Melanoma — Causes, ABCDE Signs, Staging & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Melanoma is a malignant tumour arising from melanocytes — the pigment-producing cells of the skin — and is the most dangerous form of skin cancer due to its high metastatic potential. While accounting for only 5% of all skin cancers, melanoma causes approximately 75% of skin cancer deaths. It can arise de novo on normal skin (70-80% of cases) or from pre-existing naevi (moles — 20-30%). The most common type, superficial spreading melanoma, initially grows radially in the epidermis before invading vertically into the dermis — at which point metastatic risk increases substantially. Other histological subtypes include nodular melanoma (fast-growing, deeply invasive, often amelanotic — lacks pigment, easily missed), lentigo maligna melanoma (arising in chronically sun-damaged skin in older adults — face, neck), and acral lentiginous melanoma (occurring on the palms, soles, and subungual regions — most common subtype in people of African and Asian ancestry, accounting for 40-60% of melanomas in these groups). Breslow thickness (vertical depth of invasion in millimetres) is the single most important prognostic factor for localised melanoma: tumours below 1 mm have an excellent prognosis (5-year survival above 90%), whereas tumours above 4 mm have a 5-year survival of 60-75% and high nodal metastasis rates. The Clark level system (I-V) assesses anatomical invasion depth. TNM staging (Stage I-IV) guides treatment decisions.

Melanoma results from the malignant transformation of melanocytes, driven by ultraviolet radiation-induced DNA damage, genetic mutations, and impaired tumour surveillance. Ultraviolet radiation: both UVB (290-320 nm — causes direct DNA damage, pyrimidine dimers) and UVA (320-400 nm — generates reactive oxygen species, penetrates deeper into the dermis) cause carcinogenic mutations; cumulative UV exposure and intermittent intense UV exposure (sunburn — especially blistering sunburn in childhood and adolescence) are the primary environmental risk factors; indoor tanning beds (UVA-emitting) increase melanoma risk by 75% with first use before age 35, classified as Group 1 carcinogens by IARC. Genetic factors: BRAF mutation (V600E) — present in 50-60% of melanomas; NRAS mutations in 15-20%; CDK4, CDKN2A (p16), and MC1R variants increase susceptibility; familial melanoma (FAMMM syndrome — familial atypical multiple mole melanoma syndrome) involves CDKN2A germline mutations. Phenotypic risk factors: fair skin (Fitzpatrick types I-II), red or blonde hair, blue or green eyes, tendency to burn, high mole count (>50 common moles or >5 atypical moles/dysplastic naevi), and congenital melanocytic naevi (giant congenital naevi — above 20 cm — carry 5-20% lifetime malignant transformation risk). Immunosuppression: organ transplant recipients and patients on long-term immunosuppressive therapy have 3-5-fold increased risk. Family history of melanoma: first-degree relatives have 2-fold increased risk; CDKN2A gene testing offered in familial cases.

The ABCDE criteria are the primary clinical tool for identifying suspicious pigmented lesions requiring biopsy. A — Asymmetry: one half of the lesion does not mirror the other; benign naevi are typically symmetric. B — Border: irregular, ragged, notched, or blurred margins; benign naevi have smooth, well-defined borders. C — Colour: variation in colour within the same lesion — multiple shades of brown, black, red, white, or blue; benign naevi are uniform. D — Diameter: lesions above 6 mm (the size of a pencil eraser) are more suspicious, though melanomas can be smaller; any growing lesion warrants assessment regardless of size. E — Evolving: any change in a mole — size, shape, colour, elevation — or new symptoms (itching, bleeding, crusting) within weeks to months is a key warning sign. Additional warning signs: the 'ugly duckling' sign — a lesion that looks different from the patient's other moles; a new pigmented lesion in an adult; a bleeding or non-healing pigmented lesion; and subungual melanoma (dark band/streak in a nail plate — Hutchinson's sign — pigmentation extending onto the nail fold). Nodular melanoma is particularly deceptive — it may be flesh-coloured or pink (amelanotic), firm, and raised — growing rapidly over weeks. Ocular melanoma: painless changes in vision, floaters, or photopsia. Metastatic melanoma symptoms: palpable lymph nodes, unexplained weight loss, neurological symptoms (brain metastases — the most common site after lymph nodes).

