Melanoma
Cutaneous, uveal, and mucosal melanoma — all stages
DefinitionClick to collapse
Cutaneous melanoma is a malignant neoplasm arising from melanocytes, pigment-producing cells of neural crest origin that normally reside in the basal layer of the epidermis and in hair follicles. It can occur on any skin surface, including sun-exposed and sun-protected sites. The AJCC 8th Edition staging system stratifies cutaneous melanoma by Breslow thickness, ulceration, and nodal involvement, with 5-year disease-specific survival (DSS) exceeding 96% for stage IA (T1a N0 M0) and ranging from 75% to 94% for localized melanomas >1.0 mm thick (stage IIC 5-year DSS ~75%) [28]. For patients with regional nodal metastases, 5-year DSS ranges from 24% to 93% depending on nodal burden, ulceration, and other factors [28]. Historically, 5-year survival for distant metastatic disease was <10%, but with modern immune checkpoint and targeted therapies, long-term remission is achievable in ~50% of patients [35]. Three clinical subtypes are recognized based on cumulative sun damage (CSD): low-CSD (superficial spreading and nodular), high-CSD (lentigo maligna type), and acral melanoma (palms, soles, subungual) [MS-2]. Mucosal, uveal, and leptomeningeal melanomas are distinct diseases with different genetic profiles and natural histories and are covered in separate NCCN guidelines [36,37]. The incidence of cutaneous melanoma has risen steadily, driven largely by diagnoses of in situ and thin (T1) lesions, raising concerns about histopathologic overinterpretation [2]. The thickest (T4) melanomas continue to increase, particularly among individuals with lower socioeconomic status and skin of color [2].
EpidemiologyClick to collapse
SubtypesClick to collapse
Superficial spreading melanoma (SSM)
Most common histologic subtype, typically arising in intermittently sun-exposed skin. Characterized by a radial growth phase before vertical invasion.
Nodular melanoma (NM)
Aggressive subtype with rapid vertical growth; often diagnosed at thicker Breslow depth. Minimal or no radial growth phase.
Lentigo maligna melanoma (LMM)
Arises in chronically sun-damaged skin, usually on the head and neck of older individuals. Begins as lentigo maligna (in situ) and may progress to invasive melanoma.
Acral lentiginous melanoma (ALM)
Occurs on non-hair-bearing skin of palms, soles, and nail beds. Not related to UV exposure. Often diagnosed at later stage.
Desmoplastic melanoma (DM)
Uncommon subtype characterized by spindle cells and dense stromal fibrosis. Pure DM (≥90% desmoplasia) has lower SLN positivity (<5%) compared to mixed DM.
BRAF V600-mutant melanoma
Melanomas harboring an activating mutation in BRAF codon V600, most commonly V600E (80%) or V600K (15%). Sensitive to BRAF and MEK inhibitors.
NRAS-mutant melanoma
Activating mutations in NRAS (most commonly Q61R/L) drive MAPK and PI3K signaling. Associated with poorer survival in localized and advanced stages.
KIT-mutant melanoma
Mutations in KIT occur primarily in mucosal, acral, and chronically sun-damaged skin subtypes. Activating mutations in exons 11, 13, 17 confer sensitivity to KIT inhibitors.
Molecular PathogenesisClick to collapse
Cutaneous melanoma arises from the accumulation of genomic alterations that activate the mitogen-activated protein kinase (MAPK) pathway and evade tumor suppression. The most frequent driver mutations occur in BRAF (45–50%), an intracellular serine-threonine kinase in the MAPK cascade. Approximately 80% are BRAF V600E, 15% V600K, and 5% V600R/M/D/G [44,146-148]. BRAF V600 mutations confer constitutive activation of MEK/ERK signaling, driving proliferation and survival. These mutations are sensitive to BRAF and MEK inhibitors, but combination therapy is superior to monotherapy [47,462-464]. NRAS mutations occur in 15–20% of melanomas, most commonly Q61R/L, and also activate MAPK signaling (via RAF-MEK-ERK) and PI3K-AKT pathways [59,60]. NRAS mutations are mutually exclusive with BRAF mutations and are associated with poor prognosis in localized and advanced disease [60]. KIT mutations are found in 10–15% of mucosal and acral melanomas and 2–3% of chronically sun-damaged skin melanomas; they involve receptor tyrosine kinase signaling and respond variably to imatinib and nilotinib [54-58]. Activating KIT mutations in exons 11 (e.g., L576P, W557R) and 13 (K642E) are sensitive, whereas exon 17 mutations (e.g., D816H) are resistant [55-58]. Melanomas also harbor TERT promoter mutations (in up to 70%), leading to telomerase reactivation, and CDKN2A deletions/losses (9p21) in ~50%, disrupting cell cycle control [171,172]. PTEN loss and PI3K/AKT pathway alterations are common in BRAF-mutant melanomas and contribute to resistance [171]. Other less frequent drivers include NF1 mutations (in desmoplastic and CSD melanomas), RAC1 P29S mutations, and gene fusions involving BRAF, NTRK1/2/3, ROS1, ALK (each <1%) [62,63,52,53]. The tumor mutational burden (TMB) is typically high in cutaneous melanoma due to ultraviolet (UV) signature mutations (C>T transitions), which correlate with response to immune checkpoint inhibitors [72-74]. PD-L1 expression is variable and not currently recommended for treatment selection [71]. Chromosomal aberrations such as gains in 7q (BRAF) and losses in 9p (CDKN2A) are common [105]. Somatic molecular testing for BRAF is recommended for patients with stage III or IV disease for targeted therapy; multigene panel testing should be considered if negative for actionable mutations [ME-C 2-3 of 8].
Risk FactorsClick to collapse
Male sex
Higher incidence and mortality compared to females; male sex is a risk factor for single and multiple primary melanomas [1].
Age >50 years
Risk increases with age; most cases are diagnosed in individuals over 50 [1].
Atypical moles/dysplastic nevi
Clinically atypical nevi serve as risk markers for melanoma elsewhere on the body; higher overall nevus count and large nevi increase risk [2,3,6].
Sun-sensitive phenotype
Light skin tone, tendency to sunburn, red hair, blue eyes, Fitzpatrick skin type I, pheomelanin-predominant phenotype [6,52,53].
Multiple and/or blistering sunburns
Especially during childhood and adolescence; intermittent intense sun exposure is a key modifiable risk factor [3,4,7].
Tanning bed use
Indoor tanning (UVA/UVB devices) significantly increases melanoma risk, particularly with earlier age of first use and greater cumulative exposure [6,19,20].
Residence in sunnier climate/latitude nearer equator
Higher ambient UV radiation correlates with increased incidence, especially for high-CSD melanomas [20,21].
Personal history of skin cancer (BCC/SCC)
Prior non-melanoma skin cancer is associated with a 2- to 3-fold increased risk of subsequent melanoma due to shared UV etiology [55,56].
Immunosuppression
Solid organ transplantation, hematopoietic cell transplantation, HIV/AIDS, and chronic lymphocytic leukemia/small lymphocytic lymphoma confer increased risk [3,6,7,8,11,12,13].
Rare genodermatoses (xeroderma pigmentosum)
Defective DNA repair leads to extreme UV sensitivity; 5% of patients develop melanoma, often at young age [14].
Germline pathogenic variants (CDKN2A, CDK4, MC1R, BAP1, TERT, POT1, MITF)
High-penetrance variants associated with familial melanoma; CDKN2A accounts for 20–40% of familial cases. Other cancer predisposition genes (TP53, PTEN, CHEK2, BRCA1/2, BLM, ATM) increase risk [3,15-17,66].
Family history of melanoma
Two or more invasive melanomas in first-degree relatives significantly increase risk; risk of second primary melanoma is higher in familial cases [62,63,65].
Intermittent intense sun exposure
Linked to truncal and extremity melanomas (low-CSD); meta-analysis shows RR = 1.6 for intermittent vs. chronic exposure [6,22,24].
Chronic sun exposure
Associated with head/neck melanomas (lentigo maligna type, high-CSD) [3,24].
Childhood cancer
Survivors of childhood cancer have 2.5-fold increased risk of subsequent melanoma [5,10].
