual inspection, for diagnosing melanoma in adults. Cochrane Database Syst. Rev. 12, CD011902 (2018).
PubMedGoogle Scholar
Longo, C. et al. Dermoscopy comparative approach for early diagnosis in familial melanoma: influence of MC1R genotype. J. Eur. Acad. Dermatol. Venereol. 35, 403–410 (2021).
ArticleCASPubMedGoogle Scholar
Wazaefi, Y. et al. Evidence of a limited intra-individual diversity of nevi: intuitive perception of dominant clusters is a crucial step in the analysis of nevi by dermatologists. J. Invest. Dermatol. 133, 2355–2361 (2013).
ArticleCASPubMedGoogle Scholar
Russo, T. et al. Indications for digital monitoring of patients with multiple nevi: recommendations from the International Dermoscopy Society. Dermatol. Pract. Concept. 12, e2022182 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Salerni, G. et al. Benefits of total body photography and digital dermatoscopy (“two-step method of digital follow-up”) in the early diagnosis of melanoma in patients at high risk for melanoma. J. Am. Acad. Dermatol. 67, e17–e27 (2012).
ArticlePubMedGoogle Scholar
Gasparini, G. et al. Usefulness of the ‘two-step method’ of digital follow-up for early-stage melanoma detection in high-risk French patients: a retrospective 4-year study. Br. J. Dermatol. 181, 415–416 (2019).
ArticleCASPubMedGoogle Scholar
Moloney, F. J. et al. Detection of primary melanoma in individuals at extreme high risk: a prospective 5-year follow-up study. JAMA Dermatol. 150, 819–827 (2014).
ArticlePubMedGoogle Scholar
Pezzini, C. et al. Reflectance confocal microscopy diagnostic accuracy for malignant melanoma in different clinical settings: systematic review and meta-analysis. J. Eur. Acad. Dermatol. Venereol. 34, 2268–2279 (2020).
ArticleCASPubMedGoogle Scholar
Dinnes, J. et al. Reflectance confocal microscopy for diagnosing cutaneous melanoma in adults. Cochrane Database Syst. Rev. 12, CD013190 (2018).
PubMedGoogle Scholar
Alarcon, I. et al. Impact of in vivo reflectance confocal microscopy on the number needed to treat melanoma in doubtful lesions. Br. J. Dermatol. 170, 802–808 (2014).
ArticleCASPubMedPubMed CentralGoogle Scholar
Pellacani, G. et al. Cost-benefit of reflectance confocal microscopy in the diagnostic performance of melanoma. J. Eur. Acad. Dermatol. Venereol. 30, 413–419 (2016).
ArticleCASPubMedGoogle Scholar
Pellacani, G. et al. Effect of reflectance confocal microscopy for suspect lesions on diagnostic accuracy in melanoma: a randomized clinical trial. JAMA Dermatol. 158, 754–761 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Esteva, A. et al. Dermatologist-level classification of skin cancer with deep neural networks. Nature 542, 115–118 (2017).
ArticleCASPubMedPubMed CentralGoogle Scholar
Barata, C. et al. A reinforcement learning model for AI-based decision support in skin cancer. Nat. Med. 29, 1941–1946 (2023).
ArticleCASPubMedPubMed CentralGoogle Scholar
Combalia, M. et al. Validation of artificial intelligence prediction models for skin cancer diagnosis using dermoscopy images: the 2019 International Skin Imaging Collaboration Grand Challenge. Lancet Digit. Health 4, e330–e339 (2022).
ArticleCASPubMedPubMed CentralGoogle Scholar
Tschandl, P. et al. Human-computer collaboration for skin cancer recognition. Nat. Med. 26, 1229–1234 (2020).
ArticleCASPubMedGoogle Scholar
Brancaccio, G. et al. Artificial intelligence in skin cancer diagnosis: a reality check. J. Invest. Dermatol. 144, 492–499 (2024).
ArticleCASPubMedGoogle Scholar
Keung, E. Z. & Gershenwald, J. E. The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care. Expert. Rev. Anticancer. Ther. 18, 775–784 (2018).
ArticleCASPubMedPubMed CentralGoogle Scholar
Torres-Cabala, C., Li-Ning-Tapia, E. & Hwu, W. J. Pathology-based biomarkers useful for clinical decisions in melanoma. Arch. Med. Res. 51, 827–838 (2020).
