Overview
Malignant Melanoma
1. Clinical Overview
Summary
Malignant melanoma is a malignant tumour arising from melanocytes. Although it accounts for only 4% of skin cancers, it is responsible for 80% of skin cancer deaths due to its high metastatic potential. Early detection and excision are curative, but advanced disease requires systemic therapy. The advent of immunotherapy and targeted therapy has revolutionised outcomes in metastatic melanoma. [1,2]
Key Facts
- Incidence: Highest in Australia/New Zealand (approximately 50/100,000). Increasing globally. [3]
- Mortality: 1.5 per 100,000 in UK; 2.3 per 100,000 in Australia.
- Risk Factors: UV exposure (intermittent burning), fair skin, multiple naevi, family history.
- Prognosis: Stage-dependent. 5-year survival: Stage I (98%), Stage II (80-90%), Stage III (45-70%), Stage IV (10-25%). [4]
- The Clock is Ticking: Breslow thickness (depth in mm) is the most important prognostic factor. Every week of delay increases depth.
- Immunotherapy Revolution: Checkpoint inhibitors have transformed Stage IV 5-year survival from 5% to 50%.
Clinical Pearls
The ABCDE Rule: Asymmetry, Border irregularity, Colour variation, Diameter greater than 6mm, Evolution (changing). But beware - nodular melanoma often fails ABCDE (symmetric, regular, uniform).
The "Ugly Duckling" Sign: A lesion that looks different from all other moles on that patient. Often more useful than ABCDE in clinical practice.
Amelanotic Melanoma: 5% of melanomas have no pigment. These present as pink/red nodules and are frequently misdiagnosed. Have high index of suspicion for any persistent nodule.
Nail Melanoma (Subungual): Hutchinson's sign (pigmentation extending to nail fold) is concerning for melanoma. Do not ignore new longitudinal melanonychia, especially if greater than 3mm width.
2. Epidemiology
Incidence and Demographics
- Global: Over 300,000 new cases annually worldwide. [5]
- Highest Rates: Australia (54/100,000), New Zealand (52/100,000).
- UK: Approximately 16,000 new cases/year; fifth most common cancer.
- USA: Approximately 100,000 new cases/year.
- Rising Incidence: Doubled every 10-20 years in fair-skinned populations.
- Sex Distribution: Male more than female in older age groups; equal in younger.
- Age: Peak incidence 50-60 years; but common in young adults aged 25-49 years.
Risk Factors with Relative Risk
| Risk Factor | Relative Risk | Notes |
|---|---|---|
| Previous melanoma | 10x | Highest risk; annual surveillance |
| Giant congenital naevus | 5-15% lifetime | Greater than 20cm diameter |
| Family history (FAMMM) | 10-70x | Familial atypical mole melanoma syndrome |
| Multiple dysplastic naevi (greater than 10) | 10-15x | Atypical mole syndrome |
| Fair skin, red hair | 2-4x | Fitzpatrick type I/II |
| High naevi count (greater than 100) | 7x | Phenotypic marker of risk |
| Intermittent intense UV | 2x | Blistering sunburns in childhood |
| Immunosuppression | 3-8x | Transplant recipients, HIV |
| Xeroderma pigmentosum | 1000x | DNA repair defect |
| CDKN2A mutation | 60-90% lifetime | High-penetrance gene |
Geographic and Ethnic Variation
- Caucasians: Highest incidence (UV susceptibility).
- African/Asian Skin: Lower incidence but acral and mucosal melanoma proportionally more common.
- Acral Melanoma: Makes up 50-70% of melanomas in dark-skinned populations.
3. Pathophysiology
Step 1: Melanocyte Biology
- Melanocytes: Neural crest-derived cells residing in basal epidermis.
- Function: Produce melanin (photoprotection); transfer to keratinocytes.
- Normal Control: Tight regulation by keratinocytes and microenvironment.
Step 2: Initiating Genetic Events
- UV Radiation: Causes DNA damage (cyclobutane pyrimidine dimers).
- Key Mutations:
- BRAF V600E (50%): Constitutive activation of MAPK pathway.
- NRAS (20%): Mutually exclusive with BRAF.
- NF1 (14%): Negative regulator of RAS.
- KIT (10-15%): Acral and mucosal melanoma.
- CDKN2A (30-40% familial): Cell cycle control loss.
