Melanoma — Symptoms, Causes & Treatment | MyMedicPlus

Melanoma is a malignant tumour arising from melanocytes — the pigment-producing cells located primarily in the basal layer of the epidermis but also in the uveal tract of the eye and mucous membranes. Although melanoma accounts for only 4% of all skin cancers by incidence, it is responsible for approximately 75% of skin cancer deaths — making it the most dangerous of all skin cancers and one of the most lethal solid tumours in young adults. Approximately 325,000 new cases are diagnosed worldwide each year; incidence has been rising by approximately 3% annually in most countries. It is most common in Australia and New Zealand (highest rates globally), Northern Europe, and North America — populations with high UV exposure and predominantly fair skin. Melanoma can occur at any age but is one of the most common cancers in people aged 20-40 years. When diagnosed at Stage I (localised, thin tumour) the 5-year survival rate exceeds 98%; Stage IV melanoma (metastatic) previously carried a median survival of 6-9 months but has been transformed by immunotherapy and targeted therapy — current 5-year survival for Stage IV is approximately 50% with combination immunotherapy. The four main subtypes are: superficial spreading melanoma (70% of cases, radial growth phase allows time for early detection); nodular melanoma (15-20%, aggressive vertical growth phase, highest risk of rapid progression); lentigo maligna melanoma (elderly, sun-damaged facial skin); and acral lentiginous melanoma (palms, soles, subungual — most common subtype in Black and Asian populations).

UV radiation is the primary causative factor for the majority of melanomas — both from natural sunlight and from artificial tanning beds. UV radiation causes thymine dimer formation in melanocyte DNA, leading to characteristic C→T substitutions and somatic mutations in oncogenes. BRAF (particularly V600E mutation) is the most common driver mutation — present in approximately 50% of melanomas — followed by NRAS (20%), NF1 (15%), and KIT mutations (particularly in acral and mucosal melanomas). Established risk factors: UV exposure history — intermittent intense UV exposure (sunburn) is more strongly associated with melanoma than cumulative chronic exposure; a single blistering sunburn in childhood doubles lifetime melanoma risk; indoor tanning bed use before age 35 increases melanoma risk by 59-75% (IARC Group 1 carcinogen). Phenotypic risk factors: fair skin (Fitzpatrick I-II), red or blonde hair, blue or green eyes, tendency to freckle, and inability to tan — all markers of reduced melanin photoprotection. Number of melanocytic naevi (moles): 50-100 common naevi confers 5-6x increased risk relative to fewer than 15 naevi; 5 or more atypical (dysplastic) naevi substantially raises risk. Familial melanoma (10%): CDKN2A (p16/p14ARF) mutation — autosomal dominant, confers 70-90% lifetime melanoma risk and 17x pancreatic cancer risk; CDK4 mutations; BAP1 germline mutations (uveal melanoma, mesothelioma, renal cell carcinoma). Personal history of prior melanoma increases risk of subsequent primary melanoma 4-9x. Immunosuppression: organ transplant recipients and HIV patients have significantly elevated melanoma risk from reduced immune surveillance. Congenital giant melanocytic naevus (CGMN) above 20cm carries a 5-15% lifetime melanoma risk. Xeroderma pigmentosum — rare nucleotide excision repair deficiency causing extreme UV sensitivity and very high melanoma risk.

The ABCDE criteria provide the standard clinical screening tool for identifying melanoma in pigmented skin lesions: Asymmetry (one half does not mirror the other); Border (irregular, scalloped, or notched borders rather than smooth); Colour (multiple colours within a single lesion — brown, black, red, white, and blue — representing different depths of melanin and regression); Diameter (above 6mm — though all melanomas start small, and the EFG criteria: Elevated, Firm, Growing, apply to nodular melanoma which may be smaller); Evolution (change in size, shape, colour, elevation, or new symptoms — bleeding, itching, crusting — is the most sensitive indicator of malignancy, as any changing pigmented lesion warrants evaluation). Specific subtypes: superficial spreading melanoma — begins as a flat or slightly raised, variably pigmented macular lesion with irregular borders, enlarging slowly for months to years before vertical invasive growth; nodular melanoma — presents as a rapidly growing, raised, darkly pigmented (occasionally amelanotic — pink or flesh-coloured) nodule that bleeds easily on trauma — disproportionately responsible for melanoma deaths due to rapid thickness increase; lentigo maligna melanoma — a large (often 3-15cm), flat, irregularly pigmented macule on chronically sun-damaged skin (face, neck) of elderly patients, with slow growth over years; acral lentiginous melanoma — pigmented lesion on the palm, sole, or subungual region (under or around the nail — nail streak, longitudinal melanonychia, Hutchinson's sign [periungual pigmentation extending onto the nail fold]). Ocular melanoma (uveal melanoma): visual field changes, floaters, or asymptomatic, detected by ophthalmoscopy — unrelated to sun exposure; driven by GNAQ/GNA11 mutations rather than BRAF. Metastatic melanoma: regional lymph node swelling, distant lesions (skin, subcutaneous nodules), dyspnoea from pulmonary metastases, headache and neurological symptoms from brain metastases.

