Malignant Melanoma

1. Clinical Overview

Summary

Malignant melanoma is a malignant neoplasm arising from melanocytes, the pigment-producing cells of the skin. Despite accounting for only 4% of skin cancers, melanoma is responsible for approximately 80% of skin cancer deaths due to its propensity for early metastasis. [1] The global incidence has been rising steadily over the past four decades, with the highest rates observed in Australia and New Zealand (exceeding 50 cases per 100,000 population annually). [2] Early detection and surgical excision of localised disease offer excellent cure rates exceeding 95%, while advanced melanoma historically carried a dismal prognosis with 5-year survival rates below 10% for stage IV disease. [3] However, the therapeutic landscape has been revolutionised over the past decade by the advent of immune checkpoint inhibitors and BRAF-targeted therapies, transforming metastatic melanoma from a uniformly fatal disease to one where long-term survival is achievable in a significant proportion of patients. [4,5]

Key Facts

• Global Burden: Over 324,000 new cases diagnosed annually worldwide, with melanoma representing the 17th most common cancer globally. [2]
• Incidence Variation: Highest in Australia/New Zealand (50-60 per 100,000), intermediate in North America and Europe (10-25 per 100,000), and lowest in Asia and Africa (less than 1 per 100,000).
• Mortality: Despite treatment advances, melanoma caused approximately 57,000 deaths globally in 2020. [2]
• Age Distribution: Median age at diagnosis is 65 years, but melanoma is one of the most common cancers in young adults aged 25-49 years, particularly in women.
• Sex Differences: Slight male predominance overall (male:female ratio 1.2:1), with males having worse prognosis at equivalent stage.
• Breslow Thickness is King: Tumour thickness (Breslow depth) remains the single most important prognostic factor, directly correlating with metastatic risk and survival.
• Immunotherapy Revolution: Five-year survival for metastatic melanoma has improved from 5% in the pre-immunotherapy era to 50-52% with combination ipilimumab and nivolumab. [4]
• BRAF Mutations: Present in approximately 50% of melanomas, enabling targeted therapy with BRAF and MEK inhibitors. [6]

Clinical Pearls

The ABCDE Rule: Asymmetry, Border irregularity, Colour variation, Diameter greater than 6mm, Evolution (changing). This mnemonic has high sensitivity (97%) for detecting melanoma when at least three features are present. [7] However, beware—nodular melanoma often fails ABCDE criteria, presenting as symmetric, uniform-coloured nodules.

The "Ugly Duckling" Sign: A lesion that looks different from all other moles on that patient. This pattern recognition approach has been shown to improve diagnostic accuracy, particularly for atypical presentations that do not fulfill ABCDE criteria. [8]

Amelanotic Melanoma Trap: Approximately 2-8% of melanomas lack visible pigment, presenting as pink or red nodules. These are frequently misdiagnosed as basal cell carcinoma, Spitz naevi, or pyogenic granulomas, leading to diagnostic delays. [9] Maintain high suspicion for any persistent, growing, non-pigmented nodule.

Subungual Melanoma - Hutchinson's Sign: Periungual pigmentation (pigment extending beyond the nail bed to involve the proximal or lateral nail fold) is a red flag for subungual melanoma. Named after Jonathan Hutchinson, this sign has high specificity for melanoma versus benign melanonychia. [10]

The "No-Touch" Biopsy Technique: Traumatic manipulation during biopsy may theoretically promote metastasis. While evidence is limited, excisional biopsy with a 2mm clinical margin and careful handling remains the gold standard. Avoid incisional or punch biopsies that cross the deep margin unless anatomically unavoidable (e.g., face, acral sites).

Sentinel Lymph Node Biopsy: Staging Not Treatment: The landmark MSLT-I and MSLT-II trials demonstrated that sentinel lymph node biopsy (SLNB) provides accurate staging and prognostic information but does not improve overall survival. [11,12] SLNB is indicated for risk stratification and to guide adjuvant therapy decisions, not as therapeutic intervention.

---

2. Epidemiology

Incidence and Prevalence

Melanoma incidence has been increasing exponentially in fair-skinned populations since the 1960s, with rates doubling approximately every 10-20 years. [13] This trend is attributed to increased recreational UV exposure, changes in sun-seeking behaviour, improved detection through screening programs, and potentially immunosuppression from aging populations.

