Melanoma (C43)

Causes

The etiology of melanoma involves malignant transformation of melanocytes, the pigment-producing cells of the skin, driven by a combination of ultraviolet (UV) radiation exposure, genetic susceptibility, and accumulated molecular damage. Intermittent intense UV exposure, particularly episodes causing blistering sunburns, is the most significant environmental risk factor because ultraviolet radiation induces DNA mutations and oxidative stress within melanocytes. Additional risk factors include fair skin, light hair or eye color, numerous or atypical nevi, family history of melanoma, immunosuppression, and inherited mutations in genes such as CDKN2A, BRAF, and CDK4. Chronic UV-induced damage disrupts pathways regulating cell cycle control, DNA repair, apoptosis, and cellular proliferation, allowing melanocytes to acquire oncogenic mutations that promote uncontrolled growth and invasive behavior. Activating mutations in the MAPK signaling pathway, particularly BRAF and NRAS mutations, are especially common and play central roles in melanoma development and progression.

Pathophysiology

The pathophysiology of melanoma involves progressive genetic and molecular alterations that transform normal melanocytes into highly invasive malignant cells capable of immune evasion and metastatic spread. Ultraviolet radiation induces DNA damage, oxidative stress, and mutational injury within melanocytes, leading to activation of oncogenic signaling pathways such as MAPK and PI3K/AKT. Activating mutations in BRAF, NRAS, and KIT are common drivers that promote uncontrolled cellular proliferation, resistance to apoptosis, and enhanced survival signaling. As melanoma progresses, additional abnormalities affecting tumor suppressor genes such as CDKN2A and PTEN further disrupt cell cycle regulation and genomic stability. Malignant melanocytes acquire the ability to invade through the basement membrane, stimulate angiogenesis, remodel the extracellular matrix, and disseminate via lymphatic and hematogenous routes to distant organs including lymph nodes, lungs, liver, brain, and bone. Melanoma is also characterized by profound interactions with the immune system, including expression of immune checkpoint molecules such as PD-L1 that suppress T-cell activity and facilitate immune escape, which is why checkpoint inhibitor therapies have become central to treatment of advanced disease.

Clinical features

The clinical features of melanoma most commonly include a new or changing pigmented skin lesion with asymmetry, irregular or poorly defined borders, multiple colors, enlargement over time, or evolving appearance, features commonly described using the ABCDE criteria (Asymmetry, Border irregularity, Color variation, Diameter, and Evolution). Lesions may appear dark brown or black but can also be red, blue, flesh-colored, or amelanotic. Patients may report itching, tenderness, bleeding, ulceration, or crusting of the lesion as the tumor progresses. Melanoma may arise on sun-exposed skin such as the back, chest, face, arms, or legs, but can also occur on mucosal surfaces, the nail bed, or the eye. Regional lymph node enlargement may develop with local spread, while advanced metastatic disease can produce systemic symptoms such as fatigue, weight loss, cough, dyspnea, neurologic deficits, bone pain, or hepatic dysfunction depending on the organs involved. Because melanoma is capable of early invasion and metastasis, subtle changes in skin lesions may represent clinically significant disease.

Diagnosis

The diagnosis of melanoma is established through clinical evaluation of suspicious skin lesions followed by histopathologic confirmation with biopsy. Lesions demonstrating asymmetry, irregular borders, color variation, enlargement, or evolution over time are considered concerning and are commonly assessed using the ABCDE criteria. Definitive diagnosis requires excisional biopsy whenever feasible, allowing microscopic evaluation of melanocytic atypia, depth of invasion, ulceration, mitotic activity, and other prognostic features. Breslow thickness, which measures tumor depth in millimeters, is one of the most important predictors of outcome and guides staging and management. Immunohistochemical markers such as S100, SOX10, Melan-A, and HMB-45 may assist in confirming melanocytic origin. Additional staging studies, including sentinel lymph node biopsy, CT, PET/CT, or MRI, may be performed in patients with higher-risk or advanced disease to assess regional or distant metastasis. Molecular testing for mutations such as BRAF, NRAS, or KIT is increasingly important in advanced melanoma because these alterations may guide targeted therapy selection.