Clinical assessment using ABCDE criteria and dermoscopy (dermatoscopy) — a handheld illuminated magnifying device that visualises subsurface structures invisible to the naked eye, significantly improving diagnostic accuracy (improving sensitivity from 71% to 90% and specificity from 81% to 90% for melanoma vs benign lesions). Dermoscopic features of melanoma include atypical pigment network, regression structures (white scar-like areas, peppering), blue-white veil, atypical vascular patterns, and peripheral black dots. Artificial intelligence (AI) dermoscopy algorithms (FDA cleared) achieve dermatologist-level accuracy and are increasingly used in primary care screening. Any lesion with dermoscopic or clinical features suspicious for melanoma requires urgent excision biopsy: complete excisional biopsy with 2mm clinical margins (do not shave or punch biopsy a suspected melanoma — complete architecture is required for accurate Breslow thickness measurement). Histopathological diagnosis and staging: Breslow thickness (measured in mm from the granular layer to the deepest invasive melanocyte — the single most important prognostic factor); Clark level (I-V — depth of invasion into skin layers); ulceration; mitotic rate; microsatellites; lymphovascular invasion. AJCC/UICC 8th edition TNM staging: Stage I (below 2mm, no ulceration) — 5-year survival above 90%; Stage II (above 2mm or ulcerated); Stage III (regional lymph node or in-transit metastases); Stage IV (distant metastases). Sentinel lymph node biopsy (SLNB): indicated for melanomas above 0.8mm Breslow thickness — identifies microscopic regional lymph node metastases (positive SLN predicts 3-4x higher distant metastasis risk) and guides adjuvant therapy decisions. Molecular testing: BRAF V600 mutation testing in Stage III-IV melanoma (targeted therapy eligibility — cobimetinib, dabrafenib/trametinib); NRAS, KIT, NTRK, NF1 mutation panel for advanced disease. Imaging for Stage III-IV: CT of chest, abdomen, pelvis; PET-CT for metastatic survey; brain MRI for symptomatic patients or Stage IV disease.

Surgery is the primary treatment for localised melanoma. Wide local excision (WLE) with safety margins based on Breslow thickness: 1cm margin for melanomas below 2mm; 2cm margin for melanomas above 2mm — achieves cure in Stage I-II disease. SLNB is performed concurrently with WLE for melanomas above 0.8mm to assess regional lymph node status. Completion lymph node dissection (CLND) following positive SLNB — now largely replaced by adjuvant systemic therapy based on MSLT-II trial data showing no survival advantage of CLND over observation plus adjuvant treatment. Adjuvant therapy for Stage III (resected regional node metastases) and high-risk Stage II melanoma: pembrolizumab (Keytruda — anti-PD-1 checkpoint inhibitor) reduces recurrence risk by 35% and is NICE-approved for SLNB-positive Stage III and Stage IIB-C; nivolumab (anti-PD-1) provides equivalent benefit. Targeted adjuvant therapy: dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) for BRAF V600-mutated Stage III melanoma — reduces recurrence by 53% vs placebo (COMBI-AD trial). Advanced/metastatic melanoma (Stage IV): Immunotherapy is the standard of care — pembrolizumab monotherapy or nivolumab plus ipilimumab (anti-CTLA-4) combination immunotherapy; nivolumab plus ipilimumab (CheckMate 067 trial) achieves 5-year overall survival of 52% vs 26% for single-agent ipilimumab — transformative improvement from historical 6-9 month median survival; immune-related adverse events (colitis, hepatitis, pneumonitis, endocrinopathies) require immunosuppressive management. BRAF/MEK-targeted therapy for BRAF V600E-mutated metastatic melanoma: dabrafenib plus trametinib or encorafenib plus binimetinib achieve rapid response rates of 60-70% with PFS of 14-15 months; relapse is universal from acquired resistance; used as alternative to immunotherapy where rapid disease control is needed. Radiotherapy: stereotactic radiosurgery (SRS) for brain metastases; palliative radiotherapy for bone or skin metastases; whole brain radiotherapy largely replaced by SRS. Talimogene laherparepvec (T-VEC — intralesional oncolytic herpes simplex virus) for injectable Stage III-IV skin and nodal metastases. Isolated limb perfusion/infusion (ILI/ILP) for unresectable in-transit metastases confined to a limb — melphalan-based chemotherapy with high local response rates.