Step 3: Radial Growth Phase
- Early Melanoma: Intraepidermal spread (melanoma in situ).
- Behaviour: Slow lateral growth; low metastatic potential.
- Duration: May persist for months to years.
Step 4: Vertical Growth Phase
- Invasion: Penetration through basement membrane into dermis.
- Behaviour: Acquisition of metastatic competence.
- Critical Threshold: Once in dermis, lymphatic and vascular spread possible.
Step 5: Metastatic Cascade
- Local Spread: Satellite lesions (within 2cm of primary), in-transit metastases (between primary and nodes).
- Lymphatic Spread: Regional lymph nodes (predictable by primary site).
- Haematogenous Spread: Skin, lung, liver, brain, bone (no organ sanctuary).
Melanoma Subtypes
| Subtype | Frequency | Clinical Features | Prognosis |
|---|---|---|---|
| Superficial Spreading | 70% | Irregular border, colour variation, horizontal growth | Best (if caught early) |
| Nodular | 15-20% | Rapidly growing nodule, may be amelanotic | Worst (vertical from start) |
| Lentigo Maligna | 5-10% | Elderly face, slow-growing macule on sun-damaged skin | Good if excised before invasion |
| Acral Lentiginous | 5% (higher in dark skin) | Palms, soles, nail bed | Intermediate; often late diagnosis |
| Desmoplastic | less than 1% | Amelanotic, neurotropic, locally aggressive | High local recurrence |
4. Clinical Presentation
The ABCDE Rule
| Criterion | Description | Example |
|---|---|---|
| A - Asymmetry | One half unlike the other | Irregular shape |
| B - Border | Irregular, ragged, blurred edges | Notched margins |
| C - Colour | Uneven distribution; multiple colours | Brown, black, red, white, blue |
| D - Diameter | Greater than 6mm (pencil eraser size) | Though small melanomas exist |
| E - Evolving | Change in size, shape, colour, or symptoms | New bleeding, itching |
Beyond ABCDE - The Expanded Glasgow Criteria
Major Criteria (2 points each)
Minor Criteria (1 point each)
Score 3 or more: Refer urgently (2-week wait).
Atypical Presentations
Nodular Melanoma Trap: Often symmetric, uniform colour, less than 6mm. Look for "EFG" (Elevated, Firm, Growing for more than 1 month).
Symptoms and Signs
| Feature | Significance |
|---|---|
| Changing mole | Most important warning sign |
| New pigmented lesion after age 40 | Higher suspicion required |
| Bleeding/ulceration | Suggests advanced lesion |
| Satellite lesions | Local spread |
| Lymphadenopathy | Regional metastasis |
| Constitutional symptoms | Systemic metastasis |
Red Flags - "The Don't Miss" Signs
- Any mole that is changing (size, shape, colour).
- New mole in patient over 40 (unusual to develop new naevi).
- Persistent pink nodule (amelanotic melanoma).
- Pigmented streak in nail (subungual melanoma).
- "Ugly duckling" (mole that stands out from others).
- Non-healing lesion after 3 weeks.
- Pigmented lesion with surrounding satellite nodules.
Change in size
Common presentation.
Change in colour
Common presentation.
Change in shape
Common presentation.
5. Clinical Examination
Systematic Skin Examination
Full Body Skin Check
- Good lighting essential.
- Examine ALL skin including scalp, ears, between toes, soles, genitalia.
- Use dermatoscope if trained.
- Document with photography (clinical and dermoscopic).
Dermoscopy (Dermatoscopy)
Key Dermoscopic Features of Melanoma
| Feature | Description | Significance |
|---|---|---|
| Atypical pigment network | Irregular, thick lines | Loss of normal architecture |
| Blue-white veil | Blue-grey structureless area | Deep melanin/fibrosis |
| Irregular dots/globules | Asymmetrically distributed | Abnormal nests |
| Pseudopods | Finger-like projections at edge | Radial growth |
| Regression structures | White scar-like areas | Immune response |
| Atypical vessels | Dotted, linear-irregular, polymorphous | Neoangiogenesis |
Seven-Point Checklist (Weighted)
| Major (2 points) | Minor (1 point) |
|---|---|
| Atypical pigment network | Irregular streaks |
| Blue-white veil | Irregular dots/globules |
| Atypical vascular pattern | Regression |
Score 3 or more: Excision recommended.