Dermoscopy (dermatoscopy): handheld 10x magnification with polarised light — significantly improves diagnostic accuracy over naked eye examination (sensitivity 80-90% for experienced dermatologists); characteristic dermoscopic features of melanoma include atypical pigment network, regression structures (white scar-like areas, blue-grey peppering), irregular streaks, atypical dots and globules, and vascular patterns. Excision biopsy: the definitive diagnostic procedure — complete excision of the suspicious lesion with a 2 mm margin is recommended; punch or incision biopsy of part of a lesion is discouraged as it may miss the deepest area (affecting Breslow measurement) and cause false negative results. Histopathological reporting: Breslow thickness, Clark level, ulceration, mitotic rate, lymphovascular invasion, perineural invasion, and surgical margin involvement — all reported by a specialist dermatopathologist. Molecular pathology: BRAF V600E mutation testing by immunohistochemistry and PCR — performed on all metastatic melanomas (guides targeted therapy eligibility); NRAS, c-KIT (acral/mucosal melanoma) testing. Staging investigations for tumours above 1 mm Breslow, ulcerated tumours, or clinical lymphadenopathy: sentinel lymph node biopsy (SLNB — injection of radioactive tracer + blue dye at primary site, intraoperative identification and biopsy of the first draining lymph node); CT of chest, abdomen, pelvis, and brain (or PET-CT); MRI brain for Stage III-IV. TNM staging by AJCC 8th edition (Stages I-IV) determines prognosis and treatment approach.

Surgical treatment is the primary curative modality for localised melanoma. Wide local excision (WLE): re-excision of the primary biopsy site with margins based on Breslow thickness — in situ (0.5 cm), 1 mm Breslow (1 cm margin), 1-2 mm (1-2 cm), above 2 mm (2 cm margin); margins are measured clinically from the scar or residual lesion edge. Sentinel lymph node biopsy (SLNB): standard of care for melanomas above 1 mm Breslow or with high-risk features (ulceration, mitotic rate above 1/mm2) — identifies occult nodal micrometastases; positive SLNB upstages disease to Stage III and informs adjuvant therapy decisions; completion lymph node dissection is no longer routinely performed after positive SLNB (MSLT-II trial). Adjuvant systemic therapy for Stage III resected melanoma: anti-PD-1 immunotherapy (pembrolizumab 200 mg every 3 weeks for 12 months, or nivolumab) significantly reduces relapse risk (55-70% 5-year relapse-free survival with pembrolizumab); for BRAF V600-mutated Stage III disease, targeted therapy doublet (dabrafenib 150 mg BD + trametinib 2 mg daily for 12 months) achieves comparable relapse-free survival benefit. Metastatic melanoma (Stage IV): PD-1 inhibitor monotherapy or combination immunotherapy (nivolumab + ipilimumab — CTLA-4 inhibitor) produces durable complete responses in 20-30% of patients (5-year overall survival 52% with combination); BRAF V600-mutated metastatic melanoma: BRAF inhibitor + MEK inhibitor combinations (vemurafenib + cobimetinib, dabrafenib + trametinib, encorafenib + binimetinib) produce rapid responses (up to 80%) but frequently relapse within 12-18 months; treatment of brain metastases with stereotactic radiosurgery, or whole brain radiation; anti-LAG-3 (relatlimab) combinations in clinical use.