Global Incidence Rates (per 100,000 population, age-standardised):

Demographics

Age Distribution:

• Median age at diagnosis: 65 years (males), 62 years (females)
• Incidence increases exponentially with age, doubling every 10 years after age 40
• However, melanoma is the most common cancer in women aged 25-29 and second most common (after breast) in women aged 30-34
• Childhood melanoma is rare (less than 1% of cases) but increasing in incidence

Sex Differences:

• Overall male:female ratio approximately 1.2:1
• In younger age groups (less than 40 years), females have higher incidence
• After age 60, males predominate
• Males have worse stage-adjusted survival, potentially due to thicker tumours at presentation and different anatomical distribution

Anatomical Distribution:

• Males: Back (33%), head/neck (20%), lower limbs (15%)
• Females: Lower limbs (45%), back (20%), upper limbs (15%)
• Acral sites (palms, soles, subungual): less than 5% in Caucasians, 50-70% in Asian and African populations

Risk Factors with Relative Risk

The following table summarises established melanoma risk factors with associated relative risks derived from meta-analyses and large cohort studies. [13,14]

Special Populations

Immunocompromised Patients: Solid organ transplant recipients have a 3- to 8-fold increased melanoma risk, with higher rates in heart versus kidney transplant patients. Melanoma in immunosuppressed patients tends to be more aggressive, with higher Breslow thickness, increased ulceration rates, and worse survival. [15] Azathioprine exposure is specifically implicated; conversion to alternative immunosuppression may be warranted.

Pregnancy-Associated Melanoma: Pregnancy does not increase melanoma risk, but physiological changes (darkening of naevi, linea nigra) can complicate diagnosis. Melanoma diagnosed during pregnancy has equivalent stage-adjusted survival to non-pregnant women. However, placental and fetal metastases, though rare (less than 1% of cases), portend poor maternal and fetal prognosis. [16]

Familial Melanoma Syndromes:

• CDKN2A/p16 mutations: Account for 20-40% of familial melanomas; lifetime penetrance 60-90% by age 80
• CDK4 mutations: Rare; similar high penetrance
• BAP1 tumour predisposition syndrome: Uveal melanoma, cutaneous melanoma, mesothelioma, renal cell carcinoma
• Genetic counselling and surveillance: Recommended for families with two or more first-degree relatives with melanoma, or melanoma diagnosed before age 40 with additional family history

---

3. Aetiology and Pathophysiology

Genetic Landscape

Melanoma arises through accumulation of genetic mutations that drive uncontrolled melanocyte proliferation, invasion, and metastasis. The genomic landscape is characterised by high mutational burden, predominantly UV-signature mutations (C to T transitions at dipyrimidine sites). [17]

Key Driver Mutations:

Melanoma Genomic Subtypes:

1. BRAF-mutant (50%): Younger patients, intermittent sun exposure, superficial spreading subtype
2. NRAS-mutant (20-30%): Intermediate prognosis, nodular subtype common
3. NF1-mutant (10-15%): Older patients, chronic sun damage, thick tumours
4. Triple wild-type (10-15%): Heterogeneous; includes KIT-mutant acral/mucosal melanomas

Ultraviolet Radiation and Carcinogenesis

UV radiation (UVA 320-400nm, UVB 290-320nm) is the dominant environmental risk factor. UVB causes direct DNA damage by formation of cyclobutane pyrimidine dimers and 6-4 photoproducts, resulting in characteristic C to T and CC to TT mutations. UVA generates reactive oxygen species causing indirect DNA damage. [18]

UV Exposure Patterns:

• Intermittent intense exposure (sunburns): Associated with superficial spreading and nodular melanoma on intermittently exposed sites (trunk, limbs)
• Chronic cumulative exposure: Associated with lentigo maligna melanoma on chronically exposed sites (head, neck, forearms)
• No significant UV exposure: Acral, mucosal, and uveal melanomas; mechanistically distinct

The Clark Model: Melanoma Progression

Melanoma progression classically follows a stepwise model, though exceptions exist (e.g., nodular melanoma lacks radial growth phase):

Step 1: Normal Melanocyte

• Dendritic cells in basal epidermis
• Ratio 1 melanocyte: 10 keratinocytes
• Melanin production regulated by keratinocyte-derived factors (α-MSH, endothelin)

Step 2: Benign Naevus

• Clonal proliferation of melanocytes
• BRAF or NRAS mutations common
• Oncogene-induced senescence prevents progression

Step 3: Dysplastic Naevus

• Architectural and cytological atypia
• Bridging of rete ridges, nuclear pleomorphism
• May represent intermediate step but most never progress

Step 4: Melanoma In Situ

• Intraepidermal malignant melanocytes
• Pagetoid spread (upward migration)
• Basement membrane intact
• No metastatic potential

Step 5: Radial Growth Phase (RGP) Melanoma

• Invasion into papillary dermis
• Predominantly horizontal growth
• Low metastatic potential
• Includes superficial spreading melanoma, lentigo maligna melanoma

Step 6: Vertical Growth Phase (VGP) Melanoma

• Deep dermal invasion, forming expansile nodules
• Acquisition of metastatic competence
• Mitotic activity in dermal component
• All nodular melanomas are VGP from onset

Step 7: Metastatic Melanoma

• Lymphatic spread: Satellite lesions (within 2cm), in-transit metastases (2cm to regional nodes), regional nodes
• Haematogenous spread: Skin, subcutaneous tissue, lung, liver, brain, bone, gastrointestinal tract (no organ is sanctuary)

Melanoma Subtypes: Clinical-Pathological Correlation

---

4. Clinical Presentation

The ABCDE Rule: Detailed Application

Originally described by Friedman et al. in 1985, the ABCDE criteria have become the cornerstone of melanoma detection in primary care and public health campaigns. [7] However, clinicians must understand both its utility and limitations.

