Definition and epidemiology
Melanoma is a malignant tumor derived from melanocytes, the pigment-producing cells of the skin. Although it can arise in other locations (eyes, mucous membranes, meninges), over 90% of melanomas are cutaneous.
Melanoma accounts for approximately 5% of all skin cancers but is responsible for the vast majority of skin cancer-related deaths due to its propensity for early metastasis. Incidence has been rising globally, particularly in fair-skinned populations. In the United States, lifetime risk is approximately 1 in 50 for whites, with much lower rates in darker-skinned populations.
The median age at diagnosis is approximately 65 years, though melanoma can occur at any age and is one of the most common cancers in young adults aged 25-29. There is a slight male predominance overall, though young women have higher incidence rates before age 50. Five-year survival exceeds 95% for localized disease but drops dramatically with regional or distant metastasis.
- ABCDE criteria: Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolution — most testable clinical features
- Breslow depth (tumor thickness in mm) is the single most important prognostic factor
- Sentinel lymph node biopsy indicated for melanomas ≥0.8 mm thickness to stage regional disease
- Wide local excision margins: 0.5-1 cm for in situ, 1 cm for ≤1 mm, 1-2 cm for 1-2 mm, 2 cm for >2 mm depth
- BRAF V600E mutation present in ~40-50% of melanomas; allows targeted therapy with BRAF/MEK inhibitor combinations
- Acral lentiginous melanoma is most common type in dark-skinned populations; look for Hutchinson sign (nail fold pigmentation)
- Nodular melanoma lacks radial growth phase, presents in vertical growth phase with worse prognosis
- First-line therapy for metastatic melanoma: anti-PD-1 immunotherapy (pembrolizumab, nivolumab) or BRAF/MEK inhibitors if BRAF-mutant
Etiology and risk factors
The primary environmental risk factor is ultraviolet (UV) radiation exposure, particularly intense intermittent sun exposure and history of sunburns, especially in childhood. Chronic cumulative sun exposure is more associated with lentigo maligna melanoma subtype.
Major risk factors
- Fair skin, light hair, blue/green eyes: Fitzpatrick skin types I-II have substantially elevated risk
- Personal history of melanoma: 5-10% lifetime risk of developing a second primary melanoma
- Family history: Approximately 10% of cases are familial; risk increases 2-3 fold with one affected first-degree relative
- Dysplastic nevus syndrome: Multiple atypical nevi significantly increase risk
- Large congenital nevi: Particularly those >20 cm (giant congenital nevi)
- Immunosuppression: Organ transplant recipients, HIV/AIDS, immunosuppressive medications
- History of non-melanoma skin cancer: Indicates high cumulative UV damage
- Xeroderma pigmentosum: Rare autosomal recessive disorder with defective DNA repair
Genetic factors
Approximately 10% of melanomas are familial. The most important susceptibility genes are CDKN2A (encodes p16, a tumor suppressor) and CDK4. Familial cases tend to occur at younger ages and may be associated with multiple primary melanomas. BRAF mutations (particularly V600E) are present in approximately 40-50% of melanomas and are important for targeted therapy, though they are somatic rather than germline mutations.
Pathophysiology
Melanoma arises from malignant transformation of melanocytes. The disease progresses through distinct phases in many cases:
Radial growth phase
Melanoma cells proliferate horizontally within the epidermis and papillary dermis with minimal invasion. These lesions have low metastatic potential.
Vertical growth phase
The tumor invades deeper into the dermis with formation of nodules and acquisition of metastatic capability. This phase correlates with worsening prognosis.
Molecular pathways
The MAPK pathway is central to melanoma pathogenesis. BRAF mutations (most commonly V600E) lead to constitutive activation of this proliferative signaling cascade. Other important mutations involve NRAS, NF1, and KIT. Loss of tumor suppressor function (CDKN2A/p16, PTEN) also contributes to melanomagenesis.
UV radiation causes characteristic DNA damage (C→T transitions at dipyrimidine sites), which accumulates over time. Melanomas in sun-protected sites have different mutational profiles and may arise through alternative pathways.