ArticleCASPubMedGoogle Scholar
Lezcano, C., Jungbluth, A. A. & Busam, K. J. Immunohistochemistry for PRAME in dermatopathology. Am. J. Dermatopathol. 45, 733–747 (2023).
ArticlePubMedPubMed CentralGoogle Scholar
Yeh, I. Melanocytic naevi, melanocytomas and emerging concepts. Pathology 55, 178–186 (2023).
ArticlePubMedGoogle Scholar
de la Fouchardiere, A. et al. ESP, EORTC, and EURACAN Expert Opinion: practical recommendations for the pathological diagnosis and clinical management of intermediate melanocytic tumors and rare related melanoma variants. Virchows Arch. 479, 3–11 (2021).
ArticlePubMedGoogle Scholar
Andea, A. A. Molecular testing in melanoma for the surgical pathologist. Pathology 55, 245–257 (2023).
ArticleCASPubMedGoogle Scholar
Whitman, E. D. et al. Integrating 31-gene expression profiling with clinicopathologic features to optimize cutaneous melanoma sentinel lymph node metastasis prediction. JCO Precis. Oncol. 5, PO.21.00162 (2021).
PubMedPubMed CentralGoogle Scholar
Yousaf, A. et al. Validation of CP-GEP (Merlin assay) for predicting sentinel lymph node metastasis in primary cutaneous melanoma patients: a U.S. cohort study. Int. J. Dermatol. 60, 851–856 (2021).
ArticleCASPubMedPubMed CentralGoogle Scholar
Amaral, T. M. S. et al. Clinical validation of a prognostic 11-gene expression profiling score in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma. Eur. J. Cancer 125, 38–45 (2020).
ArticleCASPubMedGoogle Scholar
Kott, J. et al. Sentinel lymph node risk prognostication in primary cutaneous melanoma through tissue-based profiling, potentially redefining the need for sentinel lymph node biopsy. Eur. J. Cancer 202, 113989 (2024).
ArticlePubMedGoogle Scholar
Katalinic, A. et al. Does skin cancer screening save lives?: an observational study comparing trends in melanoma mortality in regions with and without screening. Cancer 118, 5395–5402 (2012).
ArticlePubMedGoogle Scholar
Katalinic, A., Eisemann, N. & Waldmann, A. Skin cancer screening in Germany. documenting melanoma incidence and mortality from 2008 to 2013. Dtsch. Arztebl Int. 112, 629–634 (2015).
PubMedPubMed CentralGoogle Scholar
Schumann, L. et al. Association of early-stage incidence and mortality in malignant melanoma – a population-based ecological study. J. Dtsch. Dermatol. Ges. 21, 33–40 (2023).
PubMedGoogle Scholar
US Preventive Services Task Force. Screening for skin cancer: US Preventive Services Task Force recommendation statement. JAMA 329, 1290–1295 (2023).
ArticleGoogle Scholar
Argenziano, G. et al. Total body skin examination for skin cancer screening in patients with focused symptoms. J. Am. Acad. Dermatol. 66, 212–219 (2012).
ArticlePubMedGoogle Scholar
Puig, S. et al. Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma. Genet. Med. 18, 727–736 (2016).
ArticlePubMedGoogle Scholar
Taylor, N. J. et al. Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT. J. Am. Acad. Dermatol. 81, 386–394 (2019).
ArticleCASPubMedPubMed CentralGoogle Scholar
Smit, A. K. et al. Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial. Genet. Med. 23, 2394–2403 (2021).
ArticlePubMedPubMed CentralGoogle Scholar
Tabbakh, T., Volkov, A., Wakefield, M. & Dobbinson, S. Implementation of the SunSmart program and population sun protection behaviour in Melbourne, Australia: results from cross-sectional summer surveys from 1987 to 2017. PLoS Med. 16, e1002932 (2019).
ArticlePubMedPubMed CentralGoogle Scholar
The Global Health Observatory. Ultraviolet (UV) Radiation. WHOwww.who.int/data/gho/data/themes/topics/topic-details/GHO/ultraviolet-(uv)-radiation (2024).
Krutmann, J., Morita, A. & Chung, J. H. Sun exposure: what molecular photodermatology tells us about its good and bad sides. J. Invest. Dermatol. 132, 976–984 (2012).
ArticleCASPubMedGoogle Scholar
Green, A. C., Williams, G. M., Logan, V. & Strutton, G. M. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J. Clin. Oncol. 29, 257–263 (2011).