Performance Characteristics:

• When 3 or more ABCDE features present: Sensitivity 97%, Specificity 39% [7]
• Sensitivity for detecting melanoma by non-specialists: 60-80%
• "Evolving" (E) has highest sensitivity as a single criterion

Limitations of ABCDE:

1. Nodular melanoma: Often symmetric (no A), regular borders (no B), uniform colour (no C), may be less than 6mm (no D). Evolution (E) is the only consistent feature.
2. Amelanotic melanoma: Lacks colour variation (no C); appears pink or red.
3. Small early melanomas: May be less than 6mm (no D).
4. Lentigo maligna: Subtle colour variation on background of solar lentigines; requires trained eye.

Expanded Glasgow 7-Point Checklist

An alternative scoring system more commonly used in the UK, with weighted criteria:

Major Features (2 points each):

1. Change in size (enlargement)
2. Change in shape (irregular outline developing)
3. Change in colour (darkening, or colour variation appearing)

Minor Features (1 point each): 4. Diameter ≥7mm 5. Inflammation (redness, swelling) 6. Crusting or bleeding 7. Sensory change (itch, altered sensation)

Scoring: ≥3 points warrants urgent (2-week wait) dermatology referral. Sensitivity 75%, Specificity 60% for melanoma detection.

The "Ugly Duckling" Sign

Proposed by Grob and Bonerandi in 1998, this gestalt approach recognises that melanoma often appears different from the patient's other naevi. [8] Particularly useful for:

• Patients with many naevi (difficult to assess each by ABCDE)
• Nodular melanoma (fails ABCDE criteria)
• Detecting early melanoma (subtle changes)

Application: "Does this lesion stand out as distinctly different from the patient's other moles?" If yes, biopsy.

Atypical Presentations Requiring High Index of Suspicion

1. Amelanotic Melanoma (2-8% of melanomas):

• Presents as pink, red, or flesh-coloured nodule or plaque
• Lacks visible pigment due to absent or minimal melanin production
• Frequently misdiagnosed as basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, Spitz naevus
• Average diagnostic delay: 6-12 months
• Worse prognosis due to delayed diagnosis and thicker tumours at presentation
• Clinical clue: EFG criteria for nodular melanoma—Elevated, Firm, Growing for more than 1 month [9]

2. Subungual (Nail) Melanoma:

• 1-3% of melanomas; more common in thumb and great toe
• Longitudinal melanonychia (brown-black streak in nail)
• Hutchinson's sign: Pigmentation extending to proximal or lateral nail fold (periungual skin); highly specific for melanoma [10]
• Width greater than 3mm, irregular borders, rapid progression, nail destruction are concerning features
• Often misdiagnosed as subungual haematoma (history of trauma helps differentiate)
• Diagnosis requires biopsy: tangential excision of involved nail matrix
• ABCDEF criteria for nail melanoma: Age (50-70 peak), Band (brown-black, greater than 3mm, irregular), Change, Digit (thumb/great toe), Extension (Hutchinson's sign), Family history

3. Mucosal Melanoma (1% of melanomas):

• Sites: Oral cavity (55%), sinonasal (30%), anogenital (15%: vulva, vagina, penis, anus)
• Often presents late with bleeding, mass, ulceration, obstruction
• Poor prognosis: 5-year survival 25-30% (usually advanced stage at diagnosis)
• KIT mutations in 15-20% (imatinib may be therapeutic option)

4. Desmoplastic Melanoma:

• Amelanotic or hypopigmented indurated plaque or nodule
• Predilection for head and neck (60%), especially on chronically sun-damaged skin
• Neurotropic invasion common (follows nerve sheaths)
• High local recurrence (20-30%) despite wide excision
• Lower rate of nodal metastases; paradoxically better systemic survival
• Histology: Spindle cells in fibrous stroma, S100+, often misdiagnosed as scar or dermatofibroma

5. Melanoma of Unknown Primary (MUP) (2-5% of melanomas):

• Metastatic melanoma (nodes, skin, viscera) without identifiable primary tumour
• Proposed mechanisms: Complete immune regression of primary, de novo nodal/visceral melanoma
• Same stage-adjusted survival as melanoma with known primary
• Management identical to stage III/IV melanoma depending on presentation

6. Ocular (Uveal) Melanoma:

• Most common primary intraocular malignancy in adults (5 per million incidence)
• Distinct biology from cutaneous melanoma: GNAQ/GNA11 mutations (80-90%), BRAF rare
• Haematogenous spread almost exclusively to liver (90% of metastases)
• Presents with visual symptoms (blurred vision, photopsia, visual field defect) or asymptomatic (incidental finding)
• Liver metastases occur in 50% within 15 years
• Treatment: Plaque brachytherapy, proton beam, enucleation for primary; liver-directed therapies (resection, ablation, chemoembolisation) for metastases

Symptomatology and Red Flags

Common Symptoms Prompting Medical Attention:

• Change in pre-existing mole (size, shape, colour): 80%
• New mole in adulthood (especially over age 40): 60%
• Bleeding or crusting: 30%
• Itching or altered sensation: 10%
• Ulceration: Advanced disease

"Don't Miss" Clinical Scenarios:

1. Any changing mole: Evolution over weeks to months
2. New mole over age 40: Unusual to develop new naevi after fourth decade
3. Persistent non-healing nodule: Pink, red, or pigmented; especially if vascular appearance
4. New longitudinal pigmented band in nail: Especially if greater than 3mm width, irregular, or with Hutchinson's sign
5. Mole that "stands out": Ugly duckling sign
6. Satellite lesions: Multiple pigmented nodules around a primary lesion (in-transit metastases)
7. Painless lymphadenopathy with pigmented skin lesion

---

5. Clinical Examination

Systematic Full-Body Skin Examination

A comprehensive skin examination is essential for melanoma detection and screening for additional primaries (4-8% of melanoma patients develop a second primary melanoma).

Examination Technique:

1. Environment: Private, well-lit room; natural light ideal; supplemental bright lamp
2. Exposure: Complete skin examination requires full disrobing with gown; provide chaperone
3. Systematic approach: Head-to-toe to avoid missing areas
4. Key areas often missed:
   • Scalp (use comb to part hair, examine systematically)
   • Ears (including posterior auricular sulcus)
   • Interdigital spaces (fingers and toes)
   • Palms and soles
   • Nail beds and periungual skin
   • Genitalia and perineum
   • Intergluteal cleft
   • Oral mucosa (if history of dysplastic naevi or familial syndrome)

Documentation:

• Photography: Baseline total body photography for high-risk patients; close-up clinical images of concerning lesions
• Body map diagrams: Document location of biopsied lesions and naevi requiring surveillance
• Sequential digital dermoscopy imaging: For monitoring stable atypical naevi in high-risk patients

Dermoscopy (Dermatoscopy)

Dermoscopy is a non-invasive technique using a handheld device (10x magnification, polarised or non-polarised light) to visualise subsurface skin structures. Meta-analyses demonstrate dermoscopy improves melanoma diagnostic accuracy by 10-30% compared to naked eye examination when performed by trained users. [19]

Key Dermoscopic Features of Melanoma:

Dermoscopic Algorithms:

1. Seven-Point Checklist (Weighted):

Major Criteria (2 points each):

• Atypical pigment network
• Blue-white veil
• Atypical vascular pattern

Minor Criteria (1 point each):

• Irregular streaks
• Irregular dots/globules
• Irregular blotches
• Regression structures

Scoring: ≥3 points = Excise lesion. Sensitivity 95%, Specificity 75%.

2. ABCD Rule of Dermoscopy (Not to be confused with clinical ABCDE):

• A: Asymmetry (0-2 points)
• B: Border abruptness (0-8 points)
• C: Colour (1-6 points for number of colours)
• D: Diameter (proportional to size)
• Total Dermoscopy Score (TDS): Score greater than 5.45 suggestive of melanoma

3. Chaos and Clues:

• Chaos: Any asymmetry of colour and structure
• Clues: If chaotic, look for specific clues (atypical network, blue-white structures, eccentric blotch, thick lines, peripheral dots, etc.)
• Presence of chaos + any clue = Melanoma (Sensitivity 97%, Specificity 83%)

Special Dermoscopic Patterns by Subtype:

• Superficial spreading melanoma: Atypical network, pseudopods, blue-white veil
• Nodular melanoma: Blue-white veil, polymorphous vessels, ulceration
• Lentigo maligna: Asymmetric pigmented follicular openings, rhomboidal structures, grey dots (annular-granular pattern)
• Acral lentiginous melanoma: Parallel ridge pattern (pigment on dermatoglyphic ridges); benign acral naevi show parallel furrow pattern
• Amelanotic melanoma: Atypical vessels, white structureless areas, focal pigmentation

Regional Lymph Node Examination

Palpate all draining lymph node basins for the anatomical site of the primary melanoma:

Characteristics of Suspicious Nodes:

• Size: Greater than 1cm (though micrometastases not palpable)
• Consistency: Firm to hard
• Mobility: Fixed to underlying structures (advanced)
• Number: Single or matted nodes
• Associated features: Skin involvement, in-transit metastases

Sensitivity of Clinical Examination: Only 30-50% for detecting nodal metastases; SLNB required for accurate staging.

