Melanoma

Melanoma is a type of skin cancer that begins in melanocytes, the cells responsible for producing melanin, the pigment that gives skin its color.^[1] It is the most serious form of skin cancer due to its potential to spread rapidly to other parts of the body if not detected early.^[2] Unlike more common skin cancers such as basal cell or squamous cell carcinoma, melanoma accounts for the majority of skin cancer deaths, though it represents only about 1-2% of all cases.^[3] The primary cause of melanoma is exposure to ultraviolet (UV) radiation from sunlight or artificial sources like tanning beds, which damages the DNA in melanocytes and triggers uncontrolled cell growth.^[1] Key risk factors include fair skin that burns easily, a history of severe sunburns (especially in childhood), having more than 50 moles or atypical (dysplastic) nevi, a family or personal history of melanoma, and weakened immune function.^[1] Genetic factors, such as mutations in genes like BRAF or CDKN2A, also play a role in susceptibility, particularly in familial cases.^[4] Individuals with light-colored eyes, red or blond hair, and those living near the equator face higher risks due to increased UV exposure.^[1] Symptoms of melanoma often involve changes in the appearance of existing moles or the development of new, unusual growths on the skin, which may appear on sun-exposed areas like the back, legs, arms, or face, as well as less exposed sites such as the soles of the feet, palms, or mucous membranes.^[1] The ABCDE rule helps identify potential melanomas: Asymmetry (uneven shape), irregular Border, varied Color, Diameter larger than 6 mm, and Evolving (changes over time).^[1] Early detection through regular skin self-exams and professional screenings is critical, as melanoma can be nearly 100% curable in its initial stages.^[5] Treatment for melanoma depends on the stage, typically beginning with surgical excision to remove the tumor and a margin of healthy tissue; for early-stage (0-I) melanomas, this may be curative.^[5] Advanced stages (II-IV) may require immunotherapy (e.g., checkpoint inhibitors like pembrolizumab), targeted therapies (e.g., BRAF inhibitors for mutated tumors), radiation, or chemotherapy, often in combination.^[5] In the United States, melanoma incidence has risen steadily, with an estimated 104,960 new cases and 8,430 deaths projected for 2025, though the five-year survival rate stands at 94.7% overall, exceeding 99% for localized disease.^[6] Prevention through UV protection, avoiding tanning beds, and routine skin checks remains the most effective strategy.^[1]

Signs and Symptoms

Early Detection Features

Early detection of melanoma relies on recognizing subtle changes in skin lesions through regular self-examination, which can significantly improve outcomes by identifying the cancer when it is localized and more treatable.^[7] Tools like the ABCDE rule provide a structured approach to evaluating moles or spots, helping individuals distinguish potentially malignant features from normal variations.^[8] The ABCDE rule outlines key visual characteristics of suspicious lesions:

Asymmetry (A): One half of the mole does not match the other in shape, such as when one side is larger or has a different contour than the other.^[7]
Border (B): Edges are irregular, ragged, notched, or blurred, rather than smooth and well-defined.^[7]
Color (C): Variation within the lesion, including shades of brown, black, tan, red, white, or blue, often unevenly distributed.^[7]
Diameter (D): Typically larger than 6 mm (about the size of a pencil eraser), though melanomas can be smaller.^[7]
Evolving (E): Any change in size, shape, color, or symptoms over time, such as rapid growth.^[7]

Early melanomas commonly appear on sun-exposed areas, with the back being the most frequent site in men and the legs in women, though they can develop anywhere on the body.^[9] Unlike benign moles, which are usually evenly colored, symmetrical, smaller than 6 mm, and stable over time, early melanomas often exhibit rapid growth, itching, tenderness, or bleeding as warning signs that warrant prompt medical evaluation.^[8]^[10] The "ugly duckling" sign refers to a lesion that stands out distinctly from surrounding moles in size, shape, or color, serving as another critical indicator for self-examination.^[7]

Advanced Manifestations

As melanoma progresses to advanced stages, it often metastasizes beyond the primary skin lesion, leading to systemic symptoms that signal widespread disease. Common manifestations include the appearance of firm lumps under the skin from subcutaneous metastases, swollen or hardened lymph nodes due to regional spread, unexplained weight loss from metabolic effects, and persistent fatigue or general malaise.^[11]^[12] These signs typically emerge when the cancer has disseminated hematogenously, with skin and subcutaneous tissues being the most frequent initial sites of distant involvement.^[13] Organ-specific symptoms arise depending on the sites of metastasis, which commonly include the lungs, liver, bones, and brain. Pulmonary involvement may present as shortness of breath, a persistent cough, or hemoptysis, potentially leading to respiratory distress.^[11]^[12] Hepatic metastases can cause right upper abdominal pain, jaundice from biliary obstruction, nausea, and itchy skin due to bile salt accumulation.^[11] Bone metastases often result in localized, gnawing pain—particularly in the back or extremities—that worsens at night, along with an increased risk of pathological fractures.^[12]^[11] Brain metastases may manifest as severe headaches, seizures, confusion, or focal neurological deficits such as weakness in the limbs.^[12]^[11] Rare presentations occur in non-cutaneous melanomas, such as mucosal or ocular variants, which can mimic advanced cutaneous disease but originate in internal sites. Mucosal melanoma, affecting areas like the nasal cavity, oral cavity, or gastrointestinal tract, may cause epistaxis, difficulty swallowing, oral ulcers, or abdominal pain from bowel obstruction.^[14]^[15] Ocular melanoma, primarily uveal, often leads to blurred vision, floaters, flashes of light, or a growing dark spot on the iris, potentially progressing to vision loss if untreated.^[16]^[17] These advanced manifestations significantly impair quality of life, with bone metastases causing chronic pain that limits mobility and daily activities, while systemic symptoms like weight loss and fatigue contribute to cachexia and emotional distress.^[11]^[12] Unrelieved pain and neurological complications can lead to dependency on caregivers and reduced functional independence.^[18]

Causes

Environmental Risk Factors

Ultraviolet (UV) radiation, particularly from sunlight and artificial sources like tanning beds, is the primary environmental risk factor for melanoma development. Both UVA and UVB wavelengths penetrate the skin, with UVB being more energetic and directly responsible for most DNA damage leading to carcinogenesis.^[19] Exposure to UV radiation from tanning beds, which emit primarily UVA, increases melanoma risk by up to 75% when use begins before age 35.^[20] The primary mechanism by which UV radiation contributes to melanoma involves direct DNA damage, predominantly through the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts in skin cells. UVB rays induce these lesions by causing covalent bonds between adjacent pyrimidine bases (thymine or cytosine) in DNA, leading to mutations if not repaired; this process is exacerbated by UVA, which generates oxidative stress and indirect damage via reactive oxygen species.^[21]^[22] The dose-response relationship between UV exposure and melanoma risk distinguishes between intermittent intense exposures, such as sunburns, and chronic low-level exposure. Intermittent intense UV exposure, often recreational and leading to blistering sunburns especially in childhood or adolescence, is more strongly linked to melanoma than cumulative chronic exposure, which is associated more with other skin cancers like squamous cell carcinoma.^[20] A history of five or more sunburns doubles the lifetime risk of melanoma, with pooled analyses showing a 2- to 3-fold increase in risk for individuals reporting multiple severe sunburns.^[23]^[24] Beyond UV radiation, certain chemical exposures elevate melanoma risk, including occupational contact with solvents, pesticides, and polychlorinated biphenyls (PCBs). Pesticide applicators show elevated odds ratios for melanoma with specific agents like maneb and methyl-parathion, while solvents in fuels and paints are associated with a 20-50% increased risk through skin absorption and potential genotoxicity.^[25]^[26] Geographic latitude influences UV intensity and thus melanoma incidence, with rates increasing toward lower latitudes due to higher ambient UV levels; for instance, melanoma incidence rises progressively from northern to southern regions in North America and Europe.^[27] These environmental factors can interact with genetic predispositions to amplify overall risk.^[28]

Genetic and Familial Factors

Approximately 10% of all melanoma cases occur in a familial context, defined as at least two first-degree relatives affected or three or more relatives across generations with the disease.^[4] Familial melanoma syndromes are primarily linked to germline mutations in high-penetrance tumor suppressor genes that impair cell cycle regulation and DNA repair. The most common is the CDKN2A gene, with pathogenic variants identified in 20-40% of families with multiple melanoma cases; carriers face a substantially elevated lifetime risk of developing melanoma, estimated at 50-70%.^[29]^[30] Other genes contributing to familial predisposition include CDK4, which encodes a cyclin-dependent kinase that promotes cell proliferation when mutated, accounting for a small fraction of cases similar to CDKN2A but without the associated pancreatic cancer risk. BAP1 mutations underlie the BAP1 tumor predisposition syndrome, featuring cutaneous, uveal, and mesothelioma risks through disrupted deubiquitination and tumor suppression. POT1 variants, involved in telomere protection and maintenance, lead to genomic instability and are implicated in a subset of hereditary melanoma families.^[4]^[31] In non-familial cases, germline variants in the MC1R gene, which regulates melanin production, contribute to sporadic melanoma risk by conferring fair skin, red hair, and light eye phenotypes that reduce photoprotection. Individuals with two or more MC1R variants exhibit a 2- to 4-fold increased melanoma risk independent of sun exposure history.^[32]^[33] These genetic factors can interact with environmental triggers like ultraviolet radiation to accelerate melanoma onset in susceptible individuals.^[4]