ArticleCASPubMedGoogle Scholar
Goldenhersh, M. A. & Koslowsky, M. Increased melanoma after regular sunscreen use? J. Clin. Oncol. 29, e557–e558 (2011).
ArticlePubMedGoogle Scholar
Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).
ArticleCASPubMedGoogle Scholar
Kallioglu, M. A. et al. UV index-based model for predicting synthesis of (pre-)vitamin D3 in the Mediterranean basin. Sci. Rep. 14, 3541 (2024).
ArticleCASPubMedPubMed CentralGoogle Scholar
Feketea, G. M. et al. Vitamin D status in children in Greece and its relationship with sunscreen application. Children 8, 111 (2021).
ArticlePubMedPubMed CentralGoogle Scholar
Faurschou, A. et al. The relation between sunscreen layer thickness and vitamin D production after ultraviolet B exposure: a randomized clinical trial. Br. J. Dermatol. 167, 391–395 (2012).
ArticleCASPubMedGoogle Scholar
Marks, R. et al. The effect of regular sunscreen use on vitamin D levels in an Australian population. Results of a randomized controlled trial. Arch. Dermatol. 131, 415–421 (1995).
ArticleCASPubMedGoogle Scholar
Martin-Gorgojo, A., Gilaberte, Y. & Nagore, E. Vitamin D and skin cancer: an epidemiological, patient-centered update and review. Nutrients 13, 4292 (2021).
ArticleCASPubMedPubMed CentralGoogle Scholar
Lallas, A. et al. Second primary melanomas in a cohort of 977 melanoma patients within the first 5 years of monitoring. J. Am. Acad. Dermatol. 82, 398–406 (2020).
ArticlePubMedGoogle Scholar
Antunez-Lay, A. et al. Synchronous primary cutaneous melanomas: a descriptive study of their clinical features, histology, genetic background of the patients and clinical outcomes. J. Eur. Acad. Dermatol. Venereol. 36, 2364–2372 (2022).
ArticleCASPubMedGoogle Scholar
Aneja, S., Aneja, S. & Bordeaux, J. S. Association of increased dermatologist density with lower melanoma mortality. Arch. Dermatol. 148, 174–178 (2012).
ArticlePubMedGoogle Scholar
Korn, E. L. et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J. Clin. Oncol. 26, 527–534 (2008).
ArticlePubMedGoogle Scholar
Pavlick, A. C. et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0. J. Immunother. Cancer 11, e006947 (2023). This is the third version of the SITC cancer immunotherapy practice guidelines, which details the current standard of care and summarizes surgical, local-regional and systemic therapy recommendations, as well as guidelines for surveillance in low, intermediate, and high-risk settings.
ArticlePubMedPubMed CentralGoogle Scholar
Luke, J. J. et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet 399, 1718–1729 (2022).
ArticleCASPubMedGoogle Scholar
Kirkwood, J. M. et al. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat. Med. 29, 2835–2843 (2023).
ArticleCASPubMedPubMed CentralGoogle Scholar
Eggermont, A. M. M. et al. Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: updated results from the EORTC 1325-MG/KEYNOTE-054 trial. J. Clin. Oncol. 38, 3925–3936 (2020).
ArticleCASPubMedPubMed CentralGoogle Scholar
Weber, J. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).
ArticleCASPubMedGoogle Scholar
Long, G. V. et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N. Engl. J. Med. 377, 1813–1823 (2017).
ArticleCASPubMedGoogle Scholar
Swetter, S. M. et al. NCCN guidelines(R) insights: melanoma: cutaneous, version 2.2024. J. Natl Compr. Canc Netw. 22, 290–298 (2024).
ArticleCASPubMedGoogle Scholar
Andtbacka, R. H. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).
ArticleCASPubMedGoogle Scholar
Henderson, M. A. et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 16, 1049–1060 (2015).
ArticlePubMedGoogle Scholar
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
ArticleCASPubMedPubMed CentralGoogle Scholar
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
ArticleCASPubMedGoogle Scholar
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).
ArticleCASPubMedGoogle Scholar
Wolchok, J. D. et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J. Clin. Oncol. 40, 127–137 (2022).
ArticleCASPubMedGoogle Scholar
Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
ArticleCASPubMedPubMed CentralGoogle Scholar
Tawbi, H. A. et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N. Engl. J. Med. 386, 24–34 (2022).