Systemic Examination for Metastatic Disease

For thick primary melanoma (Breslow greater than 4mm) or known nodal disease, perform systems review for distant metastases:

• General: Cachexia, performance status (ECOG)
• Skin: Satellite lesions (within 2cm), in-transit metastases (beyond 2cm but before nodes), distant cutaneous metastases
• Respiratory: Dyspnoea, cough (pulmonary metastases)
• Abdominal: Hepatomegaly (liver metastases), ascites
• Neurological: Headache, focal neurology, seizures (brain metastases in 20-50% of stage IV)
• Musculoskeletal: Bone pain (skeletal metastases less common but occur)
• Constitutional: Weight loss, fatigue, fever (advanced disease)

---

6. Investigations

Initial Biopsy: Diagnostic Approach

Gold Standard: Complete Excision Biopsy

• Remove entire lesion with 2mm clinical margin of normal skin
• Incision through full thickness of dermis to subcutaneous fat (essential for Breslow depth measurement)
• Elliptical excision oriented along relaxed skin tension lines or towards draining lymph node basin (controversial; some advocate circumferential margin)
• Submit entirely for histopathological examination with orientation suture

Alternative Biopsy Techniques (When Excision Biopsy Impractical):

Biopsy Handling:

• Avoid crushing with forceps (use skin hooks)
• Place in formalin immediately
• Provide clinical information to pathologist: Site, size, clinical concern, patient age

Histopathological Examination: The Eight Essential Elements

A complete melanoma histopathology report must include the following elements per College of American Pathologists (CAP) protocol:

1. Breslow Thickness (mm)

• Definition: Maximum vertical tumour thickness from granular layer (or base of ulceration if ulcerated) to deepest invasive cell
• Measurement: Ocular micrometer to nearest 0.1mm
• Prognostic significance: Most important prognostic factor; directly correlates with metastatic risk
• T staging: T1 (≤1mm), T2 (1.01-2mm), T3 (2.01-4mm), T4 (greater than 4mm)

2. Ulceration

• Definition: Full-thickness epidermal defect with reactive changes (not trauma during biopsy)
• Prognostic significance: Worsens prognosis within each T category; upstages T1a to T1b, etc.
• Mechanism: Marker of tumour aggression; associated with increased mitotic rate, immune evasion

3. Mitotic Rate (per mm²)

• Definition: Number of mitotic figures per mm² in dermal component (count in "hot spot")
• Prognostic significance: Independent predictor of survival; ≥1/mm² indicates higher risk
• AJCC 7th edition: T1 required subclassification by mitotic rate (T1 a: 0 mitoses/mm², T1 b: ≥1 mitosis/mm²)
• AJCC 8th edition: Removed as T1 criterion; ulceration now dominates; but mitotic rate remains important prognostic marker

4. Clark Level

• Definition: Anatomical level of invasion
  • "Level I: Confined to epidermis (in situ)"
  • "Level II: Invasion into papillary dermis"
  • "Level III: Fills and expands papillary dermis"
  • "Level IV: Invasion into reticular dermis"
  • "Level V: Invasion into subcutaneous fat"
• Historic significance: Superseded by Breslow thickness; rarely reported now except for thin melanomas (less than 1mm) where it may influence SLNB decision

5. Peripheral and Deep Margins

• Peripheral margin: Distance from melanoma to closest peripheral edge (lateral margin)
• Deep margin: Distance from deepest invasive cell to deep margin
• Adequacy: Biopsy margins not expected to be clear (2mm margin only); definitive excision requires wider margins

6. Microsatellites

• Definition: Discrete tumour nests greater than 0.05mm diameter, separated from main tumour by at least 0.3mm, within 2cm of primary
• Prognostic significance: Indicates local lymphatic invasion; upstages to N1c/N2c (Stage IIIB minimum)
• Incidence: Approximately 2-3% of primary melanomas

7. Tumour-Infiltrating Lymphocytes (TILs)

• Definition: Lymphocytic infiltrate within tumour
• Grading: Absent, non-brisk, brisk
  • "Brisk: Lymphocytes throughout vertical growth phase"
  • "Non-brisk: Lymphocytes present but focal"
• Prognostic significance: Brisk TILs associated with better prognosis (30% reduction in mortality); marker of host immune response

8. Regression

• Definition: Area of tumour replaced by fibrosis, melanophages, and lymphocytic inflammation
• Prognostic significance: Controversial; may indicate immune response (favourable) or may result in understaging if extensive (unfavourable)
• Clinical correlation: May present as amelanotic area within pigmented lesion

Additional Reporting Elements:

• Melanoma subtype (SSM, NM, LMM, ALM, etc.)
• Growth phase (radial vs vertical)
• Lymphovascular invasion (rare but poor prognostic sign)
• Neurotropism (desmoplastic melanoma)
• Associated naevus (present in 20-40%)

AJCC Staging (8th Edition, 2018)

The American Joint Committee on Cancer (AJCC) 8th edition staging system, implemented in 2018, incorporated refined T, N, and M categories based on analysis of over 46,000 melanoma patients. [20]

T Staging: Primary Tumour (Breslow Thickness + Ulceration)

N Staging: Regional Lymph Nodes

M Staging: Distant Metastases

Stage Groupings:

Sentinel Lymph Node Biopsy (SLNB)

Rationale: SLNB identifies occult regional lymph node metastases in clinically node-negative patients, providing accurate staging and prognostic information. The sentinel node is the first lymph node(s) draining the primary tumour site.