Staging Examination
- Primary Site: Size, location, ulceration, satellites.
- Regional Nodes: Palpate drainage basins.
- Systemic Review: Weight loss, dyspnoea, neurological symptoms.
6. Investigations
Initial Biopsy
Excision Biopsy (Gold Standard)
- Complete removal with 2mm clinical margin.
- Include full thickness skin (need Breslow measurement).
- Punch Biopsy: Only if excision impractical (face, acral sites); must sample deepest area.
- NEVER Shave Biopsy: Precludes accurate Breslow depth.
Histopathology Report - Essential Elements
| Element | Significance |
|---|---|
| Breslow Thickness | Depth in mm - most important prognostic factor |
| Clark Level | Anatomical level (less used now) |
| Ulceration | Worsens prognosis within each T stage |
| Mitotic Rate | Greater than 1/mm² worsens prognosis |
| Microsatellites | Intralymphatic spread |
| Regression | Immune response (debated prognostic value) |
| TILs | Tumour-infiltrating lymphocytes (favourable if brisk) |
| Margins | Peripheral and deep clearance |
AJCC Staging (8th Edition)
T Staging (Breslow Depth)
| T Stage | Breslow | Ulceration | Notes |
|---|---|---|---|
| Tis | In situ | - | Melanoma in situ |
| T1a | less than 0.8mm | No | Excellent prognosis |
| T1b | less than 0.8mm with ulceration OR 0.8-1.0mm | Any | Consider SLNB |
| T2a | Greater than 1.0-2.0mm | No | SLNB recommended |
| T2b | Greater than 1.0-2.0mm | Yes | Higher risk |
| T3a | Greater than 2.0-4.0mm | No | High risk |
| T3b | Greater than 2.0-4.0mm | Yes | High risk |
| T4a | Greater than 4.0mm | No | Very high risk |
| T4b | Greater than 4.0mm | Yes | Worst primary tumour |
Staging Investigations
Sentinel Lymph Node Biopsy (SLNB)
- Indication: Breslow greater than 0.8mm OR less than 0.8mm with ulceration or mitoses.
- Technique: Lymphoscintigraphy, blue dye, gamma probe.
- Purpose: Staging (prognosis); does not improve survival (MSLT-I). [6]
Imaging for Staging
- Stage I-II No Nodes: No routine imaging unless symptoms.
- Stage IIC/III: CT CAP or PET-CT.
- Stage IV: PET-CT, MRI brain.
Molecular Testing
- BRAF Mutation: Essential in Stage III/IV (guides targeted therapy).
- NRAS, KIT: If BRAF wild-type.
7. Management
Management Algorithm
PIGMENTED LESION SUSPICIOUS FOR MELANOMA
↓
┌─────────────────────────────────────────────┐
│ EXCISION BIOPSY (2mm margin) │
│ - Full thickness │
│ - Histopathological analysis │
└─────────────────────────────────────────────┘
↓
MELANOMA CONFIRMED
↓
Breslow Thickness Assessment
↓
┌────────────────┴────────────────┐
↓ ↓
In Situ Invasive Melanoma
↓ ↓
WLE (5mm margin) ┌─────────────┴─────────────┐
↓ ↓
Breslow less than 0.8mm Breslow greater than 0.8mm
No ulceration OR ulceration
↓ ↓
WLE 1cm margin WLE + SLNB
↓
┌─────────────────┴─────────────────┐
↓ ↓
SLNB Negative SLNB Positive
↓ ↓
Surveillance MDT Discussion
↓
┌─────────────────────────────┐
│ - Completion lymphadenectomy│
│ (selected cases) │
│ - Adjuvant immunotherapy │
│ - Adjuvant BRAF/MEK │
│ (if BRAF mutant) │
└─────────────────────────────┘
Surgical Excision Margins (NICE Guidelines)
| Breslow Thickness | Excision Margin |
|---|---|
| In situ | 5mm |
| Less than 1mm | 1cm |
| 1-2mm | 1-2cm |
| Greater than 2mm | 2cm |
| Greater than 4mm | 2-3cm |
Sentinel Lymph Node Biopsy
- Indication: Greater than or equal to 0.8mm, or less than 0.8mm with adverse features.
- Positive Node Management:
- Completion lymph node dissection: Declining role (DeCOG-SLT, MSLT-II trials).