Pathophysiology

Molecular Alterations

Melanoma arises from a series of molecular alterations in melanocytes, primarily driven by somatic mutations that disrupt key signaling pathways. The most prevalent driver mutation is in the BRAF gene, particularly the V600E variant, which occurs in approximately 40-50% of cutaneous melanomas and constitutively activates the MAPK/ERK pathway, promoting uncontrolled cell proliferation.^[34] This mutation is especially common in melanomas associated with intermittent sun exposure but less frequent in other subtypes. NRAS mutations, found in 15-20% of cases, also activate the MAPK pathway through a different mechanism and are often mutually exclusive with BRAF alterations, predominating in melanomas linked to chronic sun damage or nodular histology.^[35] NF1 mutations, occurring in 12-18% of melanomas overall and particularly in those on chronically sun-exposed skin, represent another key driver of the MAPK pathway by inactivating the RAS-GAP function of neurofibromin, leading to sustained RAS activation; they are common in older patients and tumors with high mutational burden, often mutually exclusive with BRAF and NRAS mutations.^[36] In contrast, KIT mutations, which activate receptor tyrosine kinase signaling, are rare in cutaneous melanomas but occur in up to 36% of acral and 39% of mucosal subtypes, highlighting subtype-specific molecular drivers.^[35] Ultraviolet (UV) radiation from sun exposure induces characteristic C>T transition mutations at dipyrimidine sites (e.g., TC or CC sequences), known as the UV signature, which is evident across melanoma genomes and contributes to the high mutational burden observed.^[37] These mutations frequently target oncogenes and tumor suppressors, leading to activation of the MAPK/ERK pathway; for instance, UV-induced changes in BRAF and NRAS hotspots exemplify how environmental damage drives oncogenesis in sun-exposed skin.^[38] The prevalence of this signature underscores UV radiation's causal role, with melanomas showing a significantly higher proportion of such transitions compared to other cancers.^[39] Additional alterations involve other pathways essential for tumor suppression and immortality. Loss of PTEN function, through deletion or mutation, occurs in 10-30% of melanomas and cooperates with BRAF mutations to hyperactivate the PI3K/AKT pathway, enhancing cell survival and invasion.^[35] Inactivation of TP53, via mutations or loss, is less common early on but emerges in advanced lesions, impairing DNA repair and apoptosis.^[37] TERT promoter mutations, present in over 70% of melanomas, enable telomere maintenance and replicative immortality, often appearing as an early event alongside initial driver mutations.^[37] The progression from benign nevus to invasive melanoma involves sequential accumulation of these mutations. Benign nevi typically harbor initiating BRAF V600E mutations, which induce oncogene-induced senescence to halt progression; subsequent TERT promoter alterations reactivate telomerase, allowing escape from senescence.^[37] Intermediate lesions may acquire NRAS or additional MAPK activators, while advanced melanomas incorporate PTEN loss, TP53 inactivation, and CDKN2A biallelic inactivation, increasing genomic instability and enabling invasion.^[37] This stepwise model, marked by rising mutation burden and UV signatures, illustrates the multistage evolution from precursor to malignancy.^[37]

Tumor Development and Spread

Melanoma progression typically begins with the radial growth phase (RGP), where atypical melanocytes proliferate horizontally within the epidermis, forming a non-tumorigenic lesion that rarely metastasizes.^[40] This phase may persist for months to years and is characterized by limited invasion, if any, without breaching the basement membrane.^[41] Transition to the vertical growth phase (VGP) marks the shift to a more aggressive, tumorigenic state, where melanoma cells invade vertically into the dermis, expanding nodularly and acquiring metastatic potential.^[42] Invasion during the VGP occurs through the breach of the basement membrane, enabling dermal penetration and interaction with stromal components that facilitate tumor expansion.^[43] Metastasis is driven by several key mechanisms, including angiogenesis mediated by vascular endothelial growth factor (VEGF), which promotes new blood vessel formation to support tumor nourishment and dissemination.^[44] Epithelial-mesenchymal transition (EMT) further enables this process by inducing cellular changes that enhance motility, invasiveness, and resistance to apoptosis, often regulated by pathways like HIF-1α/VEGF signaling.^[45] Dissemination primarily occurs via lymphatic and vascular routes, with tumor cells entering the bloodstream or lymphatics to seed distant sites.^[46] The most common initial metastatic site is regional lymph nodes, followed by distant spread to the skin, lungs, liver, and brain, where melanoma cells establish secondary tumors that contribute to morbidity.^[47] Within the tumor microenvironment, immune evasion plays a critical role in facilitating spread, particularly through upregulated PD-L1 expression on melanoma cells, which inhibits T-cell activity and suppresses anti-tumor immunity.^[48] This PD-L1-mediated mechanism allows metastatic cells to persist in hostile environments and promotes further dissemination.^[49]

Diagnosis

Clinical Assessment

Clinical assessment of melanoma begins with a thorough medical history to identify risk factors and potential symptoms. Patients are queried about their history of ultraviolet (UV) radiation exposure, including sunburns and tanning bed use, as excessive UV exposure is a primary environmental risk factor.^[19] Family history of melanoma or other skin cancers is also elicited, given that individuals with affected first-degree relatives have a significantly elevated risk.^[50] Additionally, personal history of previous melanomas or atypical moles is documented, as prior melanoma increases the likelihood of recurrence.^[51] Changes in existing moles, such as rapid growth, irregular borders, or color variation, are specifically noted, aligning with evolving features that prompt further evaluation.^[19] The physical examination involves a comprehensive total body skin inspection to detect suspicious lesions, particularly in high-risk patients such as those with numerous moles or a history of sun damage.^[52] This systematic head-to-toe survey allows clinicians to assess all skin surfaces, including the scalp, nails, and mucous membranes, for asymmetry, border irregularity, color variation, diameter greater than 6 mm, and evolving characteristics—commonly summarized by the ABCDE criteria. For individuals at elevated risk, total body mapping via high-resolution photography is employed to create a baseline record of skin lesions, facilitating serial comparisons to identify new or changing moles over time.^[53] Dermatoscopy, or dermoscopy, enhances the clinical assessment by providing magnified, non-invasive visualization of subsurface skin structures.^[54] Suspicious melanomas often exhibit specific patterns under dermoscopy, including atypical pigment networks characterized by irregular, thickened lines with asymmetric distribution and variable hole sizes.^[55] Blue-white veils, appearing as irregular, structureless areas of confluent blue pigmentation overlaying the lesion, are another hallmark feature indicative of dermal invasion.^[54] These tools, combined with short-term monitoring through sequential photography, enable precise tracking of lesion evolution in high-risk patients without immediate intervention.^[52]

Biopsy Procedures

Biopsy procedures for melanoma involve the removal of skin tissue to confirm the diagnosis, typically performed under local anesthesia in an outpatient setting following clinical suspicion of malignancy. The primary goal is to obtain sufficient tissue for histopathological examination while minimizing distortion of the lesion's architecture. Excisional biopsy, which removes the entire suspicious lesion along with a narrow margin of 1-3 mm of normal-appearing skin, is the preferred method as it allows for accurate assessment of tumor depth and margins without transecting the lesion.^[56]^[57] For larger lesions or those in cosmetically sensitive areas such as the face or acral sites, an incisional biopsy may be used to remove only a representative portion of the lesion, often via a punch tool that extracts a cylindrical sample or a deep shave (saucerization) that reaches the subcutaneous fat. Punch biopsies are particularly useful for small, well-defined lesions, while shave biopsies are generally discouraged for suspected invasive melanoma due to the risk of incomplete sampling and underestimation of tumor depth, though they can be appropriate for superficial lesions like melanoma in situ. If a partial biopsy yields inadequate information, a subsequent excisional biopsy is recommended to ensure complete evaluation.^[56]^[57]^[56] Post-biopsy care includes wound cleaning, application of topical antibiotics or hemostatic agents like aluminum chloride, and dressing to promote healing, with sutures removed after 7-14 days depending on location. Patients are advised to avoid sun exposure and strenuous activity to prevent infection or dehiscence. Common complications include bleeding, infection, poor wound healing, and scarring, though these are infrequent with proper technique; partial biopsies carry a specific risk of sampling error leading to diagnostic delay.^[56]^[57]^[57] Sentinel lymph node biopsy (SLNB) is a key procedure for staging melanomas of intermediate thickness (typically 1-4 mm), involving injection of a radioactive tracer and blue dye around the primary lesion to identify and remove the first-draining lymph node(s) for microscopic examination. This is recommended for tumors greater than 1 mm in depth or thinner lesions with high-risk features like ulceration, as it provides prognostic information on regional metastasis without the morbidity of complete lymph node dissection. SLNB is ideally performed concurrently with or prior to wide local excision to avoid lymphatic disruption.^[56]^[57]^[56]

Histological Classification

Histological classification of melanoma relies on microscopic examination of biopsy specimens to identify growth patterns, cellular characteristics, and anatomical site, which guide subtype designation and inform prognosis. The primary subtypes are superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, and desmoplastic melanoma, each exhibiting distinct histological features that reflect their clinical behavior.^[58] The following table summarizes the major subtypes, their approximate prevalence, typical locations, key histological features, and prognostic implications:

Subtype	Approximate Prevalence	Typical Location	Key Histological Features	Prognosis Implications
Superficial spreading	70%	Trunk, legs	Radial growth phase with pagetoid spread of atypical melanocytes into the upper epidermis; nested melanocytes with asymmetry and variation in size/shape.	Favorable if detected early due to prolonged radial phase allowing thinner tumors at diagnosis.^[59]
Nodular	15%	Trunk, head/neck	Predominant vertical growth with minimal radial phase; expansile dermal nodules of epithelioid or spindle cells, often with ulceration.	Worse than other subtypes due to rapid vertical invasion and higher likelihood of metastasis at presentation.^[60]^[59]
Lentigo maligna	10-15%	Face, sun-damaged skin	In situ phase (lentigo maligna) with atypical melanocytes proliferating along the basal layer; invasive form shows nests invading dermis.	Generally better prognosis when in situ; invasive cases similar to superficial spreading but often in older patients with comorbidities.^[61]^[59]
Acral lentiginous	1-3% (higher in non-Caucasians, up to 70%)	Palms, soles, subungual	Lentiginous proliferation of atypical melanocytes along the basal layer with acanthosis and hyperkeratosis; spindle or epithelioid cells in dermis.	Poorer outcomes compared to cutaneous subtypes, with 5-year survival around 80% and 10-year around 68%, due to delayed diagnosis on acral sites.^[62]^[63]
Desmoplastic	1-4%	Sun-exposed head/neck	Spindle cell proliferation in a dense fibrous stroma; often lacks pigment and may mimic scar; neurotropism common.	Variable but often aggressive due to local recurrence risk; 5-year survival similar to other invasive melanomas but higher lymph node involvement.^[58]^[59]

Across subtypes, critical histological criteria include pagetoid spread, defined as single or nested atypical melanocytes ascending upward from the basal layer into the suprabasal epidermis, which is a hallmark of malignancy; mitotic rate, measured as mitoses per square millimeter (typically >1/mm² indicating higher proliferation and adverse risk); and ulceration, characterized by loss of the epidermal stratum corneum overlying the tumor, which independently worsens prognosis by promoting angiogenesis and invasion.^[64]^[65] Melanomas are further categorized as in situ or invasive based on dermal involvement. In situ lesions are confined to the epidermis (melanoma in situ), showing full-thickness atypical melanocytes without breaching the basement membrane. Invasive melanomas penetrate the dermis, with depth assessed using Clark levels: Level I (intraepidermal, equivalent to in situ); Level II (invades papillary dermis but expands it); Level III (fills and expands papillary dermis); Level IV (invades reticular dermis); and Level V (invades subcutaneous fat). While Clark levels historically aided classification, they are now supplementary to Breslow microstaging for prognostic accuracy.^[65]^[66] Prognostic differences among subtypes stem from growth patterns and diagnostic delays; for instance, nodular and acral lentiginous melanomas exhibit earlier vertical growth and deeper invasion at detection, leading to higher rates of lymph node metastasis and reduced survival compared to superficial spreading or lentigo maligna melanomas, which often present with a longer radial phase.^[59]^[63]

Staging Systems

The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system serves as the primary standardized framework for classifying the extent of melanoma, facilitating consistent communication among clinicians, prognostic assessment, and treatment planning.^[67] The eighth edition, implemented in 2017, incorporates refinements based on large international databases to better reflect survival outcomes and incorporates pathological and clinical data from primary tumor evaluation.^[68] This system evaluates the primary tumor (T), regional lymph node involvement (N), and distant metastasis (M), with stages grouped from 0 to IV.^[69] The T category primarily relies on Breslow thickness, a measurement of the vertical depth of the primary tumor from the granular layer of the epidermis to the deepest point of invasion, recorded in millimeters to the nearest 0.1 mm.^[68] Ulceration, defined as the absence of an intact epidermis over the tumor with reactive changes in the underlying dermis, is also a key T descriptor, indicating more aggressive behavior.^[67] Specific criteria include: T1 for tumors ≤1.0 mm (subdivided into T1a ≤0.8 mm without ulceration and T1b >0.8-1.0 mm or with ulceration); T2 for 1.01-2.0 mm; T3 for 2.01-4.0 mm; and T4 for >4.0 mm, each further subdivided by ulceration status (a: absent, b: present).^[68] Unlike prior editions, mitotic rate is no longer a T criterion, simplifying assessment while emphasizing thickness and ulceration.^[69] The N category assesses regional lymph node involvement and non-nodal regional disease, such as satellite lesions, in-transit metastases, or microsatellites (tumor deposits >0.05 mm within 2 cm of the primary but separate from it).^[67] It is stratified by the number of involved nodes and whether detection is clinical (macroscopic, b) or pathological (microscopic, a), with additions for in-transit or satellite disease (c): N1 for 1 node (N1a microscopic, N1b macroscopic, N1c in-transit/satellite without nodes); N2 for 2-3 nodes (N2a/b similarly, N2c with in-transit/satellite); and N3 for ≥4 nodes, matted nodes, or in-transit/satellite with nodes (N3a/b/c).^[68] This expansion from the seventh edition better accounts for regional disease burden.^[69] The M category classifies distant metastasis by anatomic site and incorporates serum lactate dehydrogenase (LDH) levels as a prognostic modifier.^[67] M0 indicates no distant metastasis, while M1 is subdivided: M1a for skin, subcutaneous, or distant soft tissue sites; M1b for lung metastasis; M1c for non-central nervous system (CNS) visceral sites; and M1d (a new designation) for CNS involvement, with or without other sites.^[68] LDH is denoted as a suffix: (0) for normal levels and (1) for elevated (upper limit of normal), applying across all M1a-d categories rather than solely defining M1c as in the seventh edition; this change, implemented in 2017, refines risk stratification without altering core site-based groupings.^[69] Stage groupings integrate TNM elements into prognostic stages: Stage 0 (Tis N0 M0) for melanoma in situ; Stage I for localized thin tumors without ulceration or nodes (IA: T1a N0 M0; IB: T1b/T2a N0 M0); Stage II for thicker localized tumors (IIA: T2b/T3a N0 M0; IIB: T3b N0 M0; IIC: T4a N0 M0; with higher substages for ulceration); Stage III for regional involvement (IIIA-D substages based on T/N combinations, e.g., IIIA: T1-2a with N1a/N2a M0); and Stage IV for any T/N with M1 (subdivided by M1a-d and LDH).^[68] These groupings, validated on over 17,000 patients, improve outcome prediction compared to prior systems.^[67]

Stage	TNM Combination	Description
0	Tis N0 M0	In situ melanoma, confined to epidermis.
IA	T1a N0 M0	Thin (<0.8 mm), non-ulcerated, node-negative.
IB	T1b or T2a N0 M0	Thin to intermediate (≤2.0 mm), node-negative.
IIA	T2b or T3a N0 M0	Intermediate thickness with ulceration or >2.0-4.0 mm without.
IIB	T3b or T4a N0 M0	Thicker (>2.0 mm) with ulceration or >4.0 mm without.
IIC	T4b N0 M0	Thickest (>4.0 mm) with ulceration, node-negative.
IIIA-D	Varies (T1-4 N1-3 M0)	Regional nodal or in-transit disease; substages by T/N extent.
IV	Any T Any N M1	Distant metastasis; substages by site (a-d) and LDH (0/1).

This table summarizes representative groupings; full details account for all permutations.^[68]

Laboratory and Imaging Tests

Laboratory tests play a supportive role in melanoma diagnosis by assessing systemic involvement and prognosis, particularly in advanced disease. Serum lactate dehydrogenase (LDH) is the primary blood test used, serving as a prognostic marker in stage IV melanoma where elevated levels indicate poorer outcomes and are incorporated into staging criteria to subclassify distant metastases.^[70] High LDH levels correlate with increased tumor burden and reduced survival, making it a key indicator for disease progression in metastatic settings.^[57] Imaging modalities are essential for evaluating the extent of melanoma spread and informing staging, with selection based on disease stage and symptoms. Computed tomography (CT) scans of the chest, abdomen, and pelvis are recommended for staging in patients with stage III or IV disease to detect regional or distant metastases.^[71] Positron emission tomography-computed tomography (PET-CT) combines metabolic and anatomic imaging, offering higher sensitivity for identifying occult metastases compared to CT alone, particularly in stage IIIB-IV cases.^[71] Magnetic resonance imaging (MRI) of the brain is preferred for suspected central nervous system involvement due to its superior soft tissue contrast, while ultrasound is commonly used to assess regional lymph nodes for involvement in early staging.^[71] These imaging tests contribute to accurate staging by visualizing tumor dissemination beyond clinical examination.^[72] Molecular testing on tumor tissue is routinely performed to identify actionable mutations that guide therapeutic decisions. Testing for BRAF V600 mutations is standard in advanced melanoma using immunohistochemistry (IHC) as an initial screen, followed by polymerase chain reaction (PCR) or next-generation sequencing (NGS) for confirmation if IHC is equivocal.^[57] NRAS mutations are assessed in BRAF wild-type tumors, occurring in approximately 15-20% of cases, while KIT mutations are evaluated primarily in mucosal, acral, or chronically sun-damaged melanomas, where they are found in up to 20% of such subtypes.^[73] These analyses, performed on formalin-fixed paraffin-embedded tissue from biopsies, enable precision oncology approaches.^[74] Emerging liquid biopsy techniques, such as circulating tumor DNA (ctDNA) analysis, offer non-invasive monitoring of melanoma dynamics. ctDNA detection in plasma can track tumor burden, predict relapse, and assess treatment response in advanced disease, with BRAF-mutant ctDNA levels correlating with progression-free survival.^[75] Studies demonstrate that rising ctDNA post-resection signals early recurrence, potentially earlier than imaging, though it remains investigational and not yet standard for routine clinical use.^[76]