Indications (per NCCN/NICE Guidelines):

• Breslow thickness ≥0.8mm (strong recommendation)
• Breslow thickness less than 0.8mm WITH ulceration OR mitotic rate greater than 1/mm² (consider)
• Clinically node-negative (clinical examination and/or ultrasound)

Contraindications:

• Advanced age with comorbidities limiting life expectancy
• Patient refusal
• Prior wide local excision disrupting lymphatics (relative contraindication)

Technique:

1. Lymphoscintigraphy: Preoperative injection of technetium-99m sulfur colloid at primary site; gamma camera imaging at 30min-2hrs identifies draining basin(s)
2. Intraoperative mapping: Blue dye (isosulfan blue or methylene blue) injected intradermally around primary site or scar
3. Gamma probe detection: Handheld probe identifies radioactive sentinel node(s)
4. Sentinel node excision: Remove all nodes with counts greater than 10% of hottest node, and all blue nodes
5. Histopathology: Serial sectioning, H&E staining, immunohistochemistry (S100, HMB-45, Melan-A/MART-1)

Outcomes of MSLT-I and MSLT-II Trials:

• MSLT-I (2014): SLNB provides accurate staging but does NOT improve overall survival compared to nodal observation with lymph node dissection at recurrence (10-year OS 71% in both arms). [11] However, disease-free survival was improved in SLNB arm.
• MSLT-II (2017): In SLNB-positive patients, completion lymph node dissection (CLND) does NOT improve melanoma-specific survival compared to nodal observation with ultrasound surveillance (3-year MSS 86% vs 86%). [12] High-quality ultrasound surveillance is acceptable alternative to CLND.

Current Practice:

• SLNB is performed for staging and risk stratification (guides adjuvant therapy decisions)
• Completion lymph node dissection is no longer routinely performed for positive SLNB; ultrasound surveillance is standard unless bulky nodes or multiple positive nodes
• SLNB positivity (any nodal involvement) now triggers consideration of adjuvant immunotherapy or targeted therapy

Complications of SLNB:

• Seroma/haematoma: 5-10%
• Wound infection: 5%
• Lymphoedema: 5% (lower than CLND which has 20-30% lymphoedema rate)
• Allergic reaction to blue dye: less than 1%; anaphylaxis rare (0.1%)
• False-negative rate: 5-10% (skip metastases, technical failure)

Imaging for Staging

Stage I-IIA (T1-T3a, N0):

• No routine imaging unless symptoms
• Baseline chest X-ray: Optional (low yield)

Stage IIB-IIC (T3b-T4b, N0):

• Consider CT chest/abdomen/pelvis or whole-body PET-CT
• Rationale: 5-10% have occult metastases

Stage III (Regional Nodes):

• CT chest/abdomen/pelvis or PET-CT: Standard
• MRI brain: Consider in Stage IIIC/IIID (20% risk brain metastases)
• Regional nodal basin ultrasound: For surveillance if CLND not performed

Stage IV (Distant Metastases):

• PET-CT: Preferred whole-body staging
• MRI brain: Mandatory (brain metastases in 40-50% of stage IV patients)
• Serum LDH: Prognostic marker; elevated LDH associated with worse survival

Molecular Testing

BRAF Mutation Testing:

• Indication: All Stage III (resected) and Stage IV melanoma
• Method: PCR, next-generation sequencing (NGS)
• Actionable mutations: BRAF V600E (90% of BRAF mutations), V600K (5-10%)
• Clinical significance: Guides targeted therapy with BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) plus MEK inhibitors (trametinib, cobimetinib, binimetinib)

Additional Molecular Testing (If BRAF Wild-Type):

• NRAS: No approved targeted therapy, but clinical trials available
• KIT: In acral, mucosal, or chronically sun-damaged melanomas; imatinib or nilotinib if KIT-mutant (response rate 20-30%)
• Comprehensive genomic profiling (NGS): Identifies rare actionable mutations, tumour mutational burden (TMB; predicts immunotherapy response)

PD-L1 Expression:

• Controversial role in melanoma (unlike lung cancer)
• Not routinely performed; immunotherapy effective regardless of PD-L1 status

---

7. Management

Overview: Stage-Specific Treatment Algorithm

┌─────────────────────────────────────────────────────────────┐
│              CONFIRMED CUTANEOUS MELANOMA                   │
│              (Excision Biopsy with Breslow Depth)           │
└──────────────────────┬──────────────────────────────────────┘
                       ↓
              ┌────────┴────────┐
              ↓                 ↓
        MELANOMA IN SITU    INVASIVE MELANOMA
              ↓                 ↓
       WLE (5mm margin)   Assess Breslow Thickness
              ↓                 ↓
        Surveillance      ┌─────┴──────┐
                          ↓            ↓
                    T1a (≤0.8mm,  T1b-T4 (≥0.8mm
                    no ulceration) or ulcerated)
                          ↓            ↓
                    WLE (1cm)    WLE + SLNB
                          ↓            ↓
                    Surveillance ┌────┴─────┐
                                 ↓          ↓
                           SLNB Negative  SLNB Positive
                                 ↓          ↓
                           Surveillance  Stage III
                                          ↓
                           ┌──────────────┴───────────────┐
                           │  • Ultrasound surveillance   │
                           │    vs CLND (selected cases)  │
                           │  • Adjuvant therapy:         │
                           │    - Immunotherapy (Stage III)│
                           │    - BRAF/MEK (if V600+)     │
                           │  • Clinical trials           │
                           └──────────────────────────────┘

