Melanoma

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Melanoma arises from melanocytes in skin and less commonly mucosal, acral and ocular sites. Superficial spreading melanoma often shows radial evolution before invasion; nodular melanoma grows vertically early and can be symmetric and amelanotic. Lentigo-maligna melanoma develops on chronically sun-damaged skin, while acral melanoma occurs on palms, soles and nail units across all skin tones. Visual heuristics aid recognition but dermoscopy and histology establish diagnosis.

Initial biopsy quality determines staging. Complete narrow excision preserves the entire lesion and avoids transection. Breslow thickness and ulceration define T category and guide definitive margin and sentinel-node discussion. Sentinel biopsy samples the first draining basin from an otherwise node-negative melanoma, detecting microscopic stage III disease. A positive sentinel node no longer mandates routine completion dissection because ultrasound surveillance provides regional monitoring with less lymphoedema.

Wide excision treats the primary field. Stage-based imaging looks for regional and distant disease and BRAF testing identifies targeted options. Adjuvant anti-PD-1 therapy reduces recurrence for eligible high-risk resected melanoma, while dabrafenib–trametinib is an option for qualifying BRAF V600-mutated disease. The absolute relapse reduction is weighed against immune toxicity or chronic targeted adverse effects in a patient with no visible cancer.

Metastatic therapy has transformed prognosis but requires urgent toxicity recognition. Combination ipilimumab–nivolumab may improve control at the cost of more severe immune effects. BRAF–MEK treatment often shrinks disease rapidly but resistance can emerge. Surgery, stereotactic radiation and systemic therapy cooperate for brain and oligometastatic disease. Endocrine failure from immunotherapy may be permanent even after cancer control and needs lifelong replacement.

Key points

Use ABCDE for asymmetry, border, colour, diameter and evolution, plus the ugly-duckling sign; for nodular lesions remember elevated, firm and growing because colour may be absent.
First-line specialist assessment combines full-skin and regional-node examination with dermoscopy and comparison with photographs where available.
The diagnostic reference standard for a lesion suspicious for melanoma is full-thickness complete excision with a narrow approximately 2 mm clinical margin and a cuff of subcutaneous fat.
Avoid superficial shave, curettage, cautery or destructive treatment because they can transect the lesion and prevent accurate Breslow measurement; incisional biopsy is reserved for anatomically difficult large lesions after specialist planning.
Pathology must report Breslow thickness, ulceration, mitotic and histological features, microsatellites and peripheral and deep margins; Breslow is measured from the granular layer or ulcer base to deepest invasion.
Definitive wide local excision margin is stage and thickness based: usually 0.5 cm for in-situ disease, 1 cm for stage I and 2 cm for stage II melanoma under NICE guidance.
Offer sentinel-node biopsy for eligible melanoma over 1 mm and consider it for selected 0.8 to 1 mm lesions with adverse features; it is staging and prognostic, not direct treatment of distant micrometastases.
Do not perform routine completion lymph-node dissection solely for a positive sentinel node; use nodal-basin ultrasound surveillance and adjuvant-treatment assessment.
Stage IIB, IIC, III and resected IV disease may qualify for adjuvant anti-PD-1 or BRAF–MEK treatment according to stage, BRAF status and current NICE approval.
Advanced treatment uses single or combined checkpoint blockade or BRAF–MEK inhibition for a BRAF V600 tumour, selected by tempo, symptoms, brain disease, comorbidity and need for rapid response.
A rapidly progressive symptomatic BRAF-mutated cancer may respond quickly to targeted therapy, while immunotherapy can produce longer treatment-free control; sequencing is a specialist decision.
Routine brain and body imaging is stage based rather than used for every thin melanoma; new neurological or systemic symptoms override the surveillance calendar.
Teach monthly skin and node self-examination, sun protection without vitamin-D neglect and lifelong prompt assessment of changing lesions and treatment toxicity.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Ultraviolet radiation

Intermittent intense sun exposure, sunburn and tanning devices create DNA photoproducts, with pattern and cumulative dose differing across melanoma subtype and body site.

Naevus and phenotype burden

Numerous common or atypical naevi, fair sun-sensitive skin, freckling, red hair and personal melanoma history increase risk and complicate surveillance.

Inherited susceptibility

Familial variants involving CDKN2A, CDK4, BAP1 and other pathways cause a minority of cases and can confer pancreatic, ocular or other tumour risk.