Mechanism of action videos

• Vusolimogene: Candidate Immunotherapy for Melanoma
• RAS Signaling- CYTASIA
• RAF Signaling in Cancer- Cytasia
• EGFR Signaling- CYTASIA
• KRAS- Drugging the Undruggable
• BRAF V600 Mutations in Cancer

Biological pathways

• p53 signaling pathway
• Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy
• Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition
• Melanoma
• Melanogenesis
• Cell cycle
• Adherens junction
• Diseases of signal transduction by growth factor receptors and second messengers
• MITF-M-regulated melanocyte development
• Developmental Biology
• PI3K/AKT Signaling in Cancer
• MITF-M-dependent gene expression
• PIP3 activates AKT signaling
• Negative regulation of the PI3K/AKT network
• Intracellular signaling by second messengers
• Oncogene Induced Senescence
• RAF/MAP kinase cascade
• Signaling by Receptor Tyrosine Kinases
• MAPK family signaling cascades
• MAPK1/MAPK3 signaling
• Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
• Signaling by PTK6
• Transcriptional Regulation by VENTX
• Generic Transcription Pathway
• PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
• RNA Polymerase II Transcription
• Constitutive Signaling by Aberrant PI3K in Cancer
• Diseases of cellular response to stress
• Diseases of Cellular Senescence
• Signal Transduction
• Gene expression (Transcription)
• Cellular Senescence
• GRB2 events in ERBB2 signaling
• Negative feedback regulation of MAPK pathway
• Oxidative Stress Induced Senescence
• Regulation of TP53 Expression and Degradation
• TP53 Regulates Metabolic Genes
• Regulation of MITF-M dependent genes involved in invasion
• Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects
• Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6

