Melanoma: ABCDEs, Staging, BRAF Testing & Treatment

Melanoma develops when melanocytes, the cells responsible for skin pigmentation, undergo malignant transformation and begin to grow uncontrollably. It most commonly arises on skin that has been exposed to ultraviolet (UV) light, though it can also occur in areas with little sun exposure, under the nails, on mucous membranes, or in the eye (ocular melanoma). Unlike basal cell or squamous cell skin cancers, melanoma has a stronger tendency to spread through the lymphatic system and bloodstream to distant organs such as the lungs, liver, and brain, which is why early detection matters so much.

Melanoma can develop in a pre-existing mole or appear as an entirely new pigmented spot on normal-looking skin. Its appearance varies widely, and not every melanoma is dark or classically mole-like; some are pink, red, or skin-coloured (amelanotic melanoma), which can make them easy to overlook. The disease is staged based on how deeply it has invaded the skin, whether it has ulcerated, and whether it has spread to lymph nodes or beyond.

Rates of melanoma have risen in many parts of the world over recent decades, partly reflecting increased UV exposure and partly improved detection. Despite this, mortality has been falling in many countries, largely due to earlier diagnosis and the introduction of effective systemic therapies for advanced disease over the past 15 years.

Melanoma affects people of all skin tones, although it is more common in people with lighter skin. In people with darker skin, melanoma is often diagnosed at a later stage because it more frequently appears in less commonly examined areas, such as the palms, soles, and under the nails (acral lentiginous melanoma), and clinicians and patients alike may have lower suspicion for it in these locations.

Understanding melanoma's biology, particularly its molecular drivers such as BRAF, NRAS, and NF1 mutations, has been central to developing today's targeted and immune-based treatments, which have changed what an advanced melanoma diagnosis means compared with a generation ago.

A melanoma diagnosis can be frightening, but the implications differ enormously depending on stage. A thin, early-stage melanoma removed with clear margins often requires no further treatment beyond monitoring, while a thicker or more advanced melanoma may need additional surgery, lymph node evaluation, and systemic therapy. Ask your care team to explain your specific Breslow thickness, ulceration status, and any lymph node findings, since these details shape both your treatment plan and your follow-up schedule.

For those with advanced or metastatic melanoma, biomarker testing for BRAF and other mutations, along with the emergence of highly effective immunotherapies, means that meaningful and sometimes durable disease control is achievable for many patients, even though outcomes still vary considerably from person to person.

The most common warning sign of melanoma is a new or changing pigmented spot on the skin. The ABCDE rule is widely used to help identify suspicious lesions: Asymmetry (one half looks different from the other), Border irregularity (ragged or poorly defined edges), Color variation (multiple shades of brown, black, red, white, or blue within one lesion), Diameter greater than about 6 millimetres (roughly the size of a pencil eraser), and Evolving (any change in size, shape, colour, or symptoms such as itching or bleeding over time).

Some melanomas do not fit this pattern; amelanotic melanomas may appear as a pink or reddish bump with little or no pigment, and nodular melanomas can grow rapidly without the typical asymmetric, flat appearance. Melanoma under a nail may look like a dark streak in the nail bed, and melanoma on the sole of the foot or palm can be mistaken for a bruise or callus.

Advanced melanoma that has spread may cause symptoms related to the affected organ, such as swollen lymph nodes, persistent cough or shortness of breath if the lungs are involved, abdominal discomfort if the liver is affected, or headaches and neurological changes if it has spread to the brain. Any new or changing skin lesion, or a mole that itches, bleeds, or fails to heal, should be evaluated by a clinician promptly.

Melanoma develops through the accumulation of genetic changes in melanocytes that disrupt normal controls on cell growth and survival. Ultraviolet radiation, whether from sun exposure or artificial sources such as tanning beds, is the leading cause of these DNA mutations in most melanomas, particularly those on sun-exposed skin. Intense, intermittent sun exposure and a history of severe sunburns, especially during childhood, are strongly linked to increased risk.

At the molecular level, many melanomas are driven by mutations in genes that regulate cell growth signalling, most notably BRAF, which is mutated in roughly 40-50% of cutaneous melanomas, and NRAS, found in a smaller proportion. These mutations cause continuous activation of the MAPK signalling pathway, driving uncontrolled cell division; this discovery directly led to the development of targeted BRAF and MEK inhibitor drugs.