Clinical FeaturesClick to collapse
Typical Presentation
Cutaneous melanoma typically presents as a new or changing pigmented skin lesion, often detected by the patient or during a routine skin examination. The classic presentation follows the ABCDE (asymmetry, border irregularity, color variegation, diameter >6 mm, evolution) criteria. Most melanomas arise de novo, though up to 20% may be associated with a preexisting nevus [ME-A 1 of 2]. Lesions are most common on the trunk in males and on the lower extremities in females, but can occur anywhere, including sun-protected sites (palms, soles, subungual) [MS-2]. The clinical subtype varies: low cumulative sun damage (CSD) melanomas (superficial spreading, nodular) present on intermittently sun-exposed skin; high CSD melanomas (lentigo maligna) occur on chronically sun-damaged skin, typically on the head and neck in older individuals; acral melanomas arise on non-hair-bearing surfaces (palms, soles, nail beds) and are unrelated to sun exposure [MS-3, ME-B 2 of 3]. Patients may also present with regional lymphadenopathy or in-transit metastases (cutaneous or subcutaneous nodules between the primary site and regional nodal basin) as the first manifestation. A small proportion present with distant metastatic disease, often with symptoms referable to the involved organ (e.g., brain, lung, liver) [ME-9]. Melanoma in situ (MIS) appears as a slowly enlarging, irregularly pigmented macule, often on sun-damaged skin; the lentigo maligna subtype can reach several centimeters in diameter [ME-E 1 of 3].
Symptoms
Change in a preexisting mole
Evolution in size, shape, color, or elevation over weeks to months
New pigmented lesion
Appearance of a new spot, especially in adults
Itching or tenderness
Localized pruritus or pain at the lesion site
Bleeding or ulceration
Spontaneous bleeding, crusting, or non-healing sore
Lymph node swelling
Palpable regional lymph nodes, often firm or matted
Neurological symptoms
Headache, seizure, focal deficits from brain metastases
Signs
Asymmetry, border irregularity, color variegation, diameter >6 mm, evolution
ABCDE criteria – highly suspicious for melanoma
Ulceration
Loss of epidermal integrity over the lesion, indicating deep invasion
Elevation or nodularity
Palpable nodule within or under the lesion
Satellite or in-transit metastases
Cutaneous or subcutaneous nodules within 2 cm (satellite) or between primary and nodal basin (in-transit)
Regional lymphadenopathy
Palpable, enlarged, firm lymph nodes in the draining basin
Dermatoscopic features
Pigment network, atypical dots/globules, regression structures, blue-white veil
Red FlagsClick to collapse
Rapid growth or change in a preexisting nevus within weeks to months [ME-1]
Ulceration or bleeding from a pigmented lesion [ME-1A]
Asymmetric lesion with irregular borders and multiple colors [ME-1]
Diameter >6 mm (though smaller melanomas can occur) [ME-1]
New pigmented lesion in an adult, especially after age 30 [ME-1]
Elevated or nodular component, especially with ulceration [ME-1A]
Itching, pain, or tenderness at a mole site [ME-1]
Palpable regional lymphadenopathy, particularly if firm, matted, or enlarging [ME-1]
Cutaneous or subcutaneous nodules adjacent to a melanoma scar or along lymphatic drainage (satellite/in-transit metastases) [ME-7]
Neurologic symptoms (headache, seizure, weakness) in a patient with melanoma – suspicious for brain metastases [ME-9, ME-J 1 of 5]
Unexplained weight loss, fatigue, or systemic symptoms in a melanoma patient – consider visceral metastases [ME-9]
Elevated serum lactate dehydrogenase (LDH) in the setting of suspected or confirmed metastatic disease – associated with worse prognosis [ME-9, ST-3]
Breslow thickness >1 mm, especially with ulceration or high mitotic rate (≥2/mm²) – higher risk of nodal and distant spread [ME-1A, ME-2]
Lymphovascular invasion or microsatellitosis on pathology – indicates aggressive biology [ME-1A, ME-4A]
Age ≤42 years, head/neck location, lymphovascular invasion, and/or mitotic index ≥2/mm² in thin melanomas (T1a with Breslow >0.5 mm) – additive risk for SLN positivity [ME-2]
Positive sentinel lymph node biopsy – upstages to stage III and portends decreased melanoma-specific survival [ME-2A, ME-5A]
History of multiple primary melanomas or strong family history of melanoma (especially CDKN2A, BAP1, CDK4 germline variants) – warrants genetic counseling and intensified surveillance [ME-12, ME-A 1 of 2]
InvestigationsClick to collapse
Diagnostic
Full-thickness skin biopsy (excisional, punch, saucerization, or incisional)
Gold standard to confirm diagnosis and microstage primary melanoma
Immunohistochemistry (IHC)
Aid in histopathologic diagnosis of equivocal lesions and for sentinel node evaluation
Molecular testing (CGH, FISH, GEP) for diagnostically challenging lesions
Differentiate benign from malignant melanocytic neoplasms when histopathology is equivocal
BRAF V600 mutation testing (IHC or molecular)
Required to guide targeted therapy with BRAF/MEK inhibitors in stage III (adjuvant) or stage IV (unresectable/metastatic) disease
KIT mutation testing (molecular)
Considered for patients with advanced melanoma of acral, mucosal, or chronically sun-damaged skin origin who are being considered for KIT inhibitor therapy
Multigene panel testing (MGPT) / next-generation sequencing (NGS)
Identify targetable alterations beyond BRAF/KIT (e.g., NRAS, NTRK fusions, ALK, ROS1) for clinical trial eligibility or targeted therapy
Circulating tumor DNA (ctDNA) measurement
Emerging tool for detecting minimal residual disease, monitoring response, and assessing prognosis in advanced and adjuvant settings
Serum lactate dehydrogenase (LDH)
Prognostic marker in stage IV disease; part of AJCC staging for M category
Staging
Complete history and physical examination (H&P) with emphasis on locoregional area and draining lymph nodes
Essential for clinical staging and detection of nodal or in-transit disease
Complete skin examination
Detect synchronous primary melanomas or suspicious nevi
Cross-sectional imaging: chest/abdomen/pelvis CT with IV contrast (and neck CT or MRI if clinically indicated) and/or whole-body FDG-PET/CT
Baseline staging to detect occult distant metastases. Also used for surveillance in high-risk patients
Brain MRI with and without IV contrast (preferred) or CT if MRI contraindicated
Detection of CNS metastases. Baseline for stage IIIB/C/D and stage IV; for surveillance in high-risk patients (e.g., prior brain metastases, stage IIIB without CNS metastases up to 3 years)
Nodal basin ultrasound (US)
Assess regional lymph nodes for metastatic involvement; used for equivocal physical exam, SLNB alternative if not performed, or surveillance for positive SLNB without CLND
Sentinel lymph node biopsy (SLNB)
Pathologic staging of regional nodal basin in clinically node-negative patients with appropriate risk factors
Lymph node biopsy (FNA or core biopsy) of palpable nodes
Confirm suspected regional nodal metastasis
Biopsy of suspicious metastases (core, FNA, incisional, or excisional)
Confirm stage IV disease and obtain tissue for molecular testing (BRAF, KIT, MGPT)
Serum LDH
Prognostic stratification in stage IV (M1a(0/1), M1b(0/1), M1c(0/1), M1d(0/1))
Biomarkers
BRAF V600 mutation testing
Essential for selection of BRAF/MEK targeted therapy in stage III (adjuvant) and stage IV (unresectable/metastatic) disease
KIT mutation testing
Identify patients with advanced melanoma who may benefit from KIT inhibitors (imatinib, nilotinib). Most relevant for acral, mucosal, or chronic sun-damaged subtypes
Multigene panel testing (MGPT) / NGS
Detect uncommon targetable alterations (e.g., NTRK fusions, ROS1, ALK, BRAF non-V600) for clinical trial eligibility or off-label therapy
PD-L1 immunohistochemistry
May provide prognostic information but should not guide clinical decision-making for immunotherapy selection
Tumor mutational burden (TMB)
May correlate with response to immune checkpoint inhibitors in melanoma, but use to guide treatment decisions remains investigational
VE1 immunohistochemistry for BRAF V600E
Rapid screening test for BRAF V600E mutation; can be used for prompt initiation of targeted therapy in symptomatic/rapidly progressing patients
Circulating tumor DNA (ctDNA)
Potential for minimal residual disease detection, response monitoring, and prognosis assessment
Gene expression profiling (GEP) for SLNB risk prediction
May support shared decision-making for SLNB in select patients with T1b ± T2a melanoma who would decline SLNB if risk <10%. A high-risk result portends 3x higher risk of SLN involvement. Not recommended for other GEP tests [ME-C 1 of 8, ME-F 2 of 5].