ArticleCASPubMedPubMed CentralGoogle Scholar
Nathan, P. et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N. Engl. J. Med. 385, 1196–1206 (2021).
ArticleCASPubMedGoogle Scholar
Chesney, J. et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J. Immunother. Cancer 10, e005755 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2, 561–566 (1996).
ArticleCASPubMedGoogle Scholar
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).
ArticleCASPubMedGoogle Scholar
Sullivan, R. J. & Flaherty, K. MAP kinase signaling and inhibition in melanoma. Oncogene 32, 2373–2379 (2013).
ArticleCASPubMedGoogle Scholar
Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).
ArticleCASPubMedPubMed CentralGoogle Scholar
Larkin, J. et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 371, 1867–1876 (2014).
ArticlePubMedGoogle Scholar
Grob, J. J. et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 16, 1389–1398 (2015).
ArticleCASPubMedGoogle Scholar
Dummer, R. et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 19, 603–615 (2018).
ArticleCASPubMedGoogle Scholar
Tawbi, H. A. et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 22, 1692–1704 (2021).
ArticleCASPubMedPubMed CentralGoogle Scholar
Long, G. V. et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 19, 672–681 (2018).
ArticleCASPubMedGoogle Scholar
Johnson, D. B. et al. Sequencing treatment in BRAFV600 mutant melanoma: anti-PD-1 before and after BRAF inhibition. J. Immunother. 40, 31–35 (2017).
ArticleCASPubMedPubMed CentralGoogle Scholar
Atkins, M. B. et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: the DREAMseq Trial–ECOG-ACRIN EA6134. J. Clin. Oncol. 41, 186–197 (2023). The DREAM-SEQ trial is a landmark study that demonstrated superiority of frontline ICI combination versus combination BRAF–MEK inhibition as frontline therapy for patients with BRAFV600E/K-mutant, advanced melanoma.
ArticleCASPubMedGoogle Scholar
Ascierto, P. A. et al. Sequencing of ipilimumab plus nivolumab and encorafenib plus binimetinib for untreated BRAF-mutated metastatic melanoma (SECOMBIT): a randomized, three-arm, open-label phase II trial. J. Clin. Oncol. 41, 212–221 (2023).
ArticleCASPubMedGoogle Scholar
Davies, M. A. et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 18, 863–873 (2017).
ArticleCASPubMedPubMed CentralGoogle Scholar
Wolchok, J. D. et al. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 392, 11–22 (2025). This paper summarizes the 10-year follow-up results of the Checkmate 067 trial with randomized patients with previously untreated, advanced melanoma who received single-agent anti-CTLA-4, single-agent anti-PD1 or the combination of anti-CTLA-4 and anti-PD1, demonstrating the superiority of single-agent anti-PD1 and combination therapy versus single-agent anti-CTLA4.
ArticleCASPubMedGoogle Scholar
Eggermont, A. M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 16, 522–530 (2015).
ArticleCASPubMedGoogle Scholar
Eggermont, A. M. M., Robert, C. & Suciu, S. Adjuvant pembrolizumab in resected stage III melanoma. N. Engl. J. Med. 379, 593–595 (2018).
ArticlePubMedGoogle Scholar
Dummer, R. et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N. Engl. J. Med. 383, 1139–1148 (2020).
ArticleCASPubMedGoogle Scholar
Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018).
ArticleCASPubMedGoogle Scholar
Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019).
ArticleCASPubMedGoogle Scholar
Amaria, R. N. et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature 611, 155–160 (2022).
ArticleCASPubMedPubMed CentralGoogle Scholar
Reijers, I. L. M. et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nat. Med. 28, 1178–1188 (2022).
ArticleCASPubMedGoogle Scholar
Patel, S. P. et al. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N. Engl. J. Med. 388, 813–823 (2023). This randomized trial compared perioperative therapy, including neoadjuvant and adjuvant components, with surgery followed by adjuvant therapy in patients with clinical stage III melanoma.
ArticleCASPubMedPubMed CentralGoogle Scholar
Blank, C. U. et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. N. Engl. J. Med. 391, 1696–1708 (2024). Similar to SWOG 1801, this trial compared neoadjuvant therapy with surgery and adjuvant therapy in patients with clinical stage 3 disease and demonstrated superiority of preoperative systemic therapy with single-agent anti-PD1.