Not all melanomas are UV-related. Acral melanomas (on palms, soles, and nails) and mucosal melanomas typically arise independently of sun exposure and often have a different genetic profile, sometimes involving KIT mutations rather than BRAF. Uveal (eye) melanoma has yet another distinct molecular basis, commonly involving GNAQ or GNA11 mutations, and behaves differently from skin melanoma in terms of how it spreads.

Non-modifiable risk factors for melanoma include fair skin that burns easily, light-coloured eyes and hair, a large number of moles or atypical (dysplastic) moles, a personal or family history of melanoma, inherited mutations such as in the CDKN2A gene, and a weakened immune system, for example due to organ transplantation or certain medical conditions.

Modifiable risk factors centre on UV exposure: excessive sun exposure without protection, a history of blistering sunburns (particularly in childhood or adolescence), and the use of indoor tanning beds, which significantly increase risk, especially when started at a young age.

Older age increases risk, though melanoma is also relatively common among younger adults compared with many other cancers. Living at higher altitudes or closer to the equator, where UV intensity is greater, and having outdoor occupations or hobbies with substantial sun exposure, also contribute to overall risk.

Regular use of broad-spectrum sunscreen, protective clothing, and shade, along with avoiding tanning beds, are the main modifiable steps people can take to reduce their risk, alongside routine skin self-examination and professional skin checks for those at higher risk.

Diagnosis typically begins with a visual and dermoscopic (magnified) examination of a suspicious lesion by a dermatologist, sometimes supported by digital mole-mapping to track changes over time. Any lesion suspicious for melanoma should undergo an excisional biopsy, removing the entire lesion with a narrow margin of normal skin, which allows accurate measurement of tumour thickness and other pathological features.

The pathology report from the biopsy provides key information, including Breslow thickness (depth of invasion in millimetres), presence or absence of ulceration, mitotic rate, and whether the margins are clear. Based on these findings, wider surgical excision is usually performed to remove any remaining microscopic disease with an appropriate margin of healthy skin.

For melanomas above a certain thickness, or with other high-risk features, a sentinel lymph node biopsy is often recommended at the time of wide excision. This procedure identifies and removes the first lymph node(s) that drain the area of the melanoma, to check microscopically for spread; a negative result is reassuring, while a positive result affects staging and may prompt discussion of additional treatment.

If spread beyond the local area is suspected or the melanoma is at higher stage, imaging such as CT, PET-CT, or MRI (including brain MRI) may be used to look for distant metastases and to establish a baseline before starting systemic therapy.

Melanoma staging uses the TNM system, incorporating tumour (T) thickness and ulceration status, node (N) involvement, and metastasis (M) to distant sites, combined into overall stages 0 through IV. Stage 0 (melanoma in situ) is confined to the outermost skin layer, while Stage I and II describe localised melanoma of increasing thickness and risk, without lymph node involvement.

Breslow thickness, measured in millimetres from the top of the skin to the deepest point of tumour invasion, is one of the most important prognostic factors within localised disease; thicker tumours and those with ulceration carry a higher risk of recurrence and spread. Stage III indicates that melanoma has spread to nearby lymph nodes or through in-transit or satellite deposits in the skin near the primary tumour, and is further subdivided based on the number and character of involved nodes.

Stage IV describes melanoma that has spread to distant lymph nodes, skin, or organs such as the lungs, liver, brain, bone, or gastrointestinal tract; blood levels of lactate dehydrogenase (LDH) are also factored into staging, as elevated LDH is associated with a higher disease burden. Staging determines both prognosis and the recommended treatment pathway, from observation after surgery to systemic therapy for higher-risk or advanced disease.

Molecular testing plays a central role once melanoma is diagnosed at a more advanced stage. BRAF mutation testing, most commonly for the BRAF V600E and V600K variants, is standard for anyone with Stage III or IV melanoma, because a positive result opens the option of combined BRAF and MEK inhibitor targeted therapy. Testing is typically performed on tumour tissue using PCR-based assays, immunohistochemistry, or next-generation sequencing (NGS).

Broader NGS panels may also be used to look for other actionable or informative alterations, such as NRAS, KIT (particularly relevant in acral and mucosal melanomas), and NF1 mutations, as well as tumour mutational burden, which can inform likely benefit from immunotherapy. For eye (uveal) melanoma, specific molecular and cytogenetic testing, including for GNAQ/GNA11 mutations and chromosome 3 status, is used to assess prognosis, as this subtype is managed differently from skin melanoma.