Clinical trials

• A Phase 2 Study of the ALK Inhibitor Ensartinib for Patients With Melanomas Harboring ALK Alterations or Aberrant ALK Expression
• A Randomized Phase III Trial of the Duration of Anti-PD-1 Therapy in Metastatic Melanoma
• A Phase 2 Study of Fianlimab, Cemiplimab, and Ipilimumab in Anti-PD-1 Refractory Melanoma
• A Phase 1/2 Open-Label, Dose Finding and Expansion Study to Investigate the Safety and Effectiveness and Determination of the Optimal Dose of N17350 Administered Intratumorally in Participants With Advanced Solid Tumors
• Phase II Randomized Study of Neoadjuvant Pembrolizumab Alone or in Combination With CMP-001 in Patients With Operable Melanoma: Efficacy and Biomarker Study
• A First-in-human, Phase I, Open-label, Non-randomized, Multicentre Dose Escalation and Expansion Trial of BI 3810944 in Patients With Solid Tumours and Melanoma
• A PHASE 1, OPEN-LABEL, DOSE ESCALATION AND DOSE EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND ANTI TUMOR ACTIVITY OF PF-07799933 (ARRY-440) AS A SINGLE AGENT AND IN COMBINATION THERAPY IN PARTICIPANTS 16 YEARS AND OLDER WITH ADVANCED SOLID TUMORS WITH BRAF ALTERATIONS
• A Randomized, Double-blind, Two-arm, Parallel Comparative Multi-center Study to Assess and Compare the Pharmacokinetics, Safety, and Immunogenicity of Bmab1800 and Keytruda® as Adjuvant Monotherapy in Patients With Melanoma
• A Phase II Study of Biomarker Driven Early Discontinuation of Anti-PD-1 Therapy in Patients With Advanced Melanoma (PET-Stop)
• An Open-label, Multicenter Phase Ib/II Clinical Study to Evaluate the Efficacy and Safety of LBL-024 Monotherapy, LBL-024 in Combination With LBL-007 or Toripalimab in Patients With Advanced Melanoma
• Efficacy and Safety of Neoadjuvant Cadonilimab Plus High-Dose Recombinant Human Interferon α1b in Stage III/IV Melanoma: A Single-Center, Open-Label, Phase Ib Trial
• Phase 1/2 Study Evaluating Genetically Modified Autologous T Cells Expressing a TCR Recognizing a Cancer/Germline Antigen as Monotherapy or in Combination With Nivolumab in Patients With Recurrent and/or Refractory Solid Tumors
• A Phase I Multi-center Study to Evaluate the Safety ,Tolerability and Efficacy of LBL-007 Combined With Toripalimab or LBL-007 Combined With Toripalimab and Axitinib Tablets in the Treatment of Unresectable or Metastatic Melanoma
• Randomized Phase II/III Study of Nivolumab Plus Ipilimumab Plus Sargramostim Versus Nivolumab Plus Ipilimumab in Patients With Unresectable Stage III or Stage IV Melanoma
• Phase I/II Study of Dabrafenib, Trametinib, and Navitoclax in BRAF Mutant Melanoma (Phase I and II) and Other Solid Tumors (Phase I Only)
• A Phase 2 Study of Nivolumab and Ipilimumab in Combination With Sirolimus and Prednisone in Kidney Transplant Recipients With Selected Unresectable or Metastatic Cutaneous Cancers
• A First in Human Phase 1 Open-Label, Multicenter, Dose Escalation and Expansion Study of DEG6498 in Patients With Solid Tumors
• Biomarker Stratified CaboZantinib (NSC#761968) and NivOlumab (NSC#748726) (BiCaZO) - A Phase II Study of Combining Cabozantinib and Nivolumab in Participants With Advanced Solid Tumors (IO Refractory Melanoma or HNSCC) Stratified by Tumor Biomarkers - an immunoMATCH Pilot Study
• A First-in-human Study of RLY-8161 for Treatment of Advanced NRAS-Mutant Melanoma and Other Solid Tumors
• A Phase 1 Trial of MK-3475 Plus Ziv-Aflibercept in Patients With Advanced Solid Tumors
• A Randomized Phase II Trial of Adjuvant Nivolumab With or Without Cabozantinib in Patients With Resected Mucosal Melanoma
• A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma
• Molecular Analysis for Therapy Choice (MATCH)
• A Phase II Study of Talimogene Laherparepvec Followed by Talimogene Laherparepvec + Nivolumab in Refractory T Cell and NK Cell Lymphomas, Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma, and Other Rare Skin Tumors
• A Phase I Multicentre, Open-label, Dose Escalation Study to Determine the Safety and Preliminary Efficacy of MBS8(1V270) Administered Intravenously to Cancer Patients With Advanced Solid Tumours
• A Phase 1b/2 Trial Investigating the Safety and Efficacy of Oral AMXT 1501 and Oral DFMO in Combination With Standard of Care in Patients With Advanced Solid Tumors Who Progressed After Prior Therapies
• A Study to Evaluate the Safety and Immune Activity of PeptiCRAd-1 in Combination With Pembrolizumab in Patients With Injectable Solid Tumors in Indications Known to Express NY-ESO-1 and MAGE-A3
• A Phase II Randomized Trial of LND101 for Fecal Microbiota Transplantation in Combination With Immune Checkpoint Blockade in Patients With Advanced Melanoma
• An Open Label Phase I PET Imaging Study to Investigate the Bio-distribution and Tumor Uptake of [89Zr]Zr-BI 765063 and [89Zr]Zr-BI 770371 in Patients With Head and Neck Squamous Cell Carcinoma, Non-small Cell Lung Cancer or Melanoma Who Are Treated With Ezabenlimab
• A Phase 1, Dose Escalation Study With Expansion to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of CCT3833 (BAL3833), a panRAF Inhibitor, in Patients With Advanced Solid Tumours, Including Metastatic Melanoma
• A Multicenter, Randomized, Controlled, Open-label, Phase II Trial on Autologous Tumor Infiltrating Lymphocyte Injection (LM103 TILs) for the Treatment of Advanced Melanoma
• LIMIT Melanoma: (Lysosomal Inhibition + Melanoma ImmunoTherapy) A Phase 1/2 Open Label Trial of Nivolumab and Hydroxychloroquine or Nivolumab/Ipilimumab and Hydroxychloroquine in Patients With Advanced Melanoma
• A PHASE 1A/B OPEN-LABEL MASTER STUDY OF PF-07799544 AS A SINGLE-AGENT AND IN COMBINATION WITH OTHER TARGETED AGENTS IN PARTICIPANTS WITH BRAF-MUTANT MELANOMA AND OTHER SOLID TUMORS
• Phase 1b/2 Study Investigating the Antitumor Activity, Safety, Tolerability, and Pharmacokinetics of the Anti-OX40 Agonist Monoclonal Antibody BGB-A445 in Combination With the Anti-PD-1 Monoclonal Antibody Tislelizumab in Patients With Advanced or Metastatic Urothelial Carcinoma, Renal Cell Carcinoma, or Melanoma
• A Phase Ia/Ib, Open Label, Multicenter, Dose-escalation Study to Evaluate the Safety, Pharmacokinetics, and Activity of Enzelkitug as a Single Agent and in Combination With Checkpoint Inhibitor in Patients With Locally Advanced or Metastatic Solid Tumors
• A Multicenter, Randomized, Double-Blind, Active Comparator-Controlled, Adaptive Phase 2/3 Study to Evaluate the Safety and Efficacy of EIK1001 and Pembrolizumab Versus Placebo and Pembrolizumab as First-Line Therapy in Participants With Advanced Melanoma (TeLuRide-006)
• AFFORD IO: A Phase 2 Trial of Low Dose, Reduced Frequency Nivolumab (Anti-PD-1 Antibody) in Patients With Unresectable or Metastatic Cancer
• Phase II Trial of Combination Anti-PD-1 and Aldesleukin for Metastatic Melanoma and Renal Cell Carcinoma
• A Phase II Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor-Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab
• QUILT-2.025 NANT Neoepitope Yeast Vaccine (YE-NEO-001): Adjuvant Immunotherapy Using a Personalized Neoepitope Yeast-Based Vaccine To Induce T-Cell Responses In Subjects W/ Previously Treated Cancers.