Metastatic cascade
Melanoma has high metastatic potential due to its neural crest origin and ability to undergo epithelial-mesenchymal transition. Initial spread is typically via lymphatics to regional lymph nodes, followed by hematogenous dissemination. Common distant metastatic sites include skin/subcutaneous tissue, lungs, liver, brain, and bone.
Clinical features
The ABCDE criteria are the most widely used clinical tool for identifying suspicious pigmented lesions:
- Asymmetry: One half does not match the other
- Border irregularity: Edges are ragged, notched, or blurred
- Color variation: Multiple colors (brown, black, tan, red, white, blue)
- Diameter: Greater than 6 mm (pencil eraser size), though melanomas can be smaller
- Evolution: Change in size, shape, color, elevation, or new symptoms (itching, bleeding)
Clinical subtypes
Superficial spreading melanoma (70% of cases): Most common type, typically on trunk in men and legs in women. Appears as a slowly enlarging, irregularly bordered, variegated pigmented macule or plaque.
Nodular melanoma (15-20%): Rapidly growing, often amelanotic (lacking pigment) or darkly pigmented nodule. Lacks a radial growth phase and presents in vertical growth phase, conferring worse prognosis.
Lentigo maligna melanoma (10-15%): Occurs on chronically sun-damaged skin, especially face and neck in elderly patients. Arises from lentigo maligna (in situ) over years to decades.
Acral lentiginous melanoma (5-10%): Most common type in darker-skinned populations. Occurs on palms, soles, or subungual regions. Often presents as a pigmented streak in the nail (longitudinal melanonychia) with proximal nail fold pigmentation (Hutchinson sign).
Warning signs
- New pigmented lesion in adults over age 40
- "Ugly duckling" sign: lesion that looks different from patient's other nevi
- Bleeding, ulceration, or crusting
- Satellite lesions around the primary tumor
- Regional lymphadenopathy
Diagnosis
Clinical examination
Thorough full-body skin examination including scalp, mucous membranes, palms, soles, and nail beds. Dermoscopy improves diagnostic accuracy in trained hands.
Biopsy
Excisional biopsy with narrow margins (1-3 mm) is the gold standard for suspected melanoma. The entire lesion should be removed when feasible to allow accurate histologic assessment of depth and margins. Incisional or punch biopsy may be appropriate for very large lesions or anatomically sensitive areas, but should sample the thickest portion.
Shave biopsies should be avoided as they may transect the tumor and prevent accurate Breslow depth measurement.
Histopathology
Key features reported include:
- Breslow depth: Measured in millimeters from the granular layer to the deepest tumor cell; the most important prognostic factor
- Ulceration: Presence indicates worse prognosis and upstages the tumor
- Mitotic rate: Number of mitoses per mm²
- Margins: Distance of tumor from excision edges
- Clark level: Anatomic level of invasion (largely superseded by Breslow depth)
- Lymphovascular invasion: Associated with increased metastatic risk
Staging workup
For in situ melanoma: No further workup required.
For invasive melanoma, staging depends on Breslow depth and clinical findings:
- Sentinel lymph node biopsy (SLNB): Recommended for melanomas ≥0.8 mm or T1b tumors with high-risk features. Identifies occult nodal metastases and guides adjuvant therapy.
- Imaging: Not routinely indicated for thin melanomas. For stage IIB and higher, consider CT chest/abdomen/pelvis and brain MRI to detect distant metastases.
- LDH: Elevated in many patients with distant metastatic disease
Staging (AJCC 8th edition)
Staging is based on T (tumor thickness and ulceration), N (nodal involvement), M (distant metastasis) classification. Key thresholds: <1 mm, 1-2 mm, 2-4 mm, >4 mm Breslow depth. Stage 0 is in situ; Stage I-II is localized disease; Stage III involves regional lymph nodes; Stage IV is distant metastasis.