Immune and site-specific factors

Transplant immune suppression increases risk, while acral, mucosal and uveal melanomas have less ultraviolet association and distinct genomic drivers.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Melanocytes acquire proliferative drivers
BRAF, NRAS, NF1, KIT and other alterations activate MAPK and cell-survival signalling, with driver distribution varying by cutaneous, acral and mucosal site.
2
Radial growth precedes invasion
Many superficial-spreading and lentigo-maligna melanomas extend within epidermis before dermal invasion, while nodular melanoma enters vertical growth early.
3
Breslow depth reflects metastatic access
Increasing vertical thickness exposes more lymphatic and vascular channels, making depth, ulceration and mitotic biology central to nodal and distant risk.
4
Regional spread uses skin lymphatics
Cells reach sentinel nodes or form microsatellite and in-transit deposits between primary and nodal basin before lung, liver, brain, bone and other systemic spread.
5
Immune evasion is therapeutically reversible
PD-1 and CTLA-4 signalling suppress antitumour lymphocytes; checkpoint blockade can restore durable control but can also inflame any normal organ.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Superficial spreading pattern

An enlarging asymmetric macule or plaque with irregular border and multiple colours is the classic changing pigmented melanoma presentation.

Nodular or amelanotic pattern

A new elevated firm continuously growing pink, red, blue or black nodule can be melanoma despite lacking ABCDE asymmetry.

Lentigo and acral pattern

Slow change on sun-damaged face or an expanding palm, sole or nail-unit lesion requires site-specific dermoscopic expertise.

Regional recurrence

Scar pigmentation, dermal nodules between scar and nodes or a hard basin node suggests local, in-transit or nodal spread.

Distant metastatic diseaseRed flag

Headache, seizure, cough, liver symptoms, bone pain, bowel bleeding or multiple subcutaneous nodules can reveal systemic melanoma.

Immune toxicityRed flag

Diarrhoea, dyspnoea, chest pain, jaundice, weakness, severe headache or confusion during or after checkpoint therapy needs same-day assessment.

Red flags requiring action

A changing asymmetric lesion with irregular border, colour variation, increasing diameter or evolution requires urgent dermoscopic assessment.
A new firm rapidly enlarging, elevated or persistently growing pink, red, blue or black nodule may be nodular or amelanotic melanoma.
A pigmented streak with nail dystrophy, periungual pigment or an enlarging acral lesion requires specialist assessment across all skin tones.
A hard regional node, in-transit skin nodule or new scar-site pigmentation suggests regional recurrence and requires imaging and tissue.
Headache, seizure, focal deficit, severe back pain, weakness or sphincter change raises brain or spinal metastatic disease.
New diarrhoea, dyspnoea, chest pain, weakness, confusion or endocrine symptoms during checkpoint therapy requires urgent immune-toxicity assessment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line dermoscopic full-skin assessmentFirst stepFirst line
Why
Identify malignant structures, compare the lesion with the patient’s naevus pattern and examine regional nodes and entire skin.
Interpretation and limitations
Dermoscopy improves diagnostic accuracy but does not replace histology; document dimensions and images and urgently excise a concerning evolving lesion.
02
Reference full-thickness excision biopsy
Why
Provide the complete lesion for accurate Breslow, ulceration, subtype and margin assessment.
Interpretation and limitations
Use a narrow approximately 2 mm clinical margin and include subcutaneous fat; specialist incisional biopsy is acceptable when complete excision would be anatomically harmful.
03
Definitive melanoma pathologyDefinitive
Why
Determine Breslow thickness, ulceration, mitoses, microsatellites, histological type and margin status.
Interpretation and limitations
A transected deep margin can underestimate depth and stage; expert review is appropriate for spitzoid, desmoplastic, acral, mucosal and uncertain lesions.
04
Sentinel lymph-node biopsy
Why
Detect microscopic regional stage III disease in an otherwise clinically and radiologically negative basin.
Interpretation and limitations
Offer or consider according to thickness and adverse features and perform with wide excision; explain prognostic information, false-negative risk, lymphoedema and treatment implications.
05
Stage-directed CT or PET-CT and brain MRI
Why
Assess nodal, lung, liver, bone, brain and other metastatic sites in higher-stage or symptomatic disease.
Interpretation and limitations
Thin low-risk melanoma does not need routine body imaging; confirm an isolated management-changing lesion when feasible and use MRI for neurological symptoms.
06
BRAF and other molecular testing
Why
Identify V600-targeted options in high-risk resected or advanced cutaneous melanoma and relevant drivers in rarer sites.
Interpretation and limitations
Test adequate viable tumour with a validated assay; a BRAF result informs systemic choice but does not diagnose melanoma or replace histology.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Benign melanocytic naevus

Stable symmetrical naevi show organised dermoscopic patterns, but an ugly-duckling lesion or documented evolution warrants excision rather than reassurance from familiarity.