- Adjuvant systemic therapy: Now standard of care.
- Ultrasound surveillance: Alternative to completion dissection.
Adjuvant Therapy (Stage IIB-III)
Immunotherapy
- Pembrolizumab: Anti-PD-1. Improves RFS in Stage III. [7]
- Nivolumab: Anti-PD-1. Improves RFS in Stage III/IV resected.
- Duration: 12 months.
Targeted Therapy (BRAF Mutant Only)
- Dabrafenib + Trametinib: BRAF/MEK inhibitor combination.
- Evidence: COMBI-AD trial shows RFS benefit. [8]
Metastatic Disease (Stage IV)
First-Line Immunotherapy
- Nivolumab + Ipilimumab: Highest response rates (approximately 58%). [9]
- Pembrolizumab Monotherapy: For lower fitness/toxicity concern.
- Nivolumab Monotherapy: Alternative.
Targeted Therapy (BRAF Mutant)
- Dabrafenib + Trametinib: Rapid response, but resistance develops.
- Encorafenib + Binimetinib: Alternative combination.
- Sequencing: Often immunotherapy first, targeted for rapid progression.
Radiotherapy
- Brain metastases (stereotactic radiosurgery).
- Palliation of symptomatic sites.
8. Complications
Disease-Related Complications
| Complication | Incidence | Management |
|---|---|---|
| Local recurrence | 3-10% | Re-excision if possible |
| In-transit metastases | 5-8% | Isolated limb perfusion, T-VEC, systemic therapy |
| Lymph node metastases | 15-20% | Dissection, systemic therapy |
| Distant metastases | Stage-dependent | Systemic therapy |
| Brain metastases | 20-50% in Stage IV | SRS, immunotherapy |
Treatment-Related Complications
Immunotherapy Adverse Events
| System | Examples | Management |
|---|---|---|
| Skin | Rash, vitiligo, pruritus | Topical steroids, antihistamines |
| GI | Colitis (diarrhoea) | Hold therapy, steroids |
| Endocrine | Thyroiditis, hypophysitis, adrenalitis | Hormone replacement |
| Hepatic | Immune hepatitis | Steroids |
| Pulmonary | Pneumonitis | Steroids, discontinue |
| Cardiac | Myocarditis (rare, serious) | High-dose steroids, ICU |
Targeted Therapy Adverse Events
- Pyrexia (dabrafenib).
- Photosensitivity.
- Arthralgias.
- Cardiac (QT prolongation).
- Secondary cutaneous malignancies (SCC).
9. Prognosis and Outcomes
Survival by Stage (AJCC 8th Edition)
| Stage | 5-Year Survival | 10-Year Survival |
|---|---|---|
| IA | 99% | 98% |
| IB | 97% | 94% |
| IIA | 94% | 88% |
| IIB | 87% | 82% |
| IIC | 82% | 75% |
| IIIA | 93% | 88% |
| IIIB | 83% | 77% |
| IIIC | 69% | 60% |
| IIID | 32% | 24% |
| IV | 10-25% (pre-IO) | - |
Prognostic Factors
Favourable
- Low Breslow thickness.
- No ulceration.
- Low mitotic rate.
- SLNB negative.
- Brisk TILs.
- Female sex.
- Trunk/extremity (vs head/neck).
Unfavourable
- High Breslow thickness.
- Ulceration.
- High mitotic rate.
- SLNB positive.
- Male sex.
- Head/neck primary.
- Elevated LDH (Stage IV).
- Wild-type BRAF (less targeted options).
Surveillance Protocols
| Stage | Frequency | Duration |
|---|---|---|
| Stage I | Every 6-12 months | 5 years |
| Stage II | Every 3-6 months | 5 years, then annually |
| Stage III | Every 3 months years 1-2, then 6 monthly | 10 years |
| Stage IV | Per oncology protocol | Ongoing |
10. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| NICE NG14 | UK | 2-week referral, imaging guidelines, SLNB criteria |
| ESMO Guidelines | European | Adjuvant IO for Stage III, surveillance protocols |
| NCCN Guidelines | USA | Comprehensive staging and treatment algorithms |
| AJCC Staging | International | TNM staging, prognostic factors |
Landmark Trials
1. MSLT-I Trial 2014 [6]
- Question: Does SLNB improve survival?