Prevention

Sun Exposure Reduction

Reducing sun exposure through behavioral modifications forms the foundation of melanoma prevention, targeting the primary environmental risk factor of ultraviolet (UV) radiation. Individuals are advised to seek shade during peak UV hours, typically from 10 a.m. to 4 p.m., when solar intensity is highest and the risk of skin damage escalates.^[77] This simple strategy limits direct exposure and is particularly effective in outdoor settings like beaches, parks, or sports events.00199-0/fulltext) Avoiding artificial UV sources is equally critical; tanning beds and sunlamps are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC), equivalent to tobacco in their established link to human cancer, including a 59% increased melanoma risk for first use before age 35.^[78]^[79]^[80] Incorporating protective accessories enhances these efforts: broad-brimmed hats with at least a 3-inch brim shield the face, neck, and ears, while UV-protective clothing rated UPF 50+ blocks over 98% of UV rays, offering consistent coverage superior to standard fabrics like cotton (UPF ~5).^[77]^[81] Public health initiatives have successfully promoted these practices on a population level. Australia's "Slip! Slop! Slap!" campaign, launched in 1981 by Cancer Council Victoria, encourages slipping on protective clothing, slapping on a hat, and later additions like seeking shade and sliding on sunglasses, contributing to declining melanoma incidence rates among younger age groups through widespread adoption of sun protection behaviors.^[82]^[83] Evidence underscores the impact of these strategies, with the U.S. Surgeon General estimating that up to 90% of melanomas are attributable to UV exposure and thus preventable by rigorous sun avoidance in high-risk groups, such as those with fair skin or a history of sunburns.^[84] Long-term adherence has demonstrated substantial risk reductions, reinforcing sun exposure minimization as a high-impact, accessible intervention.^[85]

Protective Measures

Protective measures against ultraviolet (UV) radiation primarily involve the use of topical and physical barriers to minimize skin exposure, thereby reducing the risk of melanoma development. Sunscreens serve as a key topical barrier, with broad-spectrum formulations recommended to block both UVA and UVB rays. These should have a sun protection factor (SPF) of 30 or higher to provide adequate protection, and water-resistant options are advised for activities involving sweat or water exposure.^[86]^[87] Sunscreens are categorized into chemical and mineral types, each offering effective broad-spectrum protection when used correctly. Chemical sunscreens absorb UV rays and convert them into heat, typically using ingredients like avobenzone or oxybenzone, while mineral sunscreens, containing zinc oxide or titanium dioxide, create a physical barrier that reflects and scatters UV radiation. Both types are suitable for melanoma prevention, though mineral variants may be preferred for sensitive skin due to lower irritation potential.^[88]^[89] Regular daily use of broad-spectrum sunscreen with SPF 15 or higher, applied as directed, can reduce the risk of melanoma by approximately 50%. For optimal efficacy, sunscreen should be applied at a rate of 2 mg per square centimeter of skin—equivalent to about one ounce for the entire body—and reapplied every two hours, or immediately after swimming, sweating, or toweling off.^[90]^[91]^[92] Beyond sunscreen, protective eyewear and lip protection are essential barriers. Sunglasses labeled with UV400 or 100% UVA/UVB protection block nearly all harmful rays, safeguarding the sensitive skin around the eyes from UV-induced damage that contributes to melanoma risk. Lip balms containing SPF 30 or higher should be applied to prevent sunburn on the lips, which are particularly vulnerable to UV exposure.^[93]^[94]^[95] While these measures significantly mitigate UV penetration, they do not offer complete protection against melanoma, as some radiation may still reach the skin. Therefore, they must be combined with strategies to limit overall sun exposure for comprehensive risk reduction.^[96]

Chemopreventive Options

Nicotinamide, a non-flushing form of vitamin B3, has emerged as a potential chemopreventive agent for skin cancers by enhancing cellular energy production, supporting DNA repair mechanisms, and mitigating UV-induced immunosuppression. In the ONTRAC phase 3 randomized, double-blind, placebo-controlled trial involving 386 high-risk patients with prior nonmelanoma skin cancers, oral nicotinamide (500 mg twice daily) reduced the rate of new nonmelanoma skin cancers by 23% (95% CI, 4-38) after 12 months compared to placebo, with similar reductions observed in actinic keratoses (13% overall incidence decrease).^[97] Although this trial reported no significant difference in melanoma incidence (five cases in each group), preclinical investigations have demonstrated that nicotinamide inhibits melanoma cell proliferation, migration, and tumor growth in vitro and in mouse models by disrupting metabolic pathways and oxidative stress responses.^[98] These findings support its safety profile, with no increased adverse events beyond minor gastrointestinal effects, positioning nicotinamide as a candidate for broader skin cancer prevention strategies, though further melanoma-specific trials are needed. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been explored for melanoma chemoprevention due to their inhibition of cyclooxygenase-2 (COX-2), which reduces proinflammatory prostaglandins implicated in carcinogenesis and UV-induced tumor promotion. Observational data from the Women's Health Initiative cohort of 59,806 postmenopausal women indicated that aspirin use was associated with a 21% lower risk of melanoma (hazard ratio 0.79, 95% CI 0.63-0.98) compared to non-use, with greater protection observed among long-term users.^[99] Similarly, a case-control study found that NSAID use for more than 5 years correlated with a 30% reduction in melanoma risk (odds ratio 0.70, 95% CI 0.52-0.94), attributed to anti-inflammatory effects on melanocyte transformation.^[100] However, randomized evidence is less conclusive; the ASPREE trial in older adults showed no significant melanoma risk reduction with daily low-dose aspirin (100 mg) over 4.7 years (hazard ratio 1.16, 95% CI 0.81-1.66).^[101] These discrepancies highlight the need for prospective studies to clarify dosing, duration, and applicability in high-risk populations. Antioxidant supplements, including vitamins C and E as well as beta-carotene, exhibit mixed evidence regarding melanoma risk reduction, primarily through their capacity to neutralize reactive oxygen species generated by UV exposure. Prospective cohort analyses, such as the Vitamins and Lifestyle study involving over 35,000 participants, found no association between supplemental intake of vitamins C, E, or beta-carotene and increased melanoma incidence, with relative risks near 1.0 across dosage categories.^[102] Dietary sources of these antioxidants may confer modest protection—e.g., higher vitamin E intake linked to a 20-30% lower risk in some case-control studies—but randomized trials like the SU.VI.MAX study reported no preventive benefit for total cancer incidence, including skin types.^[103] Caution is advised for high-dose beta-carotene, as the SU.VI.MAX trial observed a potential increase in skin cancer risk among women (relative risk 1.25 for nonmelanoma, though not statistically significant for melanoma), possibly due to pro-oxidant effects in certain contexts.^[104] Overall, current guidelines do not endorse routine antioxidant supplementation for melanoma prevention, favoring dietary approaches over isolated high-dose pills. In high-risk groups, such as those with familial melanoma syndromes or pathogenic variants in genes like CDKN2A, chemopreventive pharmacological options remain underdeveloped and are not routinely recommended over established strategies. Genetic counseling is prioritized to assess hereditary risks, interpret testing results, and guide personalized management, often integrating regular dermatologic surveillance with total-body skin examinations every 3-6 months.^[105] Enhanced monitoring in these individuals has demonstrated improved early detection rates, underscoring surveillance as the cornerstone of prevention rather than unproven systemic agents.^[106]

Treatment

Primary Surgical Approaches

The primary surgical approach for localized melanoma is wide local excision, which aims to remove the entire tumor along with a surrounding margin of normal-appearing skin to minimize local recurrence while preserving function and cosmesis. The recommended margin width is guided by the Breslow depth, a histopathological measurement of tumor thickness that informs staging and risk assessment. For melanoma in situ (Breslow depth 0 mm), margins of 0.5 to 1 cm are standard, extending to the subcutaneous fat. In invasive melanomas ≤1 mm thick, a 1 cm margin is typically sufficient; for tumors 1.01 to 2 mm thick, margins of 1 to 2 cm are used; and for those >2 mm, a 2 cm margin is employed. These recommendations derive from multicenter randomized controlled trials demonstrating no survival benefit from wider margins in thinner lesions, though deeper excisions to the muscular fascia are advised for invasive disease without routine fascia removal.^[107] For specific subtypes like lentigo maligna melanoma, often occurring on sun-damaged facial skin, Mohs micrographic surgery serves as an alternative to conventional wide local excision to optimize tissue preservation in cosmetically sensitive areas. This staged procedure involves serial excision of thin tissue layers, with immediate horizontal frozen-section histological examination to ensure 100% margin evaluation, allowing precise clearance of irregular, subclinical extensions common in lentigo maligna. Systematic reviews of over 27 studies report recurrence rates of approximately 1.35% at 1 to 5 years follow-up with Mohs surgery, significantly lower than the 6% to 20% seen with standard excision, though its use remains debated for invasive components due to concerns over frozen-section accuracy for melanocytes.^[108] Sentinel lymph node biopsy (SLNB) is frequently performed concurrently with wide local excision for melanomas ≥1 mm thick or high-risk thinner lesions to provide accurate staging without immediate lymphadenectomy. The procedure entails preoperative lymphoscintigraphy followed by intraoperative injection of a radioactive tracer (technetium-99m sulfur colloid) and/or isosulfan blue dye around the primary tumor site; the tracer and dye migrate via lymphatics to the sentinel node(s)—the first node(s) draining the tumor—which are then localized using a handheld gamma probe or visual identification of blue staining and excised for detailed pathological analysis. Meta-analyses confirm SLNB sensitivity exceeding 95%, with regional recurrence rates ≤5% in node-negative cases, supporting its role in identifying occult micrometastases that influence prognosis.^[109] Surgical excision alone offers curative intent for early-stage disease, particularly thin melanomas (<1 mm Breslow depth), where 10-year melanoma-specific survival rates exceed 95%, reaching 98% for stage IA tumors without ulceration or mitosis. These high cure rates reflect the low metastatic potential of thin lesions, with local recurrence risks under 1% when margins are achieved.^[110]