Seborrhoeic keratosis

A waxy stuck-on lesion with milia-like cysts can be heavily pigmented or irritated; atypical dermoscopy or change requires biopsy.

Pigmented basal-cell carcinoma

Blue-grey nests, arborising vessels and ulceration can mimic melanoma and require histology because excision margins and nodal risk differ.

Dermatofibroma or vascular lesion

Firm dimpling lesions, thrombosed angioma and pyogenic granuloma may be dark or rapidly growing; amelanotic melanoma remains an important mimic.

Subungual haemorrhage or infection

Trauma pigment normally grows distally with nail, while longitudinal melanonychia, nail destruction or periungual spread warrants nail-unit expertise and biopsy.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspicious lesionExcise narrowly for diagnosisFirst stepA pigmented or non-pigmented lesion is changing, ugly-duckling, elevated, firm or persistently growing.

1Take evolution, sun, immune, personal and family history and perform dermoscopic full-skin and nodal examination with photographs and measurements.
2Arrange urgent full-thickness complete excision with an approximately 2 mm clinical margin, using specialist incisional sampling only when site or size makes complete excision harmful.
3DefinitiveObtain expert pathology with Breslow and ulceration and refer confirmed melanoma for definitive margin, sentinel and staging decisions.

02Primary treatmentUse Breslow and stage for margin and sentinel planningDiagnostic histology confirms invasive cutaneous melanoma without clinical nodal disease.

1Review Breslow, ulceration, mitotic and subtype features and examine nodal basins, arranging stage-appropriate imaging before surgery when indicated.
2Perform wide local excision with the NICE stage-based margin and offer or consider sentinel-node biopsy for eligible thickness and risk at the same operation.
3Discuss final pathological stage in the melanoma MDT and select surveillance alone or adjuvant anti-PD-1 or BRAF–MEK treatment within the current indication.

03Positive sentinelSurveil the basin and assess adjuvant therapySentinel-node histology shows microscopic melanoma but there is no clinically bulky nodal disease.

1Complete stage-appropriate body and brain imaging and review primary and sentinel burden, BRAF status, comorbidity and recurrence risk.
2Use regular expert ultrasound of the nodal basin rather than automatic completion lymph-node dissection, reserving surgery for selected clinically evident disease.
3Offer eligible adjuvant systemic treatment after absolute-benefit, immune or targeted-toxicity and patient-preference discussion.

04Advanced diseaseChoose immune or targeted sequence by clinical needUnresectable stage III or distant metastatic melanoma is confirmed.

1Biopsy an accessible site, obtain BRAF status and complete CT or PET-CT and brain MRI, recording symptoms, LDH, tempo, steroid need, autoimmune and transplant context.
2Choose single or combined checkpoint blockade or BRAF–MEK treatment within current approval, using surgery or stereotactic radiation for selected brain or oligometastatic sites.
3Reassess response and every organ system early, distinguish pseudoprogression from true growth carefully and stop or treat significant immune or targeted toxicity promptly.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Blocks PD-1 to restore antitumour T-cell activity and reduce recurrence after high-risk resection or control unresectable and metastatic melanoma.

Pembrolizumab

Give pembrolizumab 200 mg intravenously every 3 weeks or 400 mg every 6 weeks for the licensed adjuvant or advanced melanoma indication, continuing to the protocol duration or stopping for progression or unacceptable toxicity.

Assess transplant and autoimmune context and monitor lung, bowel, liver, endocrine, kidney, heart, skin and nervous system during and after treatment; some endocrine injury needs permanent replacement.

Combines BRAF and MEK inhibition for rapid pathway suppression and reduces resistance compared with BRAF inhibition alone.

Dabrafenib with trametinib

Give dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily on an empty stomach within the licensed BRAF V600-mutated adjuvant or advanced melanoma indication.