Melanoma causes serious complications both from the malignancy itself and from treatment. Metastatic spread: melanoma is highly aggressive — it preferentially metastasises to regional lymph nodes, then to distant sites including lung, liver, brain, bone, and small intestine; brain metastases develop in up to 40-50% of patients with Stage IV disease, causing neurological deficits, seizures, headaches, and significantly worsening prognosis; adrenal metastases and GI metastases (causing haemorrhage and obstruction) are other serious complications. Surgical complications: wide local excision may cause chronic lymphoedema (particularly after inguinal lymph node dissection — present in 20-40%), wound infection, and seroma formation; amputation is occasionally required for advanced acral melanoma. Immunotherapy complications (immune-related adverse events — irAEs): anti-PD-1 and CTLA-4 inhibitors cause immune-mediated toxicities — colitis (diarrhoea, perforation — Grade 3-4 in 10-15% with combination therapy), hepatitis, pneumonitis, endocrinopathies (hypophysitis, thyroiditis, adrenal insufficiency, T1 diabetes), dermatitis, nephritis; irAEs can be life-threatening and require high-dose corticosteroids or immunosuppression. BRAF/MEK inhibitor complications: cutaneous toxicity (photosensitivity, keratoacanthomas, squamous cell carcinoma induction — from paradoxical MAPK pathway activation in BRAF wild-type keratinocytes), pyrexia, cardiac QT prolongation, retinal vein occlusion. Psychological complications: melanoma diagnosis causes significant anxiety, depression, and fear of recurrence — surveillance is lifelong.

Sun protection is the most effective primary prevention strategy for melanoma. Avoid peak UV hours (10am-4pm); use broad-spectrum (UVA and UVB) sunscreen SPF 30-50 on all exposed areas, reapplying every 2 hours and after swimming; wear UV-protective clothing (UPF 50+), wide-brimmed hats, and UV-blocking sunglasses; never use indoor tanning beds. Vitamin D and sun avoidance: studies confirm that sensible photoprotection does not significantly impair vitamin D production — oral supplementation (800-1000 IU daily) is preferable to UV exposure for vitamin D in melanoma survivors. Skin surveillance: whole-body skin self-examination monthly — use mirrors for back and scalp; the 'ABCDE' mnemonic guides what to look for; partner or healthcare provider assistance for areas not easily self-examined. Total-body photography (TBP) and sequential digital dermoscopy imaging (SDDI): performed at specialist mole clinics for patients with high naevus counts or dysplastic naevi — allows objective monitoring of change over time. High-risk individuals (CDKN2A carriers, FAMMM syndrome, >100 moles, previous melanoma): annual or 6-monthly specialist dermatology surveillance; CDKN2A genetic testing and counselling at specialist familial melanoma clinics. After melanoma treatment: follow-up as per stage — Stage I: 6-monthly for 3 years then annual; Stage II-III: 3-monthly for 3 years, 6-monthly for 2 years then annual; skin self-examination and monthly self-lymph node examination.

See a GP or dermatologist urgently (within 2 weeks — NICE 2-week-wait urgent referral) for any pigmented lesion with ABCDE features: asymmetry, irregular borders, colour variation, diameter above 6 mm, or evolution (any change in size, shape, or colour, or new symptoms including bleeding, itching, or crusting). Seek same-day emergency assessment for: rapidly enlarging or bleeding pigmented lesion that is clinically suspected to be nodular melanoma; new or rapidly worsening neurological symptoms (focal weakness, seizures, headaches) in a person with known metastatic melanoma — possible brain metastases requiring urgent imaging and dexamethasone. Also seek urgent medical review for: a dark streak (melanonychia) in a nail bed that is expanding or involves the nail fold (Hutchinson's sign — possible subungual melanoma); any new pigmented lesion in a person with a personal or family history of melanoma; suspicious skin lesion in an immunosuppressed patient (transplant recipients, HIV) — melanoma may be more aggressive in immunosuppression. Do not delay seeking assessment — early-stage melanoma is highly curable with surgery alone, while delayed diagnosis allows progression to metastatic disease with substantially worse outcomes. A GP can refer urgently to a skin cancer multidisciplinary team under the urgent suspected cancer pathway.