Adjuvant and Neoadjuvant Therapies

Adjuvant therapies are administered after surgical resection of melanoma to reduce the risk of recurrence in patients with higher-risk disease, particularly those with stage IIB, IIC, or III melanoma following complete resection.^[111]^[112] For patients with resected node-positive melanoma or high-risk features such as ulcerated primary tumors thicker than 1 mm, adjuvant immunotherapy with PD-1 inhibitors including pembrolizumab or nivolumab is FDA-approved; pembrolizumab based on the KEYNOTE-054 and KEYNOTE-716 trials and nivolumab based on the CheckMate 76K trial, which demonstrated significant improvements in recurrence-free survival compared to placebo.^[113]^[114]^[115]^[116] In patients with BRAF V600E-mutated stage III melanoma, adjuvant targeted therapy with the combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) is recommended, as shown in the COMBI-AD trial, where it reduced the risk of recurrence by approximately 50% and lowered the risk of death by 25% at long-term follow-up.^[117]^[118] These therapies are typically given for up to one year post-surgery to target micrometastatic disease.^[70] Neoadjuvant therapies, delivered before surgery, aim to shrink tumors and improve surgical outcomes or pathological responses in resectable stage III melanoma. Clinical trials, such as the phase 2 OpACIN-neo and subsequent studies, have evaluated neoadjuvant combinations like ipilimumab (a CTLA-4 inhibitor) and nivolumab (a PD-1 inhibitor), achieving major pathological response rates of 50-70% and near-complete responses in many cases, with 12-month recurrence-free survival reaching 95% among responders.^[119]^[120] These approaches are particularly investigated for patients with clinically detectable nodal disease, where pathological response correlates with improved event-free survival, though they remain investigational and are not yet standard outside trials.^[121] Both adjuvant and neoadjuvant immunotherapies carry risks of immune-related adverse events (irAEs), which arise from immune activation against healthy tissues and can affect up to 70% of patients. Common irAEs include colitis, presenting with symptoms such as diarrhea, abdominal pain, and bloody stools, often requiring corticosteroids or immunosuppressive agents for management; severe cases (grade 3-4) occur in 10-20% of patients on PD-1 or CTLA-4 inhibitors.^[122]^[123] Monitoring and early intervention are essential, as irAEs like colitis can lead to treatment discontinuation but are generally reversible with prompt care.^[124]

Chemotherapy Options

Chemotherapy has historically been employed as a systemic treatment option for advanced, unresectable melanoma, particularly in patients ineligible for other modalities, though its efficacy remains limited.^[70] The primary cytotoxic agent used is dacarbazine (DTIC), an alkylating agent approved by the FDA in 1970, which yields objective response rates of 10% to 20%, with complete responses occurring in fewer than 5% of cases.^[70] These responses are typically partial and short-lived, lasting 3 to 6 months on average, without demonstrating a significant impact on overall survival in randomized trials.^[70]^[125] Temozolomide serves as an oral alternative to dacarbazine, functioning as a prodrug that crosses the blood-brain barrier more effectively, which can be advantageous for patients with central nervous system metastases.^[126] Phase III trials have shown temozolomide to produce response rates comparable to dacarbazine (approximately 10% to 15%), with median overall survival of about 7.7 months versus 6.4 months for dacarbazine, though it failed to prove superiority and is not FDA-approved as equivalent.^[70]^[127] Combination regimens, such as the CVD protocol involving cisplatin, vinblastine, and dacarbazine, were developed to potentially enhance response rates but have shown only modest improvements, with overall responses around 13% to 20% and no benefit in overall survival compared to single-agent therapy.^[128]^[129] These approaches are primarily palliative, aimed at symptom control in patients with stage IV disease who are not candidates for more effective treatments, but their use has declined sharply since 2011 following the introduction of superior therapeutic options.^[70]^[130]

Targeted Molecular Therapies

Targeted molecular therapies for melanoma primarily target specific genetic alterations in tumor cells, such as mutations in the BRAF and KIT genes, to inhibit key signaling pathways driving cancer growth.^[131] These therapies have revolutionized treatment for patients with advanced disease harboring actionable mutations, offering higher response rates compared to traditional chemotherapy.^[132] BRAF inhibitors, including vemurafenib and dabrafenib, are approved for patients with BRAF V600E or V600K mutations, which occur in approximately 40-50% of cutaneous melanomas.^[133] Vemurafenib, a selective inhibitor of mutant BRAF kinase, demonstrated an objective response rate (ORR) of about 48% in a phase 3 trial of untreated metastatic melanoma patients with BRAF V600E mutations, significantly prolonging progression-free survival (PFS) compared to dacarbazine.^[132] Similarly, dabrafenib showed an ORR of 52% in the BREAK-3 phase 3 trial for the same patient population, with a median PFS of 6.9 months versus 2.7 months for dacarbazine.^[134] However, monotherapy with these agents often leads to resistance within months, primarily through reactivation of the MAPK pathway via MEK upregulation or alternative signaling.^[135] To overcome resistance and enhance efficacy, MEK inhibitors like trametinib are combined with BRAF inhibitors, blocking downstream signaling in the MAPK pathway for synergistic effects. In the COMBI-d phase 3 trial, dabrafenib plus trametinib achieved a median PFS of 11 months in BRAF V600-mutant metastatic melanoma, compared to 8.2 months with dabrafenib alone, with an ORR of 67%. This combination has become a standard first-line option, improving overall survival rates to around 30% at 5 years in responsive patients.^[136] For non-BRAF mutant subtypes, such as mucosal and acral melanomas, which frequently harbor KIT mutations, c-KIT inhibitors like imatinib provide a targeted alternative.^[137] In patients with KIT-mutated advanced mucosal or acral melanoma, imatinib yielded clinical responses in 16-29% of cases, particularly with exon 11 or 13 mutations, offering benefit in these otherwise challenging subtypes. Resistance to BRAF and MEK inhibitors commonly arises through MAPK pathway reactivation, such as via NRAS mutations, MEK mutations, or BRAF amplification, and activation of parallel pathways like PI3K/AKT.^[138] These mechanisms underscore the need for sequencing therapies or novel combinations to sustain responses.^[131]

Immunotherapeutic Agents

Immunotherapeutic agents represent a cornerstone in the treatment of advanced melanoma, leveraging the body's immune system to target and destroy cancer cells by countering mechanisms of immune evasion. These therapies primarily include immune checkpoint inhibitors, which block proteins that inhibit T-cell activity, and adoptive cell therapies, which directly infuse tumor-reactive immune cells. Since their introduction, these agents have dramatically improved outcomes, with some patients achieving durable remissions even in metastatic disease.^[139] Checkpoint inhibitors targeting the programmed death-1 (PD-1) pathway, such as nivolumab and pembrolizumab, have shown robust efficacy in advanced melanoma. Nivolumab, a monoclonal antibody, yields objective response rates of approximately 40-44% in patients with unresectable or metastatic disease, with 5-year overall survival rates reaching 44%.^[140] It can be administered subcutaneously or intravenously every 2-3 weeks.^[141] Similarly, pembrolizumab demonstrates comparable benefits, with 3-year overall survival of about 34% in unresectable melanoma and superior long-term survival compared to earlier standards like ipilimumab.^[142] These agents are typically administered intravenously every 2-3 weeks, with responses often deepening over time due to enhanced T-cell infiltration into tumors.^[143] Anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, exemplified by ipilimumab, were among the first checkpoint therapies approved for melanoma and promote broader T-cell activation. In metastatic melanoma, ipilimumab monotherapy achieves long-term survival in about 20% of patients, with median overall survival extending to 10 months versus 6.4 months with standard chemotherapy.^[144] However, its use is tempered by higher rates of immune-related adverse events, including colitis and hypophysitis, occurring in up to 28% of patients at grade 3-4 severity.^[145] Combination regimens pairing PD-1 and CTLA-4 inhibitors, such as nivolumab plus ipilimumab, enhance response rates to around 50-58% in advanced melanoma, with 5-year overall survival of 52%.^[140] This synergy arises from complementary blockade of early (CTLA-4) and later (PD-1) immune checkpoints, though it increases toxicity, with grade 3-4 adverse events in approximately 59% of recipients, necessitating careful patient selection and management with corticosteroids.^[146] Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) offers a personalized approach for patients refractory to checkpoint inhibitors. TIL therapy involves extracting, expanding, and reinfusing a patient's own tumor-reactive T cells, followed by lymphodepleting chemotherapy and interleukin-2 support. In February 2024, the U.S. Food and Drug Administration granted accelerated approval to lifileucel (Amtagvi), the first TIL product, for adults with unresectable or metastatic melanoma previously treated with at least one systemic therapy, based on an objective response rate of 31.5% in phase 2 trials, including 4.4% complete responses.^[147] This approval marks a milestone after decades of research, though manufacturing complexity and toxicity limit its broader application.^[148] Biomarkers guide the selection of immunotherapeutic agents in melanoma. Programmed death-ligand 1 (PD-L1) expression on tumor cells, assessed via immunohistochemistry, correlates with improved responses to anti-PD-1 therapies, with higher expression levels predicting better outcomes in advanced disease.^[149] Tumor mutational burden (TMB), quantifying somatic mutations per megabase, serves as another key predictor; high TMB (>10 mutations/megabase) is associated with enhanced immunotherapy efficacy due to increased neoantigen presentation, as evidenced in real-world cohorts where high-TMB patients showed superior progression-free survival.^[150] These markers help stratify patients, though their integration remains evolving in clinical practice.^[151]