ArticleCASPubMedGoogle Scholar
Reijers, I. L. M. et al. Impact of personalized response-directed surgery and adjuvant therapy on survival after neoadjuvant immunotherapy in stage III melanoma: comparison of 3-year data from PRADO and OpACIN-neo. Eur. J. Cancer 214, 115141 (2025).
ArticleCASPubMedGoogle Scholar
Cormier, J. N., Davidson, L., Xing, Y., Webster, K. & Cella, D. Measuring quality of life in patients with melanoma: development of the FACT-melanoma subscale. J. Support. Oncol. 3, 139–145 (2005).
PubMedGoogle Scholar
Hansen, A. R. et al. Development of the functional assessment of cancer therapy-immune checkpoint modulator (FACT-ICM): a toxicity subscale to measure quality of life in patients with cancer who are treated with ICMs. Cancer 126, 1550–1558 (2020).
ArticlePubMedGoogle Scholar
Egeler, M. D. et al. Understanding quality of life issues in patients with advanced melanoma: phase 1 and 2 in the development of the EORTC advanced melanoma module. Eur. J. Cancer 207, 114176 (2024).
ArticleCASPubMedGoogle Scholar
Edelen, M. O. et al. Development of an ultra-short measure of eight domains of health-related quality of life for research and clinical care: the patient-reported outcomes measurement information system(R) PROMIS(R)-16 profile. Qual. Life Res. 34, 3–15 (2025).
ArticlePubMedGoogle Scholar
Petersen, M. A. et al. International validation of the EORTC CAT Core: a new adaptive instrument for measuring core quality of life domains in cancer. Qual. Life Res. 29, 1405–1417 (2020).
ArticlePubMedGoogle Scholar
Lai-Kwon, J. et al. Impact of immune checkpoint inhibitors and targeted therapy on health-related quality of life of people with stage III and IV melanoma: a mixed-methods systematic review. Eur. J. Cancer 184, 83–105 (2023).
ArticleCASPubMedGoogle Scholar
Chen, C., Wang, Z. & Qin, Y. R. Health-related quality of life in stage III-IV melanoma treated with targeted therapy or immunotherapy: a systematic review on the adequacy of reporting and clinical issues in phase III randomized controlled trials. Cancer Med. 12, 2262–2280 (2023).
ArticleCASPubMedGoogle Scholar
Fraterman, I. et al. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma. Nat. Med. 29, 3090–3099 (2023).
ArticleCASPubMedGoogle Scholar
Bi, Z. et al. Negative correlations of psychological distress with quality of life and immunotherapy efficacy in patients with advanced NSCLC. Am. J. Cancer Res. 12, 805–815 (2022).
CASPubMedPubMed CentralGoogle Scholar
Zeng, Y. et al. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat. Med. 30, 1680–1688 (2024).
ArticleCASPubMedPubMed CentralGoogle Scholar
Globig, A. M. et al. The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion. Nature 622, 383–392 (2023).
ArticleCASPubMedPubMed CentralGoogle Scholar
Kungwengwe, G. et al. Prevalence and odds of anxiety and depression in cutaneous malignant melanoma: a proportional meta-analysis and regression. Br. J. Dermatol. https://doi.org/10.1093/bjd/ljae011 (2024).
Aggarwal, C. et al. Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial. J. Immunother. Cancer 10, e004424 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Weber, J. S. et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024).
ArticleCASPubMedGoogle Scholar
Giugliano, F. et al. First line treatment of BRAF mutated advanced melanoma: does one size fit all? Cancer Treat. Rev. 99, 102253 (2021).
ArticleCASPubMedGoogle Scholar
Van Allen, E. M. et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4, 94–109 (2014).
ArticlePubMedGoogle Scholar
Kim, K. H. et al. Exploring molecular genetic alterations and RAF fusions in melanoma: a belvarafenib expanded access program in patients with RAS/RAF-mutant melanoma. Oncologist 29, e811–e821 (2024).
ArticlePubMedPubMed CentralGoogle Scholar
Dummer, R. et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 18, 435–445 (2017).
ArticleCASPubMedGoogle Scholar
Benton, S. et al. Risk factors for the development of Spitz neoplasms. Pediatr. Dermatol. 39, 220–225 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Fortes, C. et al. Differences in individual and environmental factors between cutaneous melanoma and atypical Spitz tumour in children and adolescents. Eur. J. Pediatr. 181, 263–269 (2022).