Manage pyrexia with prompt interruption and protocol restart; monitor cardiac function, blood pressure, liver, eye, skin, glucose and interactions and confirm pregnancy avoidance.

Suppresses damaging checkpoint-induced inflammation while specialist organ and oncology teams determine second-line immunosuppression and rechallenge safety.

Prednisolone for significant immune toxicity

For many grade 2 to 3 immune toxicities, start prednisolone 0.5 to 1 mg/kg orally daily or intravenous methylprednisolone 1 to 2 mg/kg for severe disease, then taper over at least 4 to 6 weeks to the organ protocol.

Exclude and treat infection concurrently, use urgent high-dose protocols for myocarditis or neurological disease, provide gastric, bone and infection protection as indicated and avoid abrupt withdrawal.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Local and in-transit recurrence

Melanoma can recur in scar, adjacent lymphatics or dermal deposits before the regional basin, requiring complete skin and nodal restaging.

Regional nodal disease

Sentinel or clinically apparent nodal metastasis raises systemic relapse risk and can cause pain, compression and lymphoedema.

Distant organ metastasis

Lung, liver, brain, bone, bowel and subcutaneous metastases cause neurological emergencies, bleeding, obstruction, pain and organ failure.

Immune-treatment toxicity

Checkpoint blockade can produce colitis, hepatitis, pneumonitis, myocarditis, endocrine failure, nephritis and neurological syndromes during or after treatment.

Targeted-treatment toxicity

BRAF and MEK inhibition causes fever, rash, cardiac dysfunction, ocular injury, liver abnormalities and secondary skin lesions requiring structured monitoring.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

After excision, review wound, final Breslow, ulceration, margins, sentinel eligibility and stage rather than waiting for a routine skin appointment.
Use stage-based skin, scar and nodal examination and nodal-basin ultrasound where indicated, with imaging frequency matched to recurrence risk.
Teach monthly full-skin, scar and node self-examination and urgent review of a changing lesion, new lump or neurological and systemic symptom.
During checkpoint therapy, ask about every organ system and check protocol blood counts, renal, liver, thyroid and endocrine tests during and after treatment.
During BRAF–MEK therapy, track fever, rash, blood pressure, cardiac ejection fraction, eye symptoms, liver tests, glucose and new skin lesions.
For brain metastasis, monitor steroid need, seizure, cognition and MRI response and coordinate systemic treatment with stereotactic or surgical care.
Support sun protection, vitamin-D assessment, anxiety, body image and family-risk counselling without discouraging normal outdoor activity.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Nodular melanoma breaks ABCDE

It may be round, uniform and amelanotic, so persistent elevation, firmness and growth are essential additional warning features.

Breslow needs an intact deep edge

A superficial transected shave can make the most important T-stage measurement impossible and create uncertainty in sentinel and margin planning.

Sentinel biopsy stages rather than cures

Its main value is identifying microscopic stage III and adjuvant eligibility; removal of one node is not treatment of occult systemic disease.

Positive sentinel no longer means clearance

Expert ultrasound surveillance detects nodal progression with less lymphoedema than routine completion dissection in most patients.

Targeted therapy can be fast

BRAF–MEK inhibition may be valuable when symptomatic disease needs rapid shrinkage, while immune therapy may yield more durable treatment-free control.

Immune toxicity can be delayed

Endocrine, neurological and other inflammation may begin after checkpoint treatment stops, so survivorship teams need the treatment history.

11Common pitfallsFrequent interpretation and management errors.

01
Using ABCDE alone and missing a rapidly growing symmetric amelanotic nodule.
02
Shaving, curetting or cauterising a suspected melanoma and losing accurate Breslow depth.
03
Performing a wide definitive excision before sentinel drainage can be mapped.
04
Ordering routine whole-body scans for every thin low-risk melanoma.
05
Describing sentinel-node biopsy as therapeutic removal of all metastatic risk.
06
Performing completion nodal dissection automatically after a positive sentinel node.
07
Starting BRAF-targeted treatment without a validated V600 result.
08
Continuing checkpoint therapy through significant diarrhoea, dyspnoea, chest pain or neurological symptoms without urgent review.
09
Stopping corticosteroid rapidly after immune toxicity and causing rebound inflammation.
10
Limiting examination to the index scar and missing the remaining skin and nodal basins.