Radiation and Other Modalities

Radiation therapy serves as an adjunctive modality in melanoma management, particularly for specific histological subtypes where surgical margins may be challenging to achieve. In desmoplastic melanoma, adjuvant radiation following wide local excision markedly enhances local control, with 10-year rates reaching 91% when radiation is used compared to 74% with surgery alone.^[152] This benefit is most pronounced in cases with positive margins or deeper invasion, though it does not confer an overall survival advantage.^[153] For lentigo maligna melanoma, especially in cosmetically sensitive areas like the face where extensive surgery risks disfigurement, definitive or adjuvant radiation provides excellent local control, with pooled analyses showing recurrence rates as low as 5% among treated patients.^[153] In advanced disease, radiation finds utility in palliation, notably for brain metastases, where it addresses neurological symptoms and stabilizes intracranial lesions. Whole-brain radiotherapy or stereotactic radiosurgery can achieve 65% local control at 12 months and frequently improves quality of life by reducing symptoms such as headaches and seizures, though median survival remains limited to 6–8 months in this setting.^[153] These approaches are typically reserved for symptomatic or unresectable metastases, often integrated with systemic therapies for optimal outcomes. Regional perfusion techniques offer targeted control for in-transit metastases, which represent locoregional spread along lymphatic pathways in the extremities. Isolated limb perfusion (ILP) isolates the limb's circulation to deliver high-dose melphalan, yielding overall response rates of about 67% and complete responses in 48% of cases, thereby delaying the need for amputation in suitable patients.^[154] As a minimally invasive alternative, hyperthermic isolated limb infusion (ILI) circulates melphalan with mild hyperthermia via percutaneous catheters, achieving complete response rates of 38% and partial responses in 46%, with reduced hospital stays and lower procedural complexity compared to ILP.^[155] These modalities, while effective for local or regional control, are not first-line options due to associated toxicities that can limit their broader application. Radiation often induces skin changes including erythema, telangiectasia, and pigmentation alterations, with heightened risks of severe dermatitis when combined with BRAF inhibitors owing to radiosensitization effects.^[153] Similarly, ILP and ILI carry risks of regional toxicity such as edema and tissue necrosis, graded by scales like Wieberdink, though severe events occur in fewer than 10% of cases; these concerns, alongside the rise of systemic immunotherapies, position them as adjuncts rather than primary interventions.^[154]

Management of Specific Subtypes

Management of lentigo maligna, a subtype of melanoma in situ often occurring on sun-damaged skin of the face and neck, typically involves staged surgical excision to achieve clear margins while preserving cosmesis, particularly in elderly patients where wide excision may be challenging.^[156] This approach allows for incremental removal and histopathological assessment, reducing the risk of recurrence compared to standard excision.^[157] For noninvasive cases, topical imiquimod 5% cream applied five times weekly for 1-3 months serves as an alternative or neoadjuvant therapy, demonstrating clearance rates of up to 80% in select patients unsuitable for surgery, though long-term efficacy requires close monitoring due to potential subclinical persistence.^[158] Adjuvant imiquimod post-excision with narrow margins can further minimize recurrence in histologically affected areas.^[159] Mucosal melanoma, arising from mucous membranes such as the head, neck, or anorectal regions, presents unique management challenges due to its aggressive biology and limited response to traditional therapies, with immunotherapy—particularly anti-PD-1 inhibitors like nivolumab or pembrolizumab—recommended as first-line treatment for advanced disease to harness potential immune activation despite lower efficacy than in cutaneous subtypes.^[160] Surgical resection remains cornerstone for localized tumors, but systemic control often requires checkpoint inhibitors, which yield objective response rates of 10-20% in this population.^[161] Prognosis is notably poorer, with 5-year survival rates approximating 14-20%, influenced by anatomical site and delayed diagnosis.^[162] Ocular uveal melanoma, the most common primary intraocular malignancy, demands specialized management for its metastatic form, where tebentafusp—a bispecific gp100 peptide-HLA-A02:01-targeted T-cell engager—represents the frontline therapy for HLA-A02:01-positive patients with unresectable or metastatic disease, achieving a median overall survival of 21.7 months versus 16.0 months with investigator's choice.^[163] This approval stems from phase 3 trial data showing a 3-year survival benefit of 27% in previously untreated cases, marking a paradigm shift from historical options like chemotherapy, which offer limited durability.^[164] Local therapies such as plaque brachytherapy or enucleation address primary tumors, but systemic progression to liver metastases underscores the need for HLA typing to guide tebentafusp eligibility.^[165] Acral melanoma, originating on palms, soles, or subungual sites and often linked to mechanical trauma rather than UV exposure, prioritizes wide local excision with adequate margins as the primary intervention, given its propensity for local invasion despite lower metastatic potential in early stages compared to other subtypes.^[166] For advanced or metastatic cases harboring KIT mutations—present in up to 20% of acral tumors—targeted inhibition with agents like imatinib or sunitinib is pursued, yielding response rates of 15-25% and progression-free survival of 3-6 months in mutation-positive patients.^[167] Sentinel lymph node biopsy aids staging, but immunotherapy responses remain modest, reinforcing surgery's central role in curative intent.^[168]

Prognosis

Key Prognostic Indicators

Key prognostic indicators in melanoma encompass a range of clinical, pathological, and molecular features that predict disease progression and patient outcomes, guiding therapeutic decisions and staging. These factors are evaluated through histopathological examination of the primary tumor, imaging, and molecular testing, with their combined assessment incorporated into staging systems such as the American Joint Committee on Cancer (AJCC) system.^[169] Tumor-related factors are central to prognosis, with Breslow thickness—the measured depth of tumor invasion from the granular layer of the epidermis—serving as the most influential single predictor. Thinner tumors (≤1 mm) generally confer favorable outcomes, while thicker lesions (>4 mm) are associated with the highest risk of metastasis and poorest prognosis due to increased invasive potential.^[170] Ulceration of the primary tumor, characterized by loss of the epidermal covering over the lesion, independently worsens prognosis by indicating aggressive local behavior and higher metastatic risk, even after adjusting for thickness.^[169] Elevated mitotic rate, reflecting rapid cell division (typically >5 mitoses per mm²), correlates with aggressive tumor biology and adverse outcomes, as it signals heightened proliferative activity.^[169] Lymphovascular invasion, the presence of tumor cells within lymphatic or vascular channels, is a strong marker of metastatic potential and independently predicts worse disease-free survival, highlighting early vascular dissemination.^[171] Patient-specific factors also modulate prognosis. Advanced age at diagnosis (>65 years) is linked to inferior outcomes, attributed to reduced immune surveillance and comorbidities that complicate treatment.^[172] Male sex consistently portends a worse prognosis compared to females across all stages, possibly due to differences in tumor biology, sun exposure patterns, and hormonal influences.^[173] The anatomic site of the primary tumor influences risk, with lesions on the trunk associated with poorer prognosis than those on the extremities, likely owing to richer lymphatic drainage and delayed detection in concealed areas.^[66] Nodal involvement, assessed via sentinel lymph node biopsy (SLNB), is a critical determinant of systemic spread. Microscopic involvement, detected solely through pathological examination of the sentinel node (typically <2 mm deposits), indicates occult metastasis and substantially worsens prognosis compared to node-negative disease, though less severely than macroscopic involvement (clinically palpable nodes >2 cm), which signifies advanced regional disease with higher recurrence rates.^[174] The extent of nodal burden further refines risk stratification within positive nodes.^[175] Molecular alterations in the primary tumor provide additional prognostic insight. BRAF mutations (e.g., V600E) are present in approximately 40-50% of melanomas and are associated with slightly better overall survival compared to wild-type tumors, potentially due to responsiveness to targeted therapies.^[176] In contrast, NRAS mutations (in 15-20% of cases) correlate with marginally worse outcomes, characterized by more aggressive behavior and resistance to certain BRAF inhibitors.^[176] Gene expression profiling tests, such as DecisionDx-Melanoma, offer further refinement by identifying low- or high-risk molecular signatures that improve upon AJCC-based risk stratification.^[177]

Survival Outcomes by Stage

The prognosis for melanoma varies significantly by stage at diagnosis, with early-stage disease conferring excellent long-term survival and advanced stages posing substantial challenges despite therapeutic advances. Five-year melanoma-specific survival rates are approximately 97-100% for stage I, 70-95% for stage II, 40-78% for stage III, and 35% for stage IV, based on data from large registries tracking outcomes in the United States and Europe as of 2025.^[178]^[6]^[179]

Stage	5-Year Melanoma-Specific Survival Rate
I	97-100%
II	70-95%
III	40-78%
IV	35%

These rates reflect relative survival compared to the general population and are derived from patients diagnosed between 2018 and 2023, incorporating standard treatments at the time, including immunotherapy and targeted therapies that have notably improved outcomes for stage IV disease.^[178]^[180] Overall five-year survival for melanoma has improved markedly over time, rising from around 50% in the 1970s to 94% currently, driven by enhanced early detection through screening and the integration of adjuvant therapies.^[181]^[182] This progress is particularly evident in advanced stages, where immunotherapy and targeted agents have extended survival beyond historical benchmarks.^[183] Survival outcomes are influenced by factors such as access to specialized care and individual response to adjuvant therapies, which can modify recurrence risk and extend disease-free intervals in higher-risk patients.^[110]^[184] In subsets with brain metastases, a common site of stage IV spread, median survival was historically 4-6 months prior to the widespread adoption of immunotherapy, underscoring the guarded prognosis for this complication before modern interventions.^[185]

Epidemiology

Global Burden and Trends

In 2022, melanoma accounted for approximately 331,700 new cases and 58,700 deaths worldwide, representing a significant portion of the global skin cancer burden.^[186] These figures highlight melanoma's status as the 17th most common cancer globally, with incidence rates varying widely due to differences in skin pigmentation, sun exposure behaviors, and healthcare access.^[187] Incidence rates have been rising steadily, particularly in fair-skinned populations, with annual increases of 4-6% observed in regions such as North America, Northern Europe, and Australia over recent decades.^[188] This upward trend is largely attributed to increased ultraviolet radiation exposure from tanning practices and lifestyle changes, though prevention efforts may begin to stabilize rates in some areas.^[189] The highest incidence gradients are seen in Australia and New Zealand, where the age-standardized incidence rate reached 40.2 per 100,000 population in 2022, driven by high UV levels and predominantly fair-skinned demographics.^[190] Mortality rates in high-income countries have shown encouraging declines, attributed to enhanced screening programs and early detection initiatives; for instance, the United States experienced an approximately 20% reduction in melanoma mortality from 2013 to 2020.^[191] However, these global estimates likely underestimate the true burden in low-resource settings, where underreporting due to limited diagnostic infrastructure and cancer registries results in incomplete data capture.^[192]