Surgical Management of Primary Melanoma

Wide Local Excision (WLE): Margin Recommendations

Surgical margins are determined by Breslow thickness, based on randomised controlled trials demonstrating equivalent survival with narrower margins for thin melanomas but improved local control with wider margins for thick melanomas. [21]

Technical Considerations:

• Depth: Excise to deep fascia (NOT including fascia unless tumour invades fascia)
• Orientation: Along relaxed skin tension lines; some advocate towards draining nodal basin (theoretical benefit; unproven)
• Closure: Primary closure if possible; skin graft or flap if necessary
• Timing: WLE should be performed within 4-12 weeks of diagnostic biopsy (no survival difference between 4 weeks vs 12 weeks)

Special Sites Requiring Modified Approach:

• Face: Narrow margins (0.5-1cm) acceptable to preserve function/cosmesis; consider Mohs micrographic surgery for lentigo maligna
• Acral (palms/soles): 1cm margins; functional considerations paramount
• Subungual: Amputation of digit at mid-phalanx (finger) or interphalangeal joint (thumb/great toe); avoid aggressive amputation (hand/foot function)
• Mucosal: Wide local excision challenging; often requires multidisciplinary approach (ENT, colorectal, gynae-oncology)

Sentinel Lymph Node Biopsy (SLNB)

See "Investigations" section above for detailed technique, indications, and evidence.

Management of SLNB-Positive Patients (Stage III):

Following the MSLT-II trial demonstrating no survival benefit of completion lymph node dissection (CLND), current management options include:

Option 1: Ultrasound Surveillance (Preferred for Most Patients)

• High-resolution ultrasound every 3-4 months for 2 years, then every 6 months for 3 years
• Therapeutic lymph node dissection only if nodal recurrence detected
• Advantages: Avoids morbidity of CLND (lymphoedema, seroma, wound complications)
• Disadvantages: Requires compliant patient, high-quality imaging, experienced radiologist

Option 2: Completion Lymph Node Dissection (Selected Cases)

• Indications: Bulky sentinel node (greater than 3cm), multiple positive sentinel nodes, extranodal extension, patient preference
• Extent: Level I-III axillary dissection (upper limb primary), superficial + deep inguinal dissection (lower limb primary), modified radical neck dissection (head/neck primary)
• Complications: Lymphoedema (20-30%), seroma (20%), infection (10%), nerve injury (10%)

Option 3: Adjuvant Systemic Therapy (All SLNB-Positive Patients)

• See "Adjuvant Therapy" section below

Adjuvant Therapy for Stage IIB-IV (Resected)

The paradigm for adjuvant melanoma therapy has shifted dramatically with approval of immune checkpoint inhibitors and BRAF-targeted therapy based on RCTs demonstrating improved relapse-free survival (RFS) and overall survival (OS).

Indications for Adjuvant Therapy:

• Stage IIIA: Consider (lower risk, but still 30-40% recurrence rate)
• Stage IIIB/IIIC/IIID: Strong recommendation (recurrence risk 50-80%)
• Stage IIC: Consider (comparable risk to Stage IIIA; emerging data)
• Stage IV (resected): Recommended (very high recurrence risk)

Adjuvant Immunotherapy: Checkpoint Inhibitors

1. Pembrolizumab (Anti-PD-1 Monotherapy)

• Evidence: KEYNOTE-054 trial (Stage III melanoma): Pembrolizumab vs placebo; RFS 75% vs 61% at 12 months (HR 0.57, p less than 0.001); 3.5-year RFS 59% vs 41%; distant metastasis-free survival improved. [22]
• Dosing: 200mg IV every 3 weeks OR 400mg IV every 6 weeks for 12 months (maximum 18 doses)
• Adverse events: Fatigue (30%), diarrhea (20%), rash (15%), endocrinopathies (thyroid 10%, adrenal insufficiency 1%), hepatitis (5%), colitis (2%), pneumonitis (2%)
• Approval: FDA/EMA approved for Stage IIB-IV (resected)

2. Nivolumab (Anti-PD-1 Monotherapy)

• Evidence: CheckMate-238 trial (Stage IIIB/C-IV): Nivolumab vs ipilimumab; 12-month RFS 70.5% vs 60.8% (HR 0.65); better tolerated than ipilimumab. [23]
• Dosing: 240mg IV every 2 weeks OR 480mg IV every 4 weeks for 12 months
• Adverse events: Similar to pembrolizumab; less frequent than ipilimumab
• Approval: FDA/EMA approved for Stage III-IV (resected)