Genetic counselling and germline testing for CDKN2A and other hereditary melanoma-predisposition genes may be considered for people with a strong family history of melanoma or multiple primary melanomas, since this can inform surveillance recommendations for the patient and at-risk relatives.

Cutaneous (skin) melanoma is the most common form and includes several histological subtypes. Superficial spreading melanoma is the most frequent type, typically growing outward along the skin surface before invading deeper. Nodular melanoma tends to grow more quickly and vertically into the skin from the outset, often presenting at a more advanced thickness at diagnosis. Lentigo maligna melanoma usually arises on chronically sun-damaged skin, such as the face, in older adults, and tends to grow slowly over years. Acral lentiginous melanoma occurs on the palms, soles, or under the nails, is not strongly linked to UV exposure, and is proportionally more common among people with darker skin tones.

Beyond the skin, melanoma can arise in mucosal surfaces (mucosal melanoma), such as the nasal passages, mouth, or genital tract, which tends to be diagnosed later and behaves more aggressively. Ocular or uveal melanoma develops in the pigmented layers of the eye and has a distinct pattern of spread, most often to the liver, and is managed by specialised ocular oncology teams.

Amelanotic melanoma, which lacks visible pigment and can occur within any of the above subtypes, is worth specific mention because its pink or skin-coloured appearance makes it easy to mistake for a benign lesion, sometimes delaying diagnosis.

Treatment for melanoma is determined largely by stage. For melanoma in situ and thin Stage I-II tumours, wide local excision with an appropriate margin of healthy skin is often the only treatment needed, followed by regular skin surveillance. For thicker localised tumours, sentinel lymph node biopsy is typically performed alongside wide excision to check for microscopic spread.

Stage III melanoma, involving lymph nodes, is generally treated with surgery to remove involved nodes (or, in some cases, active surveillance of the node basin), followed by adjuvant (post-surgical) systemic therapy to reduce the risk of recurrence. Adjuvant options include immunotherapy with checkpoint inhibitors such as anti-PD-1 agents, or, for BRAF-mutant tumours, combined BRAF/MEK inhibitor therapy, both of which have been shown to lower recurrence risk compared with observation alone.

For Stage IV or unresectable melanoma, systemic therapy is the mainstay of treatment. Checkpoint inhibitor immunotherapy, targeting PD-1 and/or CTLA-4, has become a cornerstone of treatment and can produce durable responses in a meaningful proportion of patients. For BRAF-mutant melanoma, combination BRAF and MEK inhibitor targeted therapy offers another effective option, sometimes used before or alongside immunotherapy depending on the clinical situation, disease burden, and how quickly disease control is needed.

Additional treatments for advanced or specific situations include radiotherapy, particularly for brain metastases or symptom control, surgical removal of isolated metastases in select cases, and intralesional or locally directed therapies for in-transit skin metastases. Clinical trials are frequently available and often worth discussing, particularly for melanoma that has progressed after standard treatments, including combinations of immunotherapies or newer cellular therapies such as tumour-infiltrating lymphocyte (TIL) therapy in specialised centres.

Follow-up care after treatment includes regular skin examinations, periodic imaging based on stage and risk, and ongoing sun-safety counselling, since people who have had one melanoma have a higher risk of developing another.

Survival in melanoma is strongly tied to stage at diagnosis. According to population-based data such as SEER statistics, the five-year relative survival for localised melanoma (confined to the skin) is above 99%, reflecting how curable early-stage disease usually is with surgery alone. For melanoma that has spread to regional lymph nodes, five-year relative survival is roughly in the 70-80% range, while for melanoma that has spread to distant organs (metastatic disease), five-year relative survival has historically been much lower, though it has improved substantially, into a range of roughly 30-35% or higher in more recent cohorts, largely due to the impact of modern immunotherapy and targeted therapy.

It is important to understand that these figures are population averages drawn from large groups of patients treated in the past and do not predict what will happen to any one individual; factors such as overall health, specific tumour genetics, response to treatment, and access to newer therapies all influence an individual's outlook. Ongoing improvements in systemic therapy continue to shift these numbers, so it is worth discussing the most current data and how it may apply to your specific situation with your oncology team.