Geographic and Demographic Variations

Melanoma incidence exhibits significant geographic variations, with Australia reporting the highest rates worldwide among white populations at approximately 63 cases per 100,000 persons in 2025, particularly elevated at 78 per 100,000 for males and 50 per 100,000 for females.^[193] In the United States, an estimated 104,960 new invasive melanoma cases are projected for 2025, with overall age-adjusted incidence at 21.9 per 100,000, showing a notable rise among young women under 50, where rates have increased by about 3% annually in recent decades.^[6]^[194] Incidence remains markedly lower among Black Americans at 1 per 100,000, though prognosis is worse due to later-stage diagnoses, resulting in five-year survival rates of only 70% compared to 94% for white patients.^[195]^[90] In Europe, incidence rates are highest in Nordic countries such as Denmark and Norway, exceeding 30 per 100,000 in some populations, while Mediterranean regions like Italy and Spain report lower rates, around 10-15 per 100,000, reflecting differences in population demographics and sun exposure patterns.^[196]^[197] Demographic factors further influence melanoma risk and outcomes, with individuals of Fitzpatrick skin types I and II—characterized by fair skin, light hair, and poor tanning ability—facing up to 20 times higher risk compared to those with darker skin types V and VI.^[194] Men experience higher mortality overall, with death rates approximately twice that of women across age groups, attributed to later diagnoses and more aggressive disease presentation.^[198]^[199]

History

Early Descriptions and Discoveries

The earliest known references to melanoma appear in ancient medical texts, where the Greek physician Hippocrates (c. 460–370 BC) described "fatal black tumors" characterized by dark pigmentation and rapid dissemination throughout the body, terming the condition melanosis to denote blackish discolorations associated with malignancy.^[200] These observations, though rudimentary, marked the initial recognition of pigmented skin lesions with lethal potential, distinguishing them from other sores or ulcers prevalent in Mediterranean climates. Hippocrates' accounts, preserved in works like On the Diseases, highlighted the tumors' tendency to ulcerate and spread, providing a foundational conceptual framework for later pathologists despite lacking modern diagnostic tools.^[201] In the early 19th century, systematic pathological study advanced with René-Théophile-Hyacinthe Laënnec's pioneering work. While a medical student in Paris, Laënnec delivered the first formal lecture on melanoma in 1804, later published in 1806, where he detailed the autopsy findings of a patient with disseminated black tumors in the lungs and other organs, confirming their metastatic nature and distinguishing them from syphilitic or tuberculous lesions.^[202] Laënnec coined the term mélanose (from the Greek melas, meaning black) to describe this entity, emphasizing its uniform pigmentation and systemic involvement, which he observed in multiple cases during his tenure at hospitals like Necker.^[203] This publication not only established melanoma as a distinct disease but also introduced the idea of pigmented metastases, revolutionizing autopsy-based pathology.^[200] Further insights into melanoma's hereditary aspects emerged in 1820 when English surgeon William Norris documented the first familial cluster, describing a patient with multiple melanomas alongside affected relatives, including a father and siblings with similar pigmented lesions and early deaths.^[200] Norris' 1820 case series proposed a constitutional predisposition, noting patterns of inheritance and the disease's aggressive spread to internal organs, which laid early groundwork for genetic considerations in oncology.^[204] By the late 19th century, environmental links were articulated by British surgeon Jonathan Hutchinson, who in 1890 described "melanotic freckle" (now known as lentigo maligna), a precursor lesion typically arising on chronically sun-exposed skin of the face in older individuals.^[205] Hutchinson's observations, based on clinical examinations of over 20 cases, correlated the slow-growing, irregular pigmented patches with prolonged ultraviolet exposure, suggesting solar radiation as a precipitating factor for this subtype of melanoma.^[206] In the mid-20th century, technological advancements provided cellular-level confirmation of melanoma's origin. Electron microscopy studies, beginning in the 1950s and culminating in landmark work by researchers like Wallace H. Clark Jr. in the early 1960s, revealed premelanosomes—immature melanin-containing organelles—within tumor cells, definitively establishing their derivation from melanocytes rather than other pigmented tissues.^[207] These ultrastructural analyses, which visualized dendritic processes and melanosome maturation stages, bridged histological and embryological understandings, affirming melanocytes' neural crest lineage in malignant transformation.

Development of Modern Understanding

In the mid-20th century, significant advancements in melanoma classification emerged through histopathological assessments that quantified tumor invasion depth, providing prognostic insights distinct from other skin cancers. In 1969, Wallace H. Clark Jr. and colleagues introduced Clark's levels, a staging system categorizing melanoma invasion from level I (confined to the epidermis) to level V (invading subcutaneous fat), based on microscopic examination of skin layers.^[200] This framework highlighted melanoma's aggressive vertical growth phase, differentiating it from more superficial non-melanoma skin cancers like basal cell carcinoma. Shortly thereafter, in 1970, Alexander Breslow developed a complementary metric measuring tumor thickness in millimeters from the granular layer to the deepest invasive cell, which proved superior for predicting metastasis risk and survival.^[65] These tools, validated in large cohorts, shifted clinical practice toward precise prognostication and surgical margins tailored to invasion depth.^[200] By the 1970s, rising melanoma incidence prompted greater epidemiological and clinical distinction of the disease from indolent non-melanoma skin cancers, emphasizing its lethality and ultraviolet radiation association in public health campaigns.^[208] This period saw melanoma registries expand, underscoring its unique melanocyte origin and metastatic potential compared to keratinocyte-derived squamous or basal cell carcinomas.^[209] Concurrently, early detection aids evolved; the ABCD rule (asymmetry, border irregularity, color variation, diameter >6 mm), introduced in 1985 by dermatologists at New York University, was later expanded to ABCDE (adding evolving changes) in 2004 and popularized for lay and professional screening, improving identification of suspicious lesions.^[210] These criteria formalized visual triage, reducing confusion with benign nevi. Terminological standardization also progressed during this era, moving away from outdated labels like "melanotic sarcoma"—which implied a sarcomatous origin—to "malignant melanoma," reflecting its epithelial-melanocytic nature.^[211] In the 1980s, the World Health Organization (WHO) endorsed this nomenclature in its International Histological Classification of Tumours, adopting subtypes such as superficial spreading and nodular melanoma based on Clark's histopathological criteria, which facilitated global diagnostic consistency.^[212] The early 21st century ushered in the genetic era of melanoma understanding with the 2002 discovery of frequent BRAF gene mutations, particularly V600E, in approximately 66% of melanomas.^[213] Reported by Davies et al. through systematic genome sequencing, this finding linked aberrant MAPK signaling to tumorigenesis, distinguishing melanoma's molecular drivers from other cancers and paving the way for targeted therapies.

Research

Advances in Targeted Therapies

Targeted therapies for melanoma have evolved significantly with the development of next-generation inhibitors targeting the BRAF/MEK pathway, particularly for patients harboring BRAF V600 mutations, which occur in approximately 40-50% of cases. The combination of encorafenib, a BRAF inhibitor, and binimetinib, a MEK inhibitor, represents a key advancement over earlier regimens like vemurafenib plus cobimetinib. In the phase 3 COLUMBUS trial, this doublet achieved a median overall survival of 33.6 months in patients with advanced BRAF V600-mutant melanoma, compared to 16.9 months with vemurafenib monotherapy, demonstrating improved efficacy and a more favorable safety profile with reduced rates of severe cutaneous events.^[214] This regimen has become a standard first-line option, offering durable responses while addressing some limitations of prior BRAF/MEK combinations, such as paradoxical activation of the pathway. To counter acquired resistance, which often emerges through reactivation of the MAPK pathway downstream of MEK inhibition, triplet therapies incorporating BRAF/MEK inhibitors with immune checkpoint blockade have been explored. For instance, the addition of nivolumab to encorafenib and binimetinib in a phase 2 trial showed a significant progression-free survival benefit, with a hazard ratio of 0.51 compared to dual immunotherapy alone, particularly in BRAF V600-mutant melanoma with brain metastases.^[215] These approaches aim to enhance antitumor activity by combining targeted pathway blockade with immune modulation, though challenges like increased toxicity require careful patient selection. Emerging strategies focus on downstream ERK inhibitors to overcome resistance beyond MEK blockade. LY3214996, a selective ERK1/2 inhibitor, has demonstrated preclinical efficacy in BRAF-mutant melanoma models resistant to BRAF/MEK therapy, inducing tumor regression by fully suppressing MAPK signaling and preventing feedback reactivation.^[216] Early clinical data from a phase 2 basket trial support its activity in MAPK pathway-altered cancers, including melanoma, with ongoing studies evaluating its role in post-MEK resistant settings. As of 2025, proteolysis-targeting chimeras (PROTACs) offer a novel paradigm for BRAF targeting by inducing ubiquitination and degradation of mutant proteins rather than mere inhibition. Preclinical studies of BRAF V600E-specific PROTACs in melanoma cells have shown superior MAPK pathway suppression and delayed resistance compared to traditional inhibitors, with distinct effects on gene expression profiles.^[217] Clinically, CFT1946, a BRAF V600 degrader, is in phase 1 trials for solid tumors including melanoma, marking the first such agent to enter human testing and potentially transforming outcomes in resistant disease.^[218]