ArticlePubMedGoogle Scholar
Shitara, D. et al. Nevus-associated melanomas: clinicopathologic features. Am. J. Clin. Pathol. 142, 485–491 (2014).
ArticlePubMedGoogle Scholar
Guitera, P. et al. The steadily growing problem of lentigo maligna and lentigo maligna melanoma in Australia: population-based data on diagnosis and management. Australas. J. Dermatol. 60, 118–125 (2019).
ArticlePubMedGoogle Scholar
Swetter, S. M., Boldrick, J. C., Jung, S. Y., Egbert, B. M. & Harvell, J. D. Increasing incidence of lentigo maligna melanoma subtypes: northern California and national trends 1990-2000. J. Invest. Dermatol. 125, 685–691 (2005).
ArticleCASPubMedGoogle Scholar
Matas-Nadal, C. et al. Increasing incidence of lentigo maligna and lentigo maligna melanoma in Catalonia. Int. J. Dermatol. 58, 577–581 (2019).
ArticlePubMedGoogle Scholar
Leachman, S. A. et al. Selection criteria for genetic assessment of patients with familial melanoma. J. Am. Acad. Dermatol. 61, 677.e1–677.e14 (2009).
ArticlePubMedGoogle Scholar
Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).
ArticleCASPubMedGoogle Scholar
Haanen, J. et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33, 1217–1238 (2022).
ArticleCASPubMedGoogle Scholar
Garutti, M. et al. BRAF and MEK inhibitors and their toxicities: a meta-analysis. Cancers 15, 141 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Klobuch, S., Seijkens, T. T. P., Schumacher, T. N. & Haanen, J. Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma. Nat. Rev. Clin. Oncol. 21, 173–184 (2024).
ArticleCASPubMedGoogle Scholar
Gershenwald, J. E. & Scolyer, R. A. Melanoma staging: American Joint Committee on Cancer (AJCC) 8th edition and beyond. Ann. Surg. Oncol. 25, 2105–2110 (2018).
ArticlePubMedGoogle Scholar
Kuras, M. Exploring the complex and multifaceted interplay between melanoma cells and the tumor microenvironment. Int. J. Mol. Sci. 24, 14403 (2023).
ArticleCASPubMedPubMed CentralGoogle Scholar
Kittler, H. et al. Standardization of terminology in dermoscopy/dermatoscopy: results of the third consensus conference of the International Society of Dermoscopy. J. Am. Acad. Dermatol. 74, 1093–1106 (2016).
ArticlePubMedPubMed CentralGoogle Scholar
Download references
Acknowledgements
The authors thank C. Carrera, K. Liopiris, J. Malvehy and P. Zaballos (all from Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain) for providing the images in Figs. 5, 6 and 7 for this article. The authors extend their sincere gratitude to the patients who provided consent to publish their images in this Primer. A.T. acknowledges the support of an Emmy Noether Award from the German Research Foundation (DFG, 467788900) and the Ministry of Culture and Science of the State of North Rhine-Westphalia (NRW-Nachwuchsgruppenprogramm). A.T. acknowledges the support of an ERC starting grant (METATARGET, 101078355). A.T. holds the Peter Hans Hofschneider endowed Professorship of Molecular Medicine from the Stiftung Experimentelle Biomedizin.