Locoregional recurrence: in-transit metastases — satellite tumours in the dermal lymphatics between the primary and the regional lymph node basin, presenting as multiple pigmented or pink skin nodules between the primary scar and regional nodes — occur in 5-15% of patients with thick or ulcerated primary tumours and are difficult to treat. Immunotherapy toxicities (immune-related adverse events — irAEs) are a major complication of checkpoint inhibitor treatment: colitis (most common — presenting as diarrhoea; grade 3-4 colitis requires IV methylprednisolone, infliximab if steroid-refractory); immune hepatitis (transaminase elevation — managed with corticosteroids and mycophenolate if refractory); pneumonitis (dyspnoea, cough, bilateral infiltrates — may be life-threatening); endocrinopathies (hypophysitis causing hypopituitarism requiring lifelong hormone replacement; thyroiditis — hyperthyroidism then hypothyroidism; adrenalitis — adrenal insufficiency requiring lifelong hydrocortisone); skin toxicities (rash, vitiligo — a positive prognostic sign); and nephritis. Approximately 15-20% of patients on nivolumab plus ipilimumab develop severe (grade 3-4) irAEs requiring treatment discontinuation. Brain metastases develop in 40-50% of patients with Stage IV melanoma — causing neurological deficits, headache, seizures, and personality change; treated with SRS (Gamma Knife, CyberKnife) or neurosurgical resection for accessible large solitary metastases. Long-term psychological morbidity: anxiety and depression are prevalent in melanoma survivors, driven by fear of recurrence (particularly at skin self-examination), physical effects of surgery (scarring, lymphedema from node dissection), and treatment toxicities.

Sun protection is the most important primary preventive measure — given UV radiation is the dominant cause of melanoma in fair-skinned populations. Comprehensive sun protection includes: broad-spectrum SPF 50+ sunscreen applied 20-30 minutes before sun exposure and reapplied every 2 hours and after swimming (SPF 30 reduces UV exposure by 97%, SPF 50 by 98%); protective clothing (UPF 50+ rated clothing, wide-brimmed hats, UV-blocking sunglasses); seeking shade between 11am and 3pm (peak UV hours); avoiding intentional tanning and completely avoiding sunbeds — even one indoor tanning session increases melanoma risk by 20%. Public health campaigns promoting these behaviours in Australia have contributed to a plateau in melanoma incidence trends. Skin self-examination (SSE): monthly full-body skin self-examination using mirrors to visualise all skin surfaces — including scalp, soles, between toes, genitalia, and nails — allows early detection; any new, changing, or suspicious pigmented lesion should be reviewed by a dermatologist promptly. Annual professional skin examination by a dermatologist or trained GP is recommended for: personal history of melanoma; family history of melanoma (especially with CDKN2A mutation); large numbers of melanocytic naevi (above 50 common naevi or any atypical naevi); Fitzpatrick skin types I-II; and a history of significant sunburn or indoor tanning. Genetic counselling and CDKN2A testing for families with 3 or more first or second-degree relatives with melanoma. Total-body photography and sequential digital dermoscopy monitoring enable early detection of change in high-risk individuals. Chemoprevention: high-dose niacinamide (vitamin B3 — 500mg twice daily) reduces new non-melanoma skin cancer incidence by 23% (PKUASTR trial); potential melanoma prevention data are not yet confirmed.

Seek urgent evaluation within 2 weeks (UK 2-week wait pathway, or equivalent in your country) for any pigmented or skin lesion that: has changed in size, shape, or colour recently; has irregular borders, multiple colours, or is larger than 6mm; bleeds, itches, or crusts repeatedly without trauma; or is new and growing in an adult over 40. Do not adopt a 'wait and see' approach for any suspicious mole or lesion — melanoma detected at Stage I has over 98% 5-year survival; Stage IV has 50%. See your GP to arrange an urgent dermatology referral for: any ABCDE-positive pigmented lesion; a new non-healing pink raised nodule (amelanotic nodular melanoma — may not be pigmented); a longitudinal nail streak (longitudinal melanonychia) — particularly if associated with periungual pigmentation (Hutchinson's sign); any lesion on the palm, sole, or beneath a nail that has changed appearance. Go to A&E immediately for: any neurological symptoms (headache, confusion, weakness, vision changes) in a known melanoma patient — brain metastases; signs of severe immunotherapy toxicity (watery diarrhoea more than 7 times daily, severe abdominal pain, respiratory distress, chest pain — requires emergency immunosuppressive treatment). All melanoma patients on immunotherapy should be educated about irAE symptoms and instructed to seek immediate review for any new systemic symptoms during treatment.