Prognostic GEP tests for risk stratification
Not recommended. Current data do not support clinical utility beyond standard clinicopathologic factors
StagingClick to collapse
AJCC Cancer Staging Manual, 8th Edition (2017)
T Categories
| Stage | Description |
|---|---|
| TX | Primary tumor thickness cannot be assessed (e.g., diagnosis by curettage) [ST-1] |
| T0 | No evidence of primary tumor (e.g., unknown primary or completely regressed melanoma) [ST-1] |
| Tis | Melanoma in situ (no invasive component) [ST-1] |
| T1 | Tumor thickness ≤1.0 mm; ulceration status unknown or unspecified [ST-1] |
| T1a | Breslow thickness <0.8 mm, without ulceration [ST-1] |
| T1b | Breslow thickness <0.8 mm with ulceration; OR thickness 0.8-1.0 mm with or without ulceration [ST-1] |
| T2 | Tumor thickness >1.0-2.0 mm; ulceration status unknown or unspecified [ST-1] |
| T2a | Thickness >1.0-2.0 mm, without ulceration [ST-1] |
| T2b | Thickness >1.0-2.0 mm, with ulceration [ST-1] |
| T3 | Tumor thickness >2.0-4.0 mm; ulceration status unknown or unspecified [ST-1] |
| T3a | Thickness >2.0-4.0 mm, without ulceration [ST-1] |
| T3b | Thickness >2.0-4.0 mm, with ulceration [ST-1] |
| T4 | Tumor thickness >4.0 mm; ulceration status unknown or unspecified [ST-1] |
| T4a | Thickness >4.0 mm, without ulceration [ST-1] |
| T4b | Thickness >4.0 mm, with ulceration [ST-1] |
N Categories
| Stage | Description |
|---|---|
| NX | Regional nodes not assessed (e.g., SLNB not performed, regional nodes previously removed for another reason). Exception: For pT1 cM0 melanoma with no clinically detected regional metastases, assign cN0 instead of pNX [ST-2] |
| N0 | No regional metastases detected [ST-2] |
| N1 | One tumor-involved node OR in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes [ST-2] |
| N1a | One clinically occult (detected by SLN biopsy) [ST-2] |
| N1b | One clinically detected [ST-2] |
| N1c | No regional lymph node disease; but presence of in-transit, satellite, and/or microsatellite metastases [ST-2] |
| N2 | Two or three tumor-involved nodes OR in-transit, satellite, and/or microsatellite metastases with one tumor-involved node [ST-2] |
| N2a | Two or three clinically occult (detected by SLN biopsy) [ST-2] |
| N2b | Two or three, at least one of which was clinically detected [ST-2] |
| N2c | One clinically occult or clinically detected node plus in-transit, satellite, and/or microsatellite metastases [ST-2] |
| N3 | Four or more tumor-involved nodes OR in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes OR any number of matted nodes with or without in-transit, satellite, and/or microsatellite metastases [ST-2] |
| N3a | Four or more clinically occult (detected by SLN biopsy) [ST-2] |
| N3b | Four or more, at least one of which was clinically detected, OR presence of any number of matted nodes [ST-2] |
| N3c | Two or more clinically occult or clinically detected nodes AND presence of in-transit, satellite, and/or microsatellite metastases, OR any number of matted nodes with in-transit/satellite/microsatellite metastases [ST-2] |
M Categories
| Stage | Description |
|---|---|
| M0 | No evidence of distant metastasis [ST-3] |
| M1 | Evidence of distant metastasis; LDH level must be specified as recorded (no suffix), not elevated (0), or elevated (1) [ST-3] |
| M1a | Distant metastasis to skin, soft tissue (including muscle), and/or nonregional lymph node [ST-3] |
| M1a(0) | M1a with LDH not elevated [ST-3] |
| M1a(1) | M1a with LDH elevated [ST-3] |
| M1b | Distant metastasis to lung with or without M1a sites of disease [ST-3] |
| M1b(0) | M1b with LDH not elevated [ST-3] |
| M1b(1) | M1b with LDH elevated [ST-3] |
| M1c | Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease [ST-3] |
| M1c(0) | M1c with LDH not elevated [ST-3] |
| M1c(1) | M1c with LDH elevated [ST-3] |
| M1d | Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease [ST-3] |
| M1d(0) | M1d with LDH normal [ST-3] |
| M1d(1) | M1d with LDH elevated [ST-3] |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Stage 0 | Tis N0 M0 (clinical and pathological) [ST-4] | Melanoma in situ; no invasive component; no evidence of regional or distant metastasis. Prognosis is excellent with complete excision. Five- and 10-year disease-specific survival (DSS) >99% [MS-2]. | >99% (approximate based on MS-2 statement for in situ) | Curative (wide excision with 0.5-1 cm margins; alternatives include topical imiquimod or radiotherapy for lentigo maligna subtype in select patients) [ME-2, ME-E 1 of 3] |
| Stage IA | Clinical and pathological: T1a N0 M0 [ST-4] | Thin melanoma (<0.8 mm, nonulcerated). Very low risk of nodal (<5%) and distant metastasis. Five- and 10-year DSS >96% for patients with tumors ≤1.0 mm [MS-2]. | >96% (for T1 including both T1a and T1b) | Curative (wide excision with 1 cm margins, category 1). SLNB generally not recommended due to <5% risk unless adverse features present [ME-2, ME-2A]. |
| Stage IB | Clinical and pathological: T1b N0 M0 or T2a N0 M0 [ST-4] | Thin melanoma with ulceration or 0.8-1.0 mm thickness (T1b) or intermediate thickness 1.01-2.0 mm without ulceration (T2a). Risk of nodal positivity 5-10% for T1b. Five- and 10-year DSS for melanomas >1.0 mm: 75-94% depending on thickness, ulceration, and mitotic rate [MS-2]. | 75-94% (range for >1.0 mm localized melanomas) | Curative (wide excision 1 cm for ≤1.0 mm, 1-2 cm for 1.01-2.0 mm). Discuss and consider SLNB for T1b (5-10% risk). Offer SLNB for T2a [ME-2, ME-2A, ME-E 1 of 3]. |
| Stage IIA | Clinical and pathological: T2b N0 M0 or T3a N0 M0 [ST-4] | Intermediate thickness 1.01-2.0 mm with ulceration (T2b) or thick 2.01-4.0 mm without ulceration (T3a). Risk of nodal positivity >10%. Survival decreases with increasing thickness and ulceration [MS-2]. | Not explicitly stated; localized melanomas >1.0 mm range 75-94% | Curative. Wide excision (1-2 cm for 1.01-2.0 mm, 2 cm for >2.0 mm). SLNB offered (likelihood >10%) [ME-3, ME-3A]. |
| Stage IIB | Clinical and pathological: T3b N0 M0 or T4a N0 M0 [ST-4] | Thick melanoma 2.01-4.0 mm with ulceration (T3b) or very thick >4.0 mm without ulceration (T4a). High risk of locoregional and distant recurrence. Five-year DSS approximately 67-75% [MS-2]. | Approximately 67-75% (extrapolated from MS-2: for localized melanomas >4.0 mm, 5-year DSS ~70-75%) | Curative (wide excision 2 cm). SLNB offered. Adjuvant systemic therapy (nivolumab or pembrolizumab) may be considered after staging (category 1). Consider primary tumor site RT for high-risk local recurrence (category 2B) [ME-3, ME-3B]. |
| Stage IIC | Clinical and pathological: T4b N0 M0 [ST-4] | Very thick melanoma >4.0 mm with ulceration. Highest risk among stage II. Five-year DSS approximately 53-60% [MS-2]. | Approximately 53-60% (extrapolated from MS-2 discussion for T4b) | Curative (wide excision 2 cm). SLNB offered. Adjuvant systemic therapy (category 1) strongly considered after pathological staging. Consider primary tumor site RT (category 2B) [ME-3, ME-3B]. |
| Stage III (Clinical) | Clinical staging: Any T (including Tis) with N ≥1 and M0. Only one stage group for clinical Stage III melanoma [ST-4] | Regional lymph node metastasis (clinically detected) or in-transit/satellite/microsatellite metastases. Prognosis varies widely by nodal burden. Five- and 10-year DSS range from 24% to 93% depending on extent [MS-2]. | 24-93% (range depending on substage) | Potentially curative. Workup includes imaging to rule out distant disease. Treatment involves wide excision of primary (if present) and lymphadenectomy; may consider neoadjuvant systemic therapy for clinically node-positive disease [ME-6, ME-6A]. |
| Stage IIIA (Pathological) | T1a/b, T2a; N1a or N2a; M0 [ST-4] | One to three clinically occult nodes (detected by SLNB) in patients with thin to intermediate (nonulcerated) primary. Melanoma-specific survival 93% at 5 years (AJCC 8th Edition). Lower risk of recurrence; SLN tumor burden <0.3 mm may have survival similar to stage IB [ME-5A]. | 93% (AJCC 8th Edition, as cited in ME-5A) | Potentially curative. Wide excision + SLNB. Nodal basin surveillance (preferred over CLND). Consider adjuvant systemic therapy if SLN tumor burden ≥0.3 mm, especially if T1b-T2a/N1a or N2a; observation often appropriate for very low tumor burden [ME-5, ME-5A]. |