Author information
Authors and Affiliations
Department of Dermatology, University Hospital Essen & German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany
Alpaslan Tasdogan & Dirk Schadendorf
National Center for Tumour diseases (NCT-West), Campus Essen & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany
Alpaslan Tasdogan & Dirk Schadendorf
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
Ryan J. Sullivan
Institute for Social Medicine and Epidemiology, University of Lübeck, Lübeck, Germany
Alexander Katalinic
Université Paris Cite, AP-HP Dermato-oncology and CIC, Cancer institute APHP.nord Paris cité, INSERM U976, Saint Louis Hospital, Paris, France
Celeste Lebbe
Melanoma Advisory Board South Africa, Cape Town, South Africa
Dagmar Whitaker
Dermatology Department, IDIBAPS, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain
Susana Puig
8CIBERER, Instituto de Salud Carlos III, Barcelona, Spain
Susana Puig
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
Lonneke V. van de Poll-Franse
Department of Medical and Clinical Psychology, CoRPS - Center of Research on Psychology in Somatic Diseases, Tilburg University, Tilburg, Netherlands
Lonneke V. van de Poll-Franse
Section of Pathology, Department of Health Sciences, University of Florence, Florence, Italy
Daniela Massi
Department of Molecular Pathobiology, New York University - College of Dentistry, New York, NY, USA
Daniela Massi
Authors
Alpaslan Tasdogan
View author publications
You can also search for this author inPubMedGoogle Scholar
2. Ryan J. Sullivan
View author publications
You can also search for this author inPubMedGoogle Scholar
3. Alexander Katalinic
View author publications
You can also search for this author inPubMedGoogle Scholar
4. Celeste Lebbe
View author publications
You can also search for this author inPubMedGoogle Scholar
5. Dagmar Whitaker
View author publications
You can also search for this author inPubMedGoogle Scholar
6. Susana Puig
View author publications
You can also search for this author inPubMedGoogle Scholar
7. Lonneke V. van de Poll-Franse
View author publications
You can also search for this author inPubMedGoogle Scholar
8. Daniela Massi
View author publications
You can also search for this author inPubMedGoogle Scholar
9. Dirk Schadendorf
View author publications
You can also search for this author inPubMedGoogle Scholar
Contributions
Introduction (A.T. and D.S.); Epidemiology (A.K.); Mechanisms/pathophysiology (R.J.S. and D.M.); Diagnosis, screening and prevention (S.P. and D.M.); Management (R.J.S., C.L. and D.W.); Quality of life (L.V.v.d.P.-F.); Outlook (A.T. and D.S.); overview of the Primer (A.T.).
Corresponding authors
Correspondence to Alpaslan Tasdogan or Dirk Schadendorf.
Ethics declarations
Competing interests
A.T. declares speakers’ honoraria from Merck Sharp & Dohme. R.J.S. declares personal fees from Marengo, Merck, Novartis, Pfizer and Replimune for consulting/advisory board activity, and research grant support to his institution from Merck. C.L. declares conflicts of interest with BMS, Pierre Fabre, Sanofi, Novartis, MSD, Amgen, Merck Serono, Roche, Inflax and Pfizer. S.P. declares research grants from Almirall, Pfizer, Regeneron, Sanofi, La Roche Posay Philogen, ISDIN and International School of Derma; consulting fees from Sanofi, Regeneron, ISDIN, L’Oreal, La Roche Posay and International School of Derma; personal fees from Sanofi, Sunpharma, Cantabria, Eucerin, ISDIN, L’Oreal, La Roche Posay, Almirall, Avene and Pierre Fabre; and support for attending meetings and/or travel from Almirall, Cantabria and ISDIN. D.M. declares personal fees from Novartis, Sun Pharma, Bayer HealthCare Pharmaceuticals Inc., Pierre-Fabre Oncology, Sanofi Genzyme, MSD Italia S.r.l., Roche and Skyline Dx B.V, and Sakura; and a grant from Regeneron. D.S. reports personal fees and non-financial support from Roche/Genentech, Merck Serono, Sanofi/Regeneron, SunPharma, Neracare, Replimune, Helsinn, OncoSec and InFlaRx; grants, personal fees and non-financial support from Amgen and Novartis; grants, personal fees, non-financial and other support from BMS; and personal fees from Merck Sharp & Dohme, Immunocore, Incyte, 4SC, Pierre Fabre, Array BioPharma, Pfizer, Philogen, Regeneron, Nektar and Sandoz; outside the submitted work. A.K., D.W. and L.V.v.d.P.-F. declare no competing interests.
Peer review
Peer review information
Nature Reviews Disease Primers thanks R. Dummer, H. Gogas, E. Novis, M. Postow, R. Saw and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Informed consent
The authors affirm that human research participants provided informed consent for publication of the images in Figs. 5, 6 and 7 and Supplementary Figs. 3 and 4.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Reprints and permissions
About this article
Check for updates. Verify currency and authenticity via CrossMark
Cite this article
Tasdogan, A., Sullivan, R.J., Katalinic, A. et al. Cutaneous melanoma. Nat Rev Dis Primers 11, 23 (2025). https://doi.org/10.1038/s41572-025-00603-8
Download citation
Accepted:25 February 2025
Published:03 April 2025
DOI:https://doi.org/10.1038/s41572-025-00603-8
Share this article
Anyone you share the following link with will be able to read this content:
Get shareable link
Sorry, a shareable link is not currently available for this article.
Copy to clipboard
Provided by the Springer Nature SharedIt content-sharing initiative