Innovations in Immunotherapy

Recent advancements in immunotherapy for melanoma have focused on enhancing T-cell activation and specificity through novel modalities, including bispecific antibodies, adoptive cell therapies, personalized vaccines, and next-generation checkpoint inhibitors. These approaches aim to overcome limitations in traditional immune checkpoint blockade, such as resistance in certain subtypes like uveal melanoma and the need for more durable responses in advanced disease.^[164]^[219]^[220] Bispecific antibodies represent a promising innovation, particularly for uveal melanoma, a subtype historically resistant to standard immunotherapies. Tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T-cell engager, has demonstrated significant efficacy in previously untreated, HLA-A*02:01-positive patients with metastatic uveal melanoma. In a phase III trial, tebentafusp improved median overall survival to 21.6 months compared to 16.9 months with investigator's choice therapy (hazard ratio 0.68, 95% CI 0.54-0.87), marking the first systemic therapy to show a survival benefit in this population. This agent works by redirecting T cells to tumor cells expressing the gp100 antigen, inducing cytokine release and tumor cell lysis while minimizing off-target effects.^[164]^[221] Chimeric antigen receptor (CAR) T-cell therapies are emerging as adoptive immunotherapies tailored for solid tumors like melanoma, with ongoing phase I/II trials targeting melanoma-associated antigens. CAR-T cells engineered to recognize GD2, a disialoganglioside overexpressed on melanoma cells, have shown feasibility and biological activity in patients with metastatic melanoma. In a phase I trial, GD2-directed third-generation CAR-T cells were administered to patients with GD2-positive solid tumors, including melanoma, resulting in detectable CAR-T expansion, cytokine release, and partial responses in some cases, though with manageable neurotoxicity. Similarly, CAR-T and T-cell receptor (TCR) therapies targeting MAGE-A3, an intracellular antigen presented via HLA-A01 or HLA-A02, are under investigation in phase I/II studies for advanced melanoma, demonstrating T-cell persistence and tumor infiltration but highlighting challenges like on-target off-tumor toxicity. These trials underscore the potential of CAR-T to elicit robust anti-tumor immunity, with strategies to mitigate exhaustion via checkpoint co-expression observed on infused cells.^[222]^[223]^[224] Personalized neoantigen vaccines have advanced melanoma treatment by stimulating tumor-specific T-cell responses when combined with checkpoint inhibitors. The mRNA-4157 (V940) vaccine, an individualized mRNA-based therapy encoding up to 34 patient-specific neoantigens, has shown substantial benefit in high-risk resected melanoma when added to pembrolizumab. In the phase IIb KEYNOTE-942 trial, at three years of follow-up, the combination reduced the risk of recurrence or death by 49% (hazard ratio 0.51, 95% CI 0.35-0.74) compared to pembrolizumab alone, with consistent effects across tumor mutational burden levels and a 62% reduction in distant metastasis or death. This approach leverages next-generation sequencing to identify neoantigens, enabling rapid vaccine manufacturing in about six weeks, and has prompted ongoing phase III evaluation.^[220]^[219]^[225] Inhibitors targeting lymphocyte-activation gene 3 (LAG-3), a checkpoint that synergizes with PD-1 to suppress T-cell function, have gained traction as first-line options for advanced melanoma in recent years. The fixed-dose combination of relatlimab (anti-LAG-3) and nivolumab was approved by the FDA in 2022 for unresectable or metastatic melanoma based on the phase II/III RELATIVITY-047 trial, which reported a median progression-free survival of 10.1 months versus 4.6 months with nivolumab monotherapy (hazard ratio 0.75, 95% CI 0.62-0.92). Updated 2024 analyses confirmed its first-line efficacy, with a three-year melanoma-specific survival rate of 62.7% compared to 54.0% for nivolumab alone, and numerically superior durable responses. The phase III RELATIVITY-098 trial evaluating adjuvant nivolumab plus relatlimab versus nivolumab alone in resected stage III/IV melanoma did not demonstrate a significant improvement in recurrence-free survival (hazard ratio 0.93).^[226]^[227]^[228]

Emerging Diagnostic and Surveillance Tools

Emerging diagnostic tools in melanoma leverage artificial intelligence (AI) to enhance the accuracy of dermoscopy, a technique that magnifies skin lesions for visual examination. AI-assisted dermoscopy analyzes images captured via smartphone apps or specialized devices to differentiate malignant from benign lesions. For instance, the SkinVision app, a CE-certified mobile application, uses machine learning algorithms trained on large datasets of skin images to provide risk assessments. Clinical validation studies have reported a sensitivity of 95% and specificity of 78% for detecting skin cancers, including melanoma, when compared to histopathology.^[229] This high sensitivity enables early detection of suspicious lesions, potentially reducing unnecessary biopsies while flagging high-risk cases for dermatologist review. However, performance can vary across diverse skin types, underscoring the need for broader validation.^[229] Liquid biopsies represent a minimally invasive approach for surveillance, particularly in detecting minimal residual disease (MRD) after surgical resection of non-metastatic melanoma. These tests analyze circulating tumor DNA (ctDNA) in blood plasma, which originates from tumor cells and carries tumor-specific mutations. In patients with stage II-III melanoma, ctDNA detection post-surgery has shown prognostic value, with detectable levels correlating to higher relapse risk. Sensitivity for predicting recurrence ranges from 11% to 80%, and specificity from 55% to 100%, depending on assay sensitivity and tumor burden.^[230] Ongoing trials, such as those evaluating ctDNA-guided adjuvant therapy, aim to integrate this tool for personalized monitoring and de-escalation of treatment in low-risk cases. Challenges include low ctDNA shedding in early-stage disease and the need for highly sensitive next-generation sequencing methods to achieve clinical utility.^[230] Reflectance confocal microscopy (RCM) offers a non-invasive alternative to traditional biopsy, providing real-time, cellular-level imaging of skin lesions akin to an "optical biopsy." This technique uses a low-power laser to capture reflected light from skin structures, visualizing epidermal and dermal layers up to 200-300 micrometers deep without tissue disruption. In melanoma diagnosis, RCM identifies key architectural features such as atypical nests of melanocytes and pagetoid spread, achieving sensitivity of 85-100% and specificity of 69-99% across multiple studies when correlated with histopathology.^[231] It is particularly valuable for evaluating ambiguous lesions on the face or in lentigo maligna melanoma, where biopsy risks scarring. Beyond initial diagnosis, RCM aids in delineating surgical margins and monitoring post-treatment changes, reducing the need for multiple invasive procedures.^[231] By 2025, multispectral imaging has emerged as a promising intraoperative tool for assessing surgical margins in melanoma excision, enabling precise tumor boundary visualization through analysis of light reflectance across multiple wavelengths. This technology captures biochemical and structural differences between healthy and malignant tissue, predicting tumor depth (Breslow thickness) to guide appropriate resection margins. Algorithms applied to multispectral data have demonstrated potential to inform safety margins for curative surgery, with preliminary studies showing correlations to histopathological outcomes.^[232] Integrated with deep learning, such systems achieve high accuracy in lesion classification and could minimize positive margin rates during wide local excision.^[233] Further clinical trials are required to standardize its use in real-time surgical settings.^[233]

Novel Therapeutic Approaches

Oncolytic viruses represent an experimental class of therapies that selectively infect and lyse cancer cells while stimulating antitumor immune responses. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1 engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), is administered intralesionally to injectible melanoma lesions. In the phase III OPTiM trial involving patients with unresectable stage IIIB-IVM1c melanoma, T-VEC demonstrated an overall response rate of 26.4% compared to 5.7% with subcutaneous GM-CSF alone, with a durable response rate (defined as objective response lasting at least six months) of 16.3% versus 2.1%.^[234] Long-term follow-up from this trial confirmed sustained benefits, including a median overall survival of 23.3 months for T-VEC-treated patients, highlighting its role in inducing systemic immunity through antigen release and T-cell activation.^[235] T-VEC has been approved for advanced melanoma and is under investigation in combination regimens, though challenges include limited efficacy in visceral metastases.^[236] Nanotechnology offers promising avenues for targeted gene silencing in melanoma through nanoparticle-delivered small interfering RNA (siRNA), which inhibits specific oncogenic pathways. Lipid-based or polymer nanoparticles encapsulate siRNA to protect it from degradation and facilitate tumor-specific delivery, enabling silencing of genes like WEE1 that promote cell cycle progression and chemoresistance. In preclinical melanoma models, RRCPP peptide-conjugated nanoparticles delivering anti-WEE1 siRNA reduced tumor growth by over 70% and enhanced apoptosis when combined with chemotherapy.^[237] These systems address siRNA's instability and poor cellular uptake, with examples including liposomal formulations that achieve up to 90% gene knockdown in BRAF-mutant melanoma cells.^[238] Clinical translation is advancing, with phase I trials demonstrating safe delivery and preliminary antitumor effects, though optimization for systemic administration in metastatic disease continues.^[239] As of 2025, clinical trials are increasingly focusing on microbiome modulation to potentiate immunotherapy responses in melanoma patients. Fecal microbiota transplantation (FMT) and probiotic interventions aim to reshape the gut microbiome, which influences immune checkpoint inhibitor (ICI) efficacy by promoting pro-inflammatory T-cell profiles. A meta-analysis of trials up to June 2025 reported that microbiome modulation improved objective response rates to anti-PD-1 therapy in melanoma by 25-30%, with enriched taxa like Akkermansia muciniphila correlating to better outcomes.^[240] Phase II studies, such as those combining FMT with pembrolizumab, have shown enhanced progression-free survival in ICI-refractory patients, attributing benefits to reduced dysbiosis and increased intratumoral immune infiltration.^[241] These approaches underscore the microbiome's role as a modifiable therapeutic target, with ongoing 2025 trials evaluating safety and durability in diverse melanoma cohorts.^[242]