| Stage IIIB (Pathological) | T0 (unknown primary) with N1b or N1c; T1a/b, T2a with N1b/c or N2b; T2b, T3a with N1a/b/c or N2a/b; all M0 [ST-4] | Includes varying combinations of primary tumor thickness and nodal/direct lymphatic metastasis. Patients with microsatellites alone (SLN-negative) have more favorable survival than SLN-positive [ME-4A]. Five-year melanoma-specific survival around 83% (AJCC 8th Edition) [MS-2]. | Approximately 83% (extrapolated from MS-2 for stage IIIB) | Potentially curative. Wide excision + CLND (or nodal surveillance if microsatellites only). Adjuvant systemic therapy (category 1 for node-positive, category 2A for microsatellites alone). Consider neoadjuvant therapy for clinically positive nodes [ME-4, ME-4A, ME-5, ME-6]. |
| Stage IIIC (Pathological) | T0 with N2b/c or N3b/c; T1a/b, T2a/b, T3a with N2c or N3a/b/c; T3b, T4a with any N ≥ N1; T4b with N1a/b/c or N2a/b/c; all M0 [ST-4] | Bulkier nodal disease (≥2 clinically detected, or matted nodes, or any nodal with microsatellites/in-transit). High risk of recurrence and death. Five-year melanoma-specific survival approximately 69% (AJCC 8th Edition) [MS-2]. | Approximately 69% (extrapolated) | Potentially curative but high-risk. Wide excision + CLND (if not done). Neoadjuvant systemic therapy preferred for clinically positive/resectable nodes. Adjuvant systemic therapy recommended (category 1). Consider nodal basin RT if high risk features (category 2B) [ME-5, ME-6, ADJSYS 1 of 2]. |
| Stage IIID (Pathological) | T4b with N3a/b/c; M0 [ST-4] | Very thick, ulcerated primary with four or more involved nodes, matted nodes, and/or lymph node and in-transit/metastatic disease. Highest risk in stage III. Five-year melanoma-specific survival approximately 32% (AJCC 8th Edition) [MS-2]. | Approximately 32% (extrapolated) | Potentially curative but extremely high risk. Multi-modality treatment: neoadjuvant systemic therapy (preferred), wide excision, CLND, adjuvant systemic therapy (category 1). Consider adjuvant RT to nodal basin (category 2B) [ME-6, ADJSYS 1 of 2]. |
| Stage IV (M1a) | Any T, any N, M1a(0) or M1a(1) [ST-3, ST-4] | Distant metastases to skin, soft tissue, and/or nonregional lymph nodes. Median OS historically <1 year but improved with modern therapies. Five-year survival approximately 10-15% before targeted/immune therapy; now long-term survival in ~50% of appropriately treated patients [MS-2]. | Historically <10% at 5 years; current long-term survival ~50% (from MS-2 discussion for stage IV with effective therapy) | Palliative but potentially prolonged remission. Systemic therapy is standard (immune checkpoint inhibitors, BRAF/MEK inhibitors for BRAF-mutant). Consider local therapy for oligometastasis (resection, SBRT, T-VEC). Best supportive care [ME-17, MELSYS 1 of 10]. |
| Stage IV (M1b) | Any T, any N, M1b(0) or M1b(1) [ST-3, ST-4] | Distant metastases to lung, with or without M1a sites. Five-year survival similar to M1a but with modern therapy comparable outcomes [MS-2]. | Similar to M1a | Palliative with potential for durable remission. Systemic therapy (immunotherapy or targeted therapy). Local treatments for symptomatic lung metastases [ME-17]. |
| Stage IV (M1c) | Any T, any N, M1c(0) or M1c(1) [ST-3, ST-4] | Non-CNS visceral metastases (liver, bone, pancreas, etc.) with or without M1a/b sites. Worse prognosis if LDH elevated. Five-year survival lower than M1a/b [MS-2]. | Lower than M1a/b (exact numbers not provided) | Palliative. Systemic therapy. Consider clinical trials. Palliative RT for symptomatic lesions [ME-17]. |
| Stage IV (M1d) | Any T, any N, M1d(0) or M1d(1) [ST-3, ST-4] | Distant metastases to CNS (brain, leptomeninges) with or without other sites. Historically worst prognosis, but intracranial responses to immunotherapy and targeted therapy are improving outcomes. Leptomeningeal disease carries grave prognosis [ME-J 1 of 5]. | Poor historically; improving with modern systemic and local therapies | Palliative with multidisciplinary approach. Brain-directed therapy (SRS, surgery, WBRT) and systemic therapy (nivolumab/ipilimumab preferred, BRAF/MEK for BRAF-mutant). Consider clinical trials [ME-17, ME-J 3 of 5]. |
Staging Pearls
- Clinical staging includes microstaging of the primary melanoma plus clinical/radiological/biopsy evaluation for metastases; pathological staging adds information from wide excision and regional lymph node evaluation (SLNB or CLND) [ST-4].
- Mitotic rate is no longer part of T1 staging in AJCC 8th Edition, but remains an important prognostic factor and should still be reported in pathology [ME-1A].
- Microsatellites, clinical satellites, and in-transit metastases are classified together as N1c/N2c/N3c based on number of tumor-involved regional lymph nodes (0, 1, ≥2 respectively). They upstage to at least stage IIIB [ST-2, ME-1A].
- LDH status is incorporated into M1 subcategories: (0) for not elevated, (1) for elevated. Elevated LDH denotes worse prognosis and places patient in higher risk group [ST-3].
- For pathological stage 0 and T1 without clinically detected regional or distant metastases (pTis/pT1 cN0 cM0), pathological evaluation of lymph nodes is not required; use cN0 to assign pathological stage [ST-4].
- Patients with very low tumor volume stage IIIA (T1a/b-T2a/N1a or N2a) with SLN tumor deposits <0.3 mm have 5-year MSS similar to stage IB (T2aN0) and may be candidates for less intensive surveillance and observation rather than adjuvant therapy [ME-5A].
- Five- and 10-year DSS for localized disease (stage I-II) is >96% for tumors ≤1.0 mm and 75-94% for melanomas >1.0 mm thickness depending on ulceration and mitotic rate [MS-2].
- For stage III, clinically occult nodal disease (SLN-detected) has better prognosis than clinically evident nodal disease. Five-year DSS ranges from 93% (stage IIIA) to 32% (stage IIID) [MS-2, ST-4].
- Stage IV survival has dramatically improved with modern targeted and immune therapies; long-term (5-year) survival now approximately 50% for patients treated with effective systemic therapy, compared to historical <10% [MS-2].
Management PrinciplesClick to collapse
Cutaneous melanoma management requires a multidisciplinary, stage-specific approach integrating surgery, systemic therapy, and radiation therapy. In 2026, an estimated 112,000 new cases and 8,510 deaths are projected in the US [1]. Treatment philosophy emphasizes personalized shared decision-making, with consideration of tumor thickness, ulceration, mitotic rate, nodal status, BRAF mutation status, and patient factors. For early-stage disease (Stage 0–II), surgical excision with appropriate margins is curative for most, but adjuvant systemic therapy is increasingly considered for high-risk Stage IIB–III. For regionally advanced or metastatic disease, neoadjuvant and adjuvant immunotherapy or BRAF/MEK-targeted therapy have improved recurrence-free survival, though impact on overall survival remains under investigation [444–448]. Multimodal care integrates surgical oncology, medical oncology, radiation oncology, dermatology, pathology, and nursing. Clinical trial participation is encouraged where available.
Curative
Stage 0–III (resectable)
Wide excision with or without sentinel lymph node biopsy (SLNB) for primary tumors ≥1 mm thickness or with adverse features. Complete lymph node dissection (CLND) is no longer routine for sentinel node-positive patients; nodal ultrasound surveillance is preferred [336,452]. Adjuvant systemic therapy (anti-PD-1 or BRAF/MEK inhibitors) is recommended for high-risk Stage III and may be considered for Stage IIB/IIC [445–448].
Neoadjuvant
Stage III (clinically positive nodes) and select Stage IV oligometastatic
Neoadjuvant systemic therapy is preferred for resectable stage III with clinical nodes, based on trials showing improved event-free survival [NEOSYS 1]. Options include ipilimumab + nivolumab (category 1 for initial presentation) or pembrolizumab [3,1]. Major pathologic response correlates with excellent outcomes; adjuvant therapy may be guided by response.
Palliative
Unresectable Stage III or Stage IV
Systemic therapy with immune checkpoint inhibitors (anti-PD-1 ± ipilimumab) or BRAF/MEK inhibitors (if BRAF V600 mutant) is first-line [MELSYS 1]. Local therapies (radiation, intralesional T-VEC, isolated limb infusion) are options for symptom control. Best supportive care is reserved for poor performance status.
Multidisciplinary tumor board review is strongly recommended for patients with extensive regional adenopathy, borderline resectable disease, brain metastases, or complex clinical scenarios. The team should include surgical oncologists, medical oncologists, radiation oncologists, dermatopathologists, radiologists, and palliative care specialists [ME-J 1].
Performance status is not explicitly graded in the guidelines, but ECOG 0–1 is required for most adjuvant and neoadjuvant trials. For patients with poor functional status or limited life expectancy, observation or less intensive regimens may be appropriate, especially for melanoma in situ or low-risk Stage IIIA [ME-2B, ADJSYS 2].
Management PathwaysClick to collapse
Branching: Histologic diagnosis, Anatomic site, Patient functional status
Branching: Breslow thickness, Ulceration, Mitotic rate, Risk of SLN positivity, Patient age/comorbidities
Branching: Breslow thickness, Ulceration, Risk of SLN positivity, Pathologic stage after SLNB
Branching: Presence of microsatellites in biopsy or wide excision, SLN status
Branching: SLN tumor burden, AJCC substage (IIIA vs IIIB/C/D), BRAF mutation status, Patient risk of recurrence
Branching: Resectability, BRAF mutation, Prior therapy
Branching: Tumor burden (limited vs extensive), Resectability, Symptom control
Branching: Number and location of metastases, Resectability, BRAF mutation, Prior therapy
Branching: BRAF mutation, Brain metastases presence, Symptom burden, Prior therapy
Branching: Histology of recurrence (in situ/invasive), Prior margin status
Branching: Resectability, Prior treatment, BRAF mutation
Branching: Resectability, Prior lymph node dissection, Prior systemic therapy
Branching: Oligometastatic vs widely disseminated, Prior therapy, BRAF mutation
Pretreatment EvaluationClick to collapse
History and Physical
Pathology Report
Imaging Workup (Baseline)
Laboratory Tests
Sentinel Lymph Node Biopsy Considerations
SurgeryClick to collapse
Surgery is the primary curative modality for primary cutaneous melanoma and regional nodal disease. It is also used for isolated recurrences and oligometastatic disease. Wide excision of the primary tumor with appropriate margins achieves local control, while SLNB provides staging. For clinically positive nodes, therapeutic lymph node dissection (TLND) is performed, often after neoadjuvant systemic therapy. In the sentinel node-positive setting, completion lymph node dissection (CLND) is no longer routine due to lack of MSS/OS benefit [336,452].
Wide excision margins are based on Breslow thickness: in situ 0.5–1 cm; ≤1.0 mm 1 cm (category 1); >1.0–2.0 mm 1–2 cm (category 1); >2.0–4.0 mm 2 cm (category 1); >4.0 mm 2 cm (category 1) [ME-E 1 of 3].
Depth of excision: to subcutaneous fat for MIS; to fascia for invasive melanoma (fascia preserved unless involved). Narrower margins may be modified for anatomic/functional considerations but increase risk of margin positivity and local recurrence [ME-E 1 of 3].
SLNB should be performed at the time of wide excision for clinically node-negative patients with appropriate risk. Lymphatic mapping with blue dye and radiotracer. Sentinel nodes evaluated with serial sectioning and IHC [ME-F 3 of 4].
CLND is not routinely recommended for sentinel node-positive patients. Active nodal ultrasound surveillance is preferred. In select cases (e.g., high risk of additional positive nodes, inability to adhere to surveillance), CLND may be discussed [ME-5A].
TLND should be anatomically complete: axillary dissection levels I–III; inguinofemoral dissection for groin; superficial parotidectomy + neck dissection for head/neck with parotid involvement. Pelvic LND considered for positive Cloquet's node, ≥3 positive inguinofemoral nodes, or imaging evidence [ME-G].
Neoadjuvant systemic therapy is preferred for clinically positive nodal disease to improve EFS and potentially reduce extent of surgery. Index lymph node marking may allow targeted resection [NEOSYS 2].
For melanomas on face, ears, acral sites, Mohs micrographic surgery (MMS) may be considered for T1a lesions with appropriate immunostaining and permanent section analysis of debulking specimen [ME-E 1 of 3].
Digit-sparing surgery (wide excision or MMS) may be an option for subungual MIS and select thin tumors (<0.8 mm) [15].
Procedures
Wide Excision of Primary Melanoma
All primary cutaneous melanomas
Sentinel Lymph Node Biopsy (SLNB)
Clinical Stage IB–II with ≥5–10% risk of positivity; selected Stage III in-transit or microsatellites
Completion Lymph Node Dissection (CLND)
Select sentinel node-positive patients (high risk of non-SLN positivity, inability to adhere to surveillance, regional control needed). Also for incomplete prior LND in recurrence setting
Therapeutic Lymph Node Dissection (TLND)
Clinically positive nodes (with or without neoadjuvant therapy)
Mohs Micrographic Surgery (MMS)
Select T1a melanomas in anatomically constrained areas (face, ears, acral); also for MIS/lentigo maligna with comprehensive margin assessment
Radiation TherapyClick to collapse
Radiation therapy (RT) has several roles in melanoma management: definitive therapy for lentigo maligna (LM) when surgery is not feasible; adjuvant therapy for high-risk primary tumors (desmoplastic melanoma, extensive neurotropism, positive margins) and for nodal basins at high risk of recurrence; palliative therapy for symptomatic metastases; and definitive/ablative therapy for brain metastases (SRS/SRT) and extracranial oligometastases (SBRT). RT is not routinely used as adjuvant for primary melanoma with clear margins.
Principles
- Techniques: external beam RT (EBRT) using modern modalities (IMRT, IGRT) to reduce toxicity. Hypofractionation is commonly used for melanoma.
- Adjuvant nodal RT reduces lymph node field recurrence but does not improve RFS or OS; benefits must be weighed against toxicities (lymphedema) [410].
- Adjuvant brain RT (WBRT) after resection or SRS is not recommended due to lack of OS benefit and cognitive decline risk [34,39].
- SRS is preferred radiation modality for brain metastases; single-fraction doses based on RTOG 90-05: 24 Gy for ≤20 mm, 18 Gy for 21–30 mm, 15 Gy for 31–40 mm [31]. Fractionated SRT for larger lesions: 24–35 Gy in 3–5 fractions.
- Concurrent BRAF/MEK inhibitors with RT increases toxicity; hold BRAF/MEK inhibitors ≥3 days before and after fractionated RT and ≥1 day before and after SRS [52,749].
- Immune checkpoint inhibitors may be safely combined with RT; no clear evidence of increased toxicity [48,49].
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Definitive RT for Lentigo Maligna | 64–70 Gy | 1.8–2.0 Gy | 35 | 6–7 weeks | Medically inoperable LM or when surgery not feasible [ME-H 1] |
| Definitive RT for Lentigo Maligna (hypofractionated) | 35 Gy | 7 Gy | 5 | 1 week, for fields <3 cm | Small LM lesions [ME-H 1] |
| Adjuvant RT for High-Risk Primary | 60–66 Gy | 2.0 Gy | 30 | 6–7 weeks | Desmoplastic melanoma with risk factors (T4, head/neck, neurotropism, positive margins) [ME-H 1] |
| Adjuvant Nodal Basin RT (Standard Fractionation) | 50–66 Gy | 2.0 Gy | 25 | 5–7 weeks | High risk of nodal recurrence (extracapsular extension, multiple positive nodes, large nodes) [ME-H 2] |
| Adjuvant Nodal Basin RT (Hypofractionated) | 30 Gy | 6 Gy | 5 | 2 weeks (twice weekly) | Alternative to standard fractionation [ME-H 2] |
| SRS for Brain Metastases – Single Fraction | 15–24 Gy | 15–24 Gy | 1 | 1 day | Small tumors (≤40 mm): 24 Gy (≤20 mm), 18 Gy (21–30 mm), 15 Gy (31–40 mm) [ME-H 3] |
| Fractionated SRT for Brain Metastases | 24–35 Gy | 8–12 Gy | 3 | 1–2 weeks | Larger tumors where single-fraction unsuitable [ME-H 3] |
| Palliative WBRT | 30 Gy | 3 Gy | 10 | 2 weeks | When SRS/SRT not feasible; consider hippocampal avoidance + memantine for better prognosis [ME-H 3] |
| Palliative RT for Extracranial Metastases | 8–30 Gy | 8–6. | 1 | 1 day | Bone pain, compression symptoms; higher doses/larger fractions for durable palliation [ME-H 4] |
| SBRT for Extracranial Oligometastases (Spine) | 16–24 Gy | 16–24 Gy | 1 | 1 day | Spinal metastases with <3 segments involved [ME-H 4] |
| SBRT for Extracranial Oligometastases (Other Sites) | 48–60 Gy | 16–20 Gy | 3 | 1 week (qod) | Lung, liver, nodal metastases [ME-H 4] |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Adjuvant Nodal Basin RT | 48 Gy/20 fractions or 30 Gy/5 fractions | Not indicated | Patients at high risk for nodal recurrence after TLND: non-response or non-receipt of neoadjuvant therapy, extracapsular extension, location, number/size of nodes (category 2B) [ME-H 2] | ANZMTG 01.02/TROG 02.01: reduced lymph node field recurrence (HR 0.54) but no RFS or OS benefit [410] | Lymphedema (limb), skin fibrosis, pain, nerve damage, joint stiffness [410] |
| SRS for Brain Metastases | Single fraction 15–24 Gy per RTOG 90-05 or fractionated SRT 24–35 Gy/3–5 fractions | BRAF/MEK inhibitors should be held; immune checkpoint inhibitors safe [52,49] | Primary treatment for brain metastases; adjuvant to resection cavity (12–20 Gy per cavity volume) [ME-H 3] | NCCTG N107C/CEC.3: Adjuvant SRS vs WBRT after resection; SRS associated with less cognitive decline, no OS difference [34] | Radionecrosis (risk increased with lesion size), edema, headache, seizures |
| Palliative RT for Symptomatic Metastases | 8 Gy/1 fraction, 20 Gy/5 fractions, 30 Gy/10 fractions, or 40 Gy/8 fractions | Generally not given | Symptomatic extracranial metastases (bone pain, bleeding, obstruction) [ME-H 4] | Overgaard et al. showed 60% clinical regression with hypofractionated RT [705] | Fatigue, skin reaction, organ-specific effects |
Systemic TherapyClick to collapse
Systemic therapy for cutaneous melanoma has evolved dramatically since the early 2010s. For unresectable Stage III/IV, immune checkpoint inhibitors (anti-PD-1 alone or combined with ipilimumab) and BRAF/MEK inhibitors (for BRAF V600-mutant) are the mainstays, offering long-term remissions in ~50% of patients [35]. In the adjuvant setting, anti-PD-1 agents and dabrafenib/trametinib improve RFS and are FDA-approved for Stage III and Stage IIB/IIC. Neoadjuvant systemic therapy is preferred for clinically positive Stage III nodes, with ipilimumab + nivolumab showing highest pathologic response rates. For second-line or subsequent therapy, options include switching class (e.g., from immunotherapy to targeted therapy or vice versa), TIL therapy (lifileucel) for selected patients, and less effective cytotoxic agents. Subcutaneous formulations of nivolumab, pembrolizumab, and atezolizumab are available [SYSCON 2].
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Principles of Treatment Response Assessment
Timing
For patients receiving neoadjuvant therapy, cross-sectional imaging is recommended after 6 to 12 weeks to exclude residual or metastatic disease and assess for surgical planning. For active systemic therapy (other than complete surgical resection), imaging throughout treatment at clinically appropriate intervals (every 2–6 months) is recommended for Stage III in-transit disease, unresectable nodal disease, limited resectable distant disease, and disseminated disease. For patients rendered NED by surgery, follow-up imaging recommendations are stage-specific (see follow-up guidelines).
Response Logic
-
Radiographic or clinically evident increase in tumor size may precede regression early in the course of immune-based therapy (pseudoprogression). Average time to response ranges from 6 to 12 weeks for most asymptomatic patients. It is reasonable to continue immunotherapy beyond progression for an additional interval of 6 to 10 weeks with short-interval imaging. Continued growth 16 weeks after starting immunotherapy should be considered true progression [SYSCON 1].
-
For BRAF-targeted therapy, median time to response is approximately 1.5 months. Responses are relatively short-lived, with median duration ~5–10 months [151,463].
-
Active nodal basin surveillance for sentinel node-positive patients who did not undergo CLND: clinical exam and ultrasound/imaging every 4 months for first 2 years, then every 6 months for years 3–5 (consistent with MSLT-II and DeCOG protocols) [ME-5A].
Imaging Recommendations
-
Cross-sectional imaging (CT chest/abdomen/pelvis with IV contrast, ± neck CT/MRI) and/or whole-body FDG-PET/CT are used. Brain MRI with and without IV contrast is preferred for CNS imaging [ME-D 1].
-
For stage IIB–IV NED after treatment, consider imaging every 3–12 months for 2 years, then every 6–12 months for another 3 years (category 2B). More frequent brain MRI recommended for patients with prior brain metastases. Routine imaging after 3–5 years not recommended [ME-11].
-
Nodal basin ultrasound is recommended for post-SLNB surveillance (if CLND not performed), where expertise available. It is preferred over cross-sectional imaging for nodal assessment [ME-D 4].
Biopsy Or Salvage Logic
-
Repeat biopsy is essential for confirming recurrence when clinically indicated. Tissue is always preferred over cytology for molecular testing; obtain tissue to ascertain BRAF, KIT, and consider MGPT [ME-9].
-
For true scar recurrence (persistent disease), biopsy to confirm before re-excision. For local satellite/in-transit recurrence, biopsy to confirm and differentiate from scar recurrence [ME-14, ME-13].
-
Salvage surgery should be considered for oligometastatic or isolated nodal recurrence after multidisciplinary discussion. Neoadjuvant systemic therapy is preferred for resectable nodal recurrence [ME-16].
-
For patients who progress on systemic therapy, selection of subsequent therapy should be informed by prior response: if progression during/shortly after prior therapy, consider agents of a different class; if disease control with relapse >3 months after discontinuation, reinduction with same class may be considered [ME-7A].
SurveillanceClick to collapse
Clinical Follow Up Schedule
- Stage 0 in situ: annual skin exam for life.
- Stage IA–IIA NED: H&P every 6–12 months for 5 years, then annually. Routine blood tests not recommended. Routine imaging not recommended.
- Stage IIB–IV NED: H&P every 3–6 months for 2 years, then every 3–12 months for 3 years, then annually. Routine blood tests not recommended unless for post-treatment monitoring. Consider imaging every 3–12 months for 2 years, then every 6–12 months for another 3 years (category 2B). Routine imaging not recommended after 3–5 years.
- CT chest/abdomen/pelvis with IV contrast and/or FDG-PET/CT may be used for surveillance in high-risk patients. Brain MRI with/without contrast preferred for CNS imaging; consider periodic brain MRI for patients with prior brain metastases or high-risk stage IIIB or higher without CNS mets [ME-D].
Imaging Strategy
- Nodal basin ultrasound: Preferred surveillance for patients with positive SLNB who did not undergo CLND; frequency every 4 months for first 2 years, then every 6 months for years 3–5 (consistent with MSLT-II and DeCOG trials).
- Cross-sectional imaging (CT or FDG-PET/CT): For stage IIB–IV, consider every 3–12 months for 2 years, then every 6–12 months for 3 years (category 2B). Choice depends on clinical circumstances; FDG-PET/CT may be more sensitive for distant metastases.
- Brain MRI: For patients with prior brain metastases, more frequent surveillance recommended. Periodic brain MRI up to 3 years may be appropriate in stage IIIB or higher without prior CNS metastases.
- Imaging is not recommended for stage 0, IA, IIA NED. Chest x-ray has non-uniform application; cross-sectional imaging preferred.
- Treatment response assessment: For active systemic therapy, imaging every 2–6 months as clinically indicated.
Laboratory Monitoring
- Routine blood tests are not recommended for surveillance in asymptomatic patients.
- LDH may be obtained at diagnosis of stage IV disease for prognostic value.
- Role of circulating tumor DNA (ctDNA) for surveillance is still being defined; not routinely recommended.
- For patients on immune checkpoint inhibitors, monitor thyroid function, liver enzymes, and creatinine periodically as clinically indicated.
Supportive Follow Up
- Patient education on regular skin and lymph node self-examination.
- Sun safety counseling: avoid peak hours, protective clothing, broad-spectrum sunscreen.
- Genetic counseling referral for p16/CDKN2A testing if >2 invasive melanomas or family history patterns.
- Referral for lymphedema management and psychosocial support as needed.
- Coordination of care across specialties for annual skin exam to avoid duplication.
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Local recurrence after primary excision | Re-excision to appropriate margins; consider sentinel lymph node biopsy if not previously performed; adjuvant radiation or systemic therapy based on stage. |
| In-transit/satellite metastases | Complete excision if limited; intralesional injection (T-VEC, IL-2); isolated limb infusion/perfusion; systemic therapy; clinical trial. |
| Regional lymph node recurrence | Completion lymph node dissection (if not done); excision; adjuvant systemic therapy; consider adjuvant nodal basin RT in selected high-risk patients (category 2B). |
| Distant metastases (visceral, CNS, bone) | Systemic therapy (immunotherapy, targeted therapy); palliative RT; surgical resection for oligometastases; best supportive care. |
| Brain metastases | Multidisciplinary evaluation; stereotactic radiosurgery (SRS) or fractionated SRT; surgery for large/symptomatic lesions; systemic therapy with intracranial activity (nivolumab/ipilimumab, BRAF/MEK inhibitors); corticosteroids for symptoms; whole brain RT for palliation when SRS not feasible. |
Supportive CareClick to collapse
Supportive care in melanoma patients should be integrated throughout treatment and survivorship. Key areas include management of treatment-related toxicities, nutritional support, antiemetic protocols, growth factor support, VTE prophylaxis, pain management, psychosocial support, and dental care. The NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities provide detailed management algorithms. Best supportive care should be considered for patients with poor performance status or those who progress despite multiple lines of therapy.
Routine nutritional screening is recommended. For patients receiving systemic therapy with significant gastrointestinal toxicities (colitis, nausea/vomiting, diarrhea), dietary modifications, oral supplements, and involvement of a registered dietitian may be necessary. For severe colitis on immune checkpoint inhibitors, corticosteroids and supportive care are indicated.
Antiemetic prophylaxis should be based on emetogenic potential of chemotherapy agents. For highly emetogenic regimens (e.g., cisplatin-based), recommend NK1 receptor antagonist + 5-HT3 antagonist + dexamethasone. For moderately emetogenic (e.g., carboplatin/paclitaxel), 5-HT3 antagonist + dexamethasone. For immunotherapy, antiemetics as needed for mild nausea; corticosteroids may be used for irAE management.
G-CSF prophylaxis is not routinely indicated for melanoma chemotherapy regimens except in high-risk patients. For cytotoxic regimens like carboplatin/paclitaxel, primary prophylaxis may be considered if febrile neutropenia risk >20% or based on patient factors. Refer to NCCN Guidelines for Myeloid Growth Factors.
VTE risk in melanoma patients is elevated due to malignancy and potential surgery. For hospitalized patients, pharmacologic prophylaxis recommended. For ambulatory patients receiving systemic therapy, consider VTE prophylaxis if high risk (Khorana score ≥2). Inpatient surgical patients should receive prophylaxis; early mobilization encouraged.
Pain should be assessed regularly using validated scales. For mild pain, acetaminophen/NSAIDs (with caution for renal or GI issues). For moderate-severe pain, opioids as per WHO ladder. Neuropathic pain from surgery or chemotherapy may benefit from gabapentinoids or tricyclic antidepressants. Palliative RT for bone metastases. Refer to NCCN Guidelines for Adult Cancer Pain.
Patients with melanoma have significant psychosocial needs including anxiety, depression, body image concerns, and fear of recurrence. Routine screening with validated tools (PHQ-9, GAD-7) is recommended. Offer counseling, support groups, and psychiatric referral as needed. Early structured psychiatric intervention may improve survival outcomes [782]. Patient education on sun safety and self-examination is crucial.
Dental evaluation is recommended before initiating therapy that may cause mucositis or immunosuppression. For patients receiving immune checkpoint inhibitors, dental procedures should be considered if needed. Patients on BRAF/MEK inhibitors with mucositis may benefit from oral hygiene protocols and topical anesthetics.
PrognosisClick to collapse
Outcome for cutaneous melanoma depends on stage at presentation. For localized disease with primary tumors ≤1.0 mm, 5-year and 10-year disease-specific survival (DSS) exceeds 96%. For localized melanomas >1.0 mm, 5- and 10-year DSS range from 75% to 94% depending on thickness, ulceration, and mitotic rate. When regional nodes are involved, 5- and 10-year DSS range from 24% to 93% based on extent of nodal involvement, though these survival rates exclude data following use of novel targeted and immune therapies. Patients with clinically occult nodal disease detected by sentinel lymph node biopsy generally have better survival than those with clinically evident nodal disease [28-30]. Historically, long-term survival in distant metastatic melanoma was <10% at 5 years [31-34], but effective systemic therapies have made long-term remission possible for approximately 50% of patients [35].
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| Stage IA (T1a) | >96% DSS | Localized disease, primary tumor ≤1.0 mm thickness, no ulceration. |
| Stage IB–II (T1b–T4) | 75–94% DSS | Localized melanomas >1.0 mm, depending on thickness, ulceration, and mitotic rate [28]. |
| Stage III (nodal involvement) | 24–93% DSS | Depends on extent of nodal involvement; clinically occult (sentinel node detected) have better survival than clinically evident nodal disease [28-30]. |
| Stage IV (distant metastatic) | Historically <10% at 5 years | Long-term survival <10% at 5 years prior to targeted/immunotherapy; median survival <1 year [31-34]. With effective systemic therapies, long-term remission possible in ~50% [35]. |
Prognostic Factors
- Breslow tumor thickness
- Ulceration status
- Mitotic rate
- Age
- Sex
- Regional lymph node status (number of positive nodes, tumor burden, clinical vs. occult)
- Site of distant metastases (M1a skin/soft tissue, M1b lung, M1c other visceral, M1d CNS)
- Serum lactate dehydrogenase (LDH) level
- Sentinel lymph node status is the strongest predictor of survival for clinical stage I/II
Follow UpClick to collapse
Post Curative Treatment
Follow-up schedules are based on stage and risk of recurrence. For stage 0 in situ: annual skin exam for life. For stage IA–IIA (NED): H&P every 6–12 months for 5 years, then annually. For stage IIB–IV (NED): H&P every 3–6 months for 2 years, every 3–12 months for 3 years, then annually. Lifetime dermatologic surveillance is appropriate due to increased risk of subsequent melanomas [63,757,760,777]. Common recommendations include complete skin exam, patient education on self-examination, sun protection, and genetic counseling referral for >2 invasive melanomas or family history patterns [ME-12].
Surveillance Rationale
Rationale includes early detection of recurrence (which may be more amenable to treatment) and identification of second primary melanomas. Most recurrences are detected by patient or physician exam [756-762]. Imaging-detected recurrences are more likely distant. The impact of surveillance on overall survival is not proven in prospective trials, but early detection of asymptomatic recurrence may improve outcomes with effective therapies [17]. Follow-up should be individualized based on risk.
Late Effects Screening
- Lymphedema: Assess for extremity swelling after lymph node dissection; refer to certified lymphedema therapist; consider compressive garments, massage, and exercise. Referral for lymphovascular revascularization for refractory cases.
- Endocrine dysfunction: Monitor for hypothyroidism, adrenal insufficiency, hypophysitis in patients treated with immune checkpoint inhibitors; approximately 15% risk of lifelong endocrine dysfunction. Screening labs as clinically indicated.
- Neurocognitive effects: Patients who received whole brain radiotherapy should be monitored for cognitive decline; consider memantine during/after WBRT [38].
- Second primary cancers: Skin cancer screening; consider cancer surveillance based on germline findings (CDKN2A, BAP1, etc.).
Recurrence Patterns
Recurrence risk is stage-dependent. For stage I–II, recurrences are ~15–20% local/in-transit, ~50% regional nodes, ~29% distant. For stage III, ~50% are distant. Median time to recurrence is shorter with higher stage. Over 95% of recurrences occur within 3 years for stage IIIA/B, and within 2 years for stage IIIC [183]. Late recurrence (>10 years) can occur, especially for early-stage [774-776].
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| COMBI-AD | Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma | 2017 | 870 | Dabrafenib 150 mg BID + trametinib 2 mg QD for 12 months. | Placebo | Resected stage III melanoma with BRAF V600E/K mutation (AJCC 7th ed. IIIA >1 mm, IIIB/C). | Relapse-free survival (RFS) | 3-year RFS 58% vs. 39% (HR 0.47; 95% CI 0.39-0.58; P<.001). 3-year OS 86% vs. 77% (HR 0.57; 95% CI 0.42-0.79; P=.0006, did not cross interim boundary). | Distant metastasis-free survival (HR 0.51; 95% CI 0.40-0.65; nominal P<.001). Grade 3-4 AEs 41% vs. 14%. | Established adjuvant BRAF/MEK inhibition as standard for resected stage III BRAF-mutant melanoma. FDA approved. | N Engl J Med |
| CHECKMATE 238 | Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma | 2017 | 906 | Nivolumab 3 mg/kg Q2W | Ipilimumab 10 mg/kg Q3W x 4 then Q12W | Resected stage IIIB/C or stage IV melanoma (AJCC 7th ed.). | Recurrence-free survival (RFS) | 1-year RFS 71% vs. 61% (HR 0.65; 95% CI 0.51-0.83; P<.001). Grade 3-4 AEs 25% vs. 55%. | DMFS at 1 year: 80% vs. 73% (HR 0.73; 95% CI 0.55-0.95). OS data not mature at initial report. | Nivolumab became preferred adjuvant option due to better safety and efficacy than ipilimumab. FDA approved for resected nodal or metastatic melanoma. | N Engl J Med |
| KEYNOTE-054 | Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma | 2018 | 1019 | Pembrolizumab 200 mg Q3W for up to 1 year | Placebo | Resected stage III melanoma (AJCC 7th ed. IIIA >1 mm, IIIB/C, excluding in-transit). | Recurrence-free survival (RFS) | 1-year RFS 75% vs. 61% (HR 0.57; 95% CI 0.43-0.74; P<.001). Grade 3-4 AEs 32% vs. 19%. | Distant metastasis as first recurrence: HR 0.53; 95% CI 0.37-0.76. OS data not mature. | Established pembrolizumab as adjuvant therapy for resected stage III melanoma. FDA approved for lymph node involvement. | N Engl J Med |
| CHECKMATE 067 | Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma | 2015 | 945 | Nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W x 4, then nivolumab monotherapy | Nivolumab 3 mg/kg Q2W or Ipilimumab 3 mg/kg Q3W x 4 | Previously untreated unresectable stage III or stage IV melanoma. | Progression-free survival (PFS) and overall survival (OS) for nivolumab ± ipilimumab vs. ipilimumab. | Median PFS: combination 11.5 mo, nivolumab 6.9 mo, ipilimumab 2.9 mo. Median OS: combination not reached, nivolumab 36.9 mo, ipilimumab 19.9 mo. 4-year OS: 53%, 46%, 30%. | ORR: 58% vs. 45% vs. 19%. Grade 3-4 AEs: 59% vs. 22% vs. 28%. | Established nivolumab/ipilimumab combination as preferred first-line for many patients due to high response and long-term survival. Nivolumab monotherapy is an alternative for those with contraindications to combination. | N Engl J Med |
| DREAMseq (EA6134) | Combination Dabrafenib and Trametinib versus Combination Nivolumab and Ipilimumab for Advanced BRAF-Mutant Melanoma | 2023 | 265 | Nivolumab/ipilimumab followed by dabrafenib/trametinib at progression (arm A) or reverse sequence (arm B). | Sequence comparison. | Previously untreated unresectable or metastatic BRAF V600-mutant melanoma. | Overall survival (OS) | 2-year OS: arm A 72% vs. arm B 52% (HR 0.53; 95% CI 0.35-0.81). | PFS favored arm A. ORR: combination immunotherapy 46% vs. BRAF/MEK 43%. | Demonstrated superiority of first-line immunotherapy over BRAF/MEK targeted therapy in BRAF-mutant metastatic melanoma. Supports current recommendation for immunotherapy as preferred first-line. | J Clin Oncol |
| NADINA | Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma | 2024 | 423 | Neoadjuvant ipilimumab 80 mg + nivolumab 240 mg Q3W x 2 cycles, then surgery + response-driven adjuvant therapy. | Surgery + adjuvant nivolumab | Resectable stage III melanoma (clinically positive nodes). | Event-free survival (EFS) | 12-month EFS 83.7% vs. 57.2% (P<.01). MPR 59% in neoadjuvant arm. | OS data not mature. Grade 3-4 AEs comparable. | Established neoadjuvant nivolumab/ipilimumab as preferred approach for resectable stage III disease. Category 1 for initial presentation with clinical nodes. | N Engl J Med |
| SWOG S1801 | Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma | 2023 | 313 | Neoadjuvant pembrolizumab 200 mg Q3W x 3 doses, then surgery, then adjuvant pembrolizumab to complete 1 year. | Surgery + adjuvant pembrolizumab (1 year). | Resectable stage III–IV melanoma. | Event-free survival (EFS) | 2-year EFS 72% vs. 49% (P<.01). MPR 53%. | OS data not mature. | Established neoadjuvant pembrolizumab as an option for resectable stage III/IV melanoma. | N Engl J Med |
| CheckMate 204 | Combined Nivolumab and Ipilimumab in Patients with Melanoma and Active Brain Metastases | 2018 | 94 | Nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W x 4, then nivolumab monotherapy. | Single arm | Melanoma with at least one untreated brain metastasis, no prior local therapy for that lesion, asymptomatic. | Intracranial response rate | Intracranial response rate 50% (complete response 16%). Grade 3-4 AEs 55%. | Median PFS not reached. OS not reached. | Demonstrated high intracranial activity of combination immunotherapy. Patients with asymptomatic brain metastases may be treated with upfront systemic therapy. | N Engl J Med |
| COMBI-MB | Dabrafenib plus trametinib in patients with BRAF V600-mutant melanoma brain metastases | 2017 | 125 | Dabrafenib 150 mg BID + trametinib 2 mg QD. | Single arm, four cohorts. | BRAF V600-mutant melanoma with brain metastases (cohort A: asymptomatic, no prior local therapy; cohort B: no prior local therapy, any symptoms; cohort C: prior local therapy, asymptomatic; cohort D: prior local therapy, symptomatic). | Intracranial response rate (cohort A). | Intracranial response: cohort A 58%, cohort B 56%, cohort C 44%, cohort D 59%. Median OS: 10.8, 24.3, 10.2, 11.5 months respectively. | Extracranial response similar. Grade 3-4 AEs ≤60%. | Demonstrated intracranial activity of BRAF/MEK inhibition in patients with brain metastases. | Lancet Oncol |
| KEYNOTE-006 | Pembrolizumab versus Ipilimumab in Advanced Melanoma | 2015 | 834 | Pembrolizumab 10 mg/kg Q2W or Q3W. | Ipilimumab 3 mg/kg Q3W x 4. | Previously untreated or one prior therapy (no prior immune checkpoint inhibitor) advanced melanoma. | Progression-free survival (PFS) and overall survival (OS). | Median OS: pembro (pooled) not reached vs. ipi 16 mo; 2-year OS 55% vs. 43%. PFS improved (HR ~0.57). | ORR 37% vs. 13%. Grade 3-4 AEs 17% vs. 20%. | Established pembrolizumab as superior to ipilimumab in first-line advanced melanoma. Led to FDA approval. | N Engl J Med |
Clinical PearlsClick to collapse
- Pearl 1: Sentinel lymph node biopsy is the most important prognostic tool for clinical stage I/II melanoma; a positive SLN upstages to stage III and is associated with significantly decreased melanoma-specific survival [Montcreif MD, et al. J Clin Oncol 2022;40:3940-3951]. However, SLNB has not been proven to improve RFS or OS, but improves regional nodal control [Crystal JS, et al. JAMA Surg 2022;157:835-842].
- Pearl 2: For thin melanomas (≤0.75 mm), SLNB is not recommended unless there is uncertainty about microstaging or adverse features. The Merlin_001 trial suggests CP-GEP testing may be used in select T1b ± T2a patients for shared decision-making when the true risk is <10% [Hieken TJ, et al. JAMA Surg 2025;160:1358-1366].
- Pearl 3: Adjuvant therapy for stage III melanoma should be considered based on risk of recurrence and toxicity. Both anti-PD-1 agents (nivolumab, pembrolizumab) and BRAF/MEK inhibitors (dabrafenib/trametinib) improve relapse-free survival. The impact on overall survival remains undefined for anti-PD-1 agents; COMBI-AD showed a trend but did not cross interim boundary.
- Pearl 4: For metastatic melanoma, first-line systemic therapy options include combination checkpoint blockade (ipilimumab/nivolumab or nivolumab/relatlimab) or anti-PD-1 monotherapy. BRAF/MEK inhibitors are alternative first-line for BRAF V600-mutant, especially if rapid response needed. DREAMseq trial confirmed superiority of first-line immunotherapy over BRAF/MEK therapy in BRAF-mutant patients [Atkins MB, et al. J Clin Oncol 2023;41:186-197].
- Pearl 5: The role of completion lymph node dissection after positive SLNB is limited. Two prospective trials (MSLT-II, DeCOG-SLT) showed no benefit in melanoma-specific or overall survival. Nodal basin ultrasound surveillance is preferred over CLND for most patients.
- Pearl 6: Neoadjuvant immunotherapy (nivolumab/ipilimumab or pembrolizumab) improves event-free survival compared to adjuvant therapy alone in resectable stage III melanoma. NADINA trial: 12-month EFS 84% vs. 57% with neoadjuvant nivolumab/ipilimumab [Blank CU, et al. N Engl J Med 2024;391:1696-1708]. SWOG 1801: 2-year EFS 72% vs. 49% for neoadjuvant pembrolizumab [Patel SP, et al. N Engl J Med 2023;388:813-823].
- Pearl 7: For patients with brain metastases, nivolumab/ipilimumab combination provides high intracranial response rates (CheckMate 204: 50-57%). BRAF/MEK inhibitors also have intracranial activity (COMBI-MB: 44-58%). Whole brain RT is reserved for palliation when SRS is not feasible.
- Pearl 8: Circulating tumor DNA (ctDNA) is an emerging biomarker for minimal residual disease and response assessment, but its clinical utility is not yet defined. Detectable ctDNA after surgery correlates with worse prognosis in adjuvant trials, but integration into clinical decision-making remains unclear [ME-C 3 of 8].