Differential diagnosis
Benign pigmented lesions
- Seborrheic keratosis: Stuck-on appearance, warty surface, keratin pearls
- Benign nevus: Symmetric, uniform color, regular borders, stable over time
- Solar lentigo: Flat, uniform tan-brown macule on sun-exposed areas in older adults
- Dermatofibroma: Firm nodule with dimple sign, often on lower legs
Other malignancies
- Basal cell carcinoma (pigmented variant): Pearly, rolled borders, telangiectasias
- Squamous cell carcinoma: Hyperkeratotic, scaly, often on sun-damaged skin
- Merkel cell carcinoma: Rapidly growing red-violet nodule
- Cutaneous metastases: From other primary tumors
Vascular lesions
- Angiokeratoma: Dark papule with vascular component
- Thrombosed hemangioma: Can mimic nodular melanoma
- Pyogenic granuloma: Rapidly growing friable red nodule
Other
- Subungual hematoma: History of trauma, grows out with nail (unlike acral melanoma)
- Blue nevus: Deep dermal melanocytes, stable blue-gray papule
- Atypical nevus: May meet some ABCDE criteria but clinically stable; biopsy if uncertain
When in doubt, biopsy is essential as clinical diagnosis alone has limited sensitivity and specificity.
Management
Surgical management
Wide local excision (WLE) is the definitive treatment for primary melanoma. Surgical margins depend on Breslow depth:
- In situ: 0.5-1 cm margins
- ≤1 mm: 1 cm margins
- 1-2 mm: 1-2 cm margins
- >2 mm: 2 cm margins
Margins are measured clinically from the edge of the lesion (or biopsy scar). Excision should extend to fascia or deeper as needed.
Sentinel lymph node biopsy should be performed at the time of WLE for appropriate candidates to stage regional disease. If positive, completion lymph node dissection is no longer routinely recommended based on recent trials (MSLT-II, DeCOG-SLT); observation with close surveillance is preferred unless there are palpable nodes or high tumor burden.
Adjuvant therapy
For stage III (node-positive) and resected stage IV melanoma, adjuvant systemic therapy reduces recurrence risk:
- Anti-PD-1 immunotherapy: Nivolumab or pembrolizumab
- Targeted therapy: Dabrafenib plus trametinib for BRAF V600-mutant melanomas
Current guidelines favor adjuvant therapy for stage III disease; decisions for high-risk stage II are evolving.
Advanced/metastatic disease
Immunotherapy is first-line for most patients:
- Anti-PD-1 monotherapy: Pembrolizumab or nivolumab
- Combination immunotherapy: Nivolumab plus ipilimumab (anti-CTLA-4) for higher response rates but increased toxicity
Targeted therapy for BRAF V600-mutant melanomas:
- BRAF inhibitor plus MEK inhibitor: Combinations such as dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib
- Rapid responses but eventual resistance; may be preferred for symptomatic disease needing quick response
Other treatments:
- Intralesional talimogene laherparepvec (T-VEC) for injectable lesions
- Radiation therapy for brain metastases, symptomatic bone lesions, or adjuvant treatment for high-risk resected disease
- Surgery for oligometastatic disease in selected patients
Surveillance
Post-treatment follow-up includes:
- Regular skin examinations: Self-exams monthly, clinical exams every 3-6 months for 2 years, then every 6-12 months
- Regional nodal basin examination
- Imaging for stage IIB and higher: frequency depends on stage and risk
- Patient education on sun protection and self-monitoring
Complications and prognosis
Prognosis
Prognosis depends primarily on Breslow depth and presence of metastases. Five-year survival rates approximately:
- Stage 0 (in situ): >99%
- Stage I (thin, localized): 95-99%
- Stage II (thicker, localized): 65-95%
- Stage III (regional nodes): 40-70%
- Stage IV (distant metastases): 10-30%, though improving with modern immunotherapy
Adverse prognostic factors include increased Breslow depth, ulceration, high mitotic rate, lymphovascular invasion, satellitosis, nodal involvement, elevated LDH, and visceral metastases (especially brain).
Complications
Local recurrence: May occur near the excision site; requires re-excision and restaging.
In-transit metastases: Cutaneous or subcutaneous metastases between primary site and regional nodes, indicating lymphatic spread.