3. Ipilimumab (Anti-CTLA-4 Monotherapy)

• Evidence: EORTC 18071: Ipilimumab vs placebo in Stage III; improved RFS (HR 0.75) and distant metastasis-free survival, but OS benefit marginal and high toxicity. [24]
• Dosing: 10mg/kg IV every 3 weeks x 4 doses, then every 12 weeks for up to 3 years
• Adverse events: High-grade immune-related adverse events in 50%; colitis (15%), hepatitis (10%), endocrinopathies (10%), dermatitis
• Current role: Largely superseded by anti-PD-1 monotherapy due to better tolerability of PD-1 inhibitors

Adjuvant Targeted Therapy: BRAF/MEK Inhibitors (BRAF V600-Mutant Only)

Dabrafenib + Trametinib

• Evidence: COMBI-AD trial (Stage III, BRAF V600E/K-mutant): Dabrafenib + trametinib vs placebo; 3-year RFS 58% vs 39% (HR 0.47); 3-year OS 86% vs 77% (HR 0.57). [25]
• Dosing: Dabrafenib 150mg PO BID + Trametinib 2mg PO daily for 12 months
• Adverse events: Pyrexia (60%), fatigue (50%), nausea (40%), chills (30%), arthralgia (25%), rash (20%); permanent discontinuation rate 26%
• Approval: FDA/EMA approved for Stage III BRAF V600E/K-mutant melanoma

Adjuvant Therapy Selection: Immunotherapy vs Targeted Therapy

For BRAF-mutant Stage III melanoma, both adjuvant immunotherapy (pembrolizumab/nivolumab) and targeted therapy (dabrafenib + trametinib) are options. No head-to-head trials exist. Considerations:

Current Practice Consensus:

• Anti-PD-1 monotherapy is generally preferred first-line adjuvant therapy due to better tolerability, broader applicability (BRAF wild-type and mutant), and emerging OS data
• BRAF/MEK combination is a reasonable alternative for BRAF-mutant patients, particularly if contraindications to immunotherapy (active autoimmune disease) or patient preference for oral therapy

Systemic Therapy for Advanced/Metastatic Melanoma (Stage IV)

The treatment of metastatic melanoma has been revolutionised by immunotherapy and targeted therapy, improving 5-year overall survival from less than 10% (historical chemotherapy era) to 50-52% with modern combination immunotherapy. [4]

First-Line Immunotherapy: Checkpoint Inhibitors

1. Nivolumab + Ipilimumab (Combination Therapy - Preferred for Fit Patients)

• Evidence: CheckMate 067 trial: Nivolumab 1mg/kg + ipilimumab 3mg/kg vs nivolumab alone vs ipilimumab alone; 5-year OS 52% vs 44% vs 26%; 5-year PFS 36% vs 29% vs 8%; ORR 58% vs 44% vs 19%. [4]
• Dosing: Nivolumab 1mg/kg + ipilimumab 3mg/kg IV every 3 weeks x 4 doses (induction), then nivolumab 240mg IV every 2 weeks OR 480mg every 4 weeks (maintenance)
• Adverse events: Grade 3-4 irAEs in 55-59%; colitis (10-15%), hepatitis (10%), endocrinopathies (10%), dermatitis, pneumonitis, neurological (rare but serious)
• Patient selection: ECOG 0-1, normal organ function, no active autoimmune disease, able to tolerate high toxicity
• Advantage: Highest response rate and longest survival tail
• Disadvantage: High toxicity; 30-40% discontinue due to adverse events

2. Pembrolizumab Monotherapy (Alternative for Broader Population)

• Evidence: KEYNOTE-006: Pembrolizumab vs ipilimumab; 4-year OS 44% vs 36%; ORR 41% vs 13%; better tolerated. [26]
• Dosing: 200mg IV every 3 weeks OR 400mg IV every 6 weeks; continue until progression or unacceptable toxicity (up to 2 years)
• Adverse events: Grade 3-4 irAEs in 15%; better tolerated than combination
• Patient selection: ECOG 0-2, comorbidities precluding combination, patient preference for monotherapy

3. Nivolumab Monotherapy (Alternative)

• Evidence: CheckMate 067: Nivolumab monotherapy; 5-year OS 44%, ORR 44%
• Dosing: 240mg IV every 2 weeks OR 480mg every 4 weeks
• Similar efficacy and toxicity to pembrolizumab monotherapy

Which Immunotherapy to Choose?

• Nivolumab + ipilimumab: Fit patients (ECOG 0-1), low-volume disease or need for rapid response, normal LDH, BRAF wild-type, no contraindications
• Anti-PD-1 monotherapy: Elderly, ECOG 2, comorbidities, patient preference for lower toxicity, BRAF-mutant (may sequence with targeted therapy)

First-Line Targeted Therapy: BRAF + MEK Inhibitors (BRAF V600-Mutant Only)

Approximately 50% of melanomas harbour BRAF V600 mutations, enabling targeted therapy with BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) combined with MEK inhibitors (cobimetinib, trametinib, binimetinib). Combination therapy