- N: 1,269 patients with intermediate thickness melanoma.
- Result: SLNB provides accurate staging but no overall survival benefit.
- Impact: SLNB for staging not therapeutic intent.
- PMID: 24553149.
2. MSLT-II Trial 2017 [11]
- Question: Completion dissection vs observation for positive SLNB?
- N: 1,934 patients.
- Result: No survival benefit from completion dissection.
- Impact: Observation with ultrasound now acceptable.
- PMID: 28552318.
3. KEYNOTE-054 Trial 2018 [7]
- Question: Adjuvant pembrolizumab for Stage III?
- N: 1,019 patients.
- Result: RFS 75% vs 61% at 1 year (HR 0.57).
- Impact: Established adjuvant immunotherapy as standard.
- PMID: 29658430.
4. CheckMate 067 Trial 2015 [9]
- Question: Ipilimumab + Nivolumab vs monotherapy in Stage IV?
- N: 945 patients.
- Result: Combination ORR 58%, 5-year OS 52%.
- Impact: Transformed metastatic melanoma outcomes.
- PMID: 26027431.
5. COMBI-AD Trial 2017 [8]
- Question: Adjuvant dabrafenib + trametinib for BRAF-mutant Stage III?
- N: 870 patients.
- Result: RFS 67% vs 44% at 3 years (HR 0.47).
- Impact: Option for BRAF-mutant patients.
- PMID: 29028924.
11. Patient and Layperson Explanation
What is Melanoma?
Melanoma is a type of skin cancer that develops from the cells that give your skin its colour (melanocytes). Although it is less common than other skin cancers, melanoma is more dangerous because it can spread to other parts of the body.
What Causes It?
- UV Exposure: Sunburn and intense sun exposure, especially in childhood.
- Fair Skin: People with pale skin, red hair, or freckles are at higher risk.
- Many Moles: Having lots of moles increases risk.
- Family History: Melanoma can run in families.
Warning Signs - The ABCDE Rule
Check your moles for:
- A - Asymmetry (one half different from the other)
- B - Border (irregular or blurred edges)
- C - Colour (uneven colours, multiple shades)
- D - Diameter (bigger than 6mm, or growing)
- E - Evolving (any change in size, shape, or colour)
How is it Treated?
- Surgery: The melanoma is cut out with a margin of healthy skin.
- Sentinel Node Biopsy: For deeper melanomas, nearby lymph nodes are checked.
- Immunotherapy: Drugs that help your immune system fight cancer.
- Targeted Therapy: For melanomas with specific gene changes (BRAF).
What is the Outlook?
- When caught early (before it spreads), melanoma is highly curable (more than 95%).
- Even advanced melanoma can now be treated effectively with new drugs.
- Regular skin checks are essential for early detection.
Prevention
- Avoid Burns: Use SPF 30+ sunscreen, reapply every 2 hours.
- Cover Up: Wear hats, long sleeves, and sunglasses.
- Avoid Tanning Beds: They dramatically increase melanoma risk.
- Check Your Skin: Monthly self-examination, annual professional skin check if high risk.
When to Seek Help
- Any mole that is changing, growing, or looks different from others.
- A new mole appearing after age 40.
- Any skin lesion that bleeds, itches, or doesn't heal.
- A dark streak appearing under a fingernail or toenail.
12. References
Primary Sources
- Schadendorf D, et al. Melanoma. Lancet. 2018;392:971-984. PMID: 30238891.
- Swetter SM, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2019;80:208-250. PMID: 30392755.
- Arnold M, et al. Global burden of cutaneous melanoma in 2020 and projections to 2040. JAMA Dermatol. 2022;158:495-503. PMID: 35353115.
- Gershenwald JE, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition. CA Cancer J Clin. 2017;67:472-492. PMID: 29028110.
- Sung H, et al. Global Cancer Statistics 2020. CA Cancer J Clin. 2021;71:209-249. PMID: 33538338.
- Morton DL, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370:599-609. PMID: 24553149.
- Eggermont AMM, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378:1789-1801. PMID: 29658430.
- Long GV, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377:1813-1823. PMID: 29028924.
- Larkin J, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:23-34. PMID: 26027431.
- Michielin O, et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of melanoma. Ann Oncol. 2019;30:1884-1901. PMID: 31566658.
- Faries MB, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376:2211-2222. PMID: 28552318.
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