Distant metastases: Melanoma can metastasize to virtually any organ. Common sites include:
- Skin, subcutaneous tissue, and distant lymph nodes (most common)
- Lungs
- Liver
- Brain (often multiple lesions)
- Bone
- Gastrointestinal tract
Treatment-related complications:
- Surgery: Wound complications, lymphedema (after lymph node dissection)
- Immunotherapy: Immune-related adverse events (colitis, pneumonitis, hepatitis, hypophysitis, thyroiditis, dermatitis)
- Targeted therapy: Rash, photosensitivity, arthralgias, pyrexia, fatigue
Prevention
Primary prevention focuses on UV protection: sunscreen (SPF ≥30, broad-spectrum), protective clothing, avoiding tanning beds, and minimizing midday sun exposure. Regular skin self-examination and clinical screening for high-risk individuals enable early detection when cure rates are highest.
ABCDE: Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolution
Practice questions
1. A 58-year-old fair-skinned man presents with a 1.2 cm pigmented lesion on his upper back that has grown over the past 8 months. The lesion is asymmetric with irregular, notched borders and variation in color from tan to dark brown to black. Excisional biopsy reveals melanoma with Breslow depth of 1.8 mm and no ulceration. Sentinel lymph node biopsy is negative. What is the most appropriate next step in management?
2. A 45-year-old woman with a history of stage IIIC melanoma (three positive lymph nodes) resected 6 months ago presents for follow-up. She completed adjuvant pembrolizumab. On examination, a new 8 mm firm subcutaneous nodule is palpated 5 cm proximal to the original excision site on her thigh. Biopsy confirms melanoma. Staging CT and brain MRI show no distant metastases. What is the most appropriate management?
3. A 72-year-old Black man presents with a 2-year history of a dark streak in his right thumbnail that has widened and now involves the proximal nail fold. The streak measures 4 mm wide and extends the full length of the nail. Pigmentation is also present on the adjacent proximal nail fold skin. What is the most likely diagnosis and appropriate next step?
Frequently asked questions
What causes melanoma?
The primary cause is ultraviolet (UV) radiation exposure, particularly intense intermittent sun exposure and history of sunburns. Major risk factors include fair skin, family or personal history of melanoma, dysplastic or large congenital nevi, immunosuppression, and genetic mutations such as CDKN2A. Approximately 40-50% of melanomas have BRAF mutations (typically V600E), which drive tumor growth through the MAPK pathway.
What are the first symptoms of melanoma?
Melanoma typically presents as a changing pigmented lesion. The ABCDE criteria capture key features: asymmetry, irregular borders, color variation, diameter greater than 6mm, and evolution (change over time). Patients may notice a new mole in adulthood, or an existing mole changing in size, shape, or color. Warning symptoms include itching, bleeding, ulceration, or a lesion that looks different from other moles (ugly duckling sign).
How is melanoma diagnosed?
Diagnosis is made by excisional biopsy with narrow margins, removing the entire suspicious lesion when possible. Histopathology confirms melanoma and reports critical prognostic factors including Breslow depth (thickness), ulceration, and mitotic rate. Sentinel lymph node biopsy is then performed for tumors ≥0.8 mm to detect regional spread. Staging workup with imaging (CT, MRI) is reserved for thicker melanomas or those with high-risk features to identify distant metastases.
Is melanoma curable?
Yes, melanoma is highly curable when detected early. Thin, localized melanomas (stage I) have over 95% five-year survival with surgical excision alone. However, prognosis worsens significantly with deeper invasion and metastasis. Even advanced melanoma has become more treatable with modern immunotherapy and targeted therapies, though cure rates are much lower for stage IV disease. Early detection through skin self-examination and prompt biopsy of suspicious lesions is critical.
Melanoma vs dysplastic nevus — what is the difference?
Dysplastic (atypical) nevi are benign but have irregular features that may clinically resemble melanoma, including asymmetry, border irregularity, and color variation. Key differences: dysplastic nevi are generally stable over time, while melanoma evolves; histologically, dysplastic nevi show architectural disorder and cytologic atypia but lack invasion beyond the dermoepidermal junction. Multiple dysplastic nevi increase melanoma risk 10-fold, requiring close surveillance. When clinical distinction is uncertain, biopsy is mandatory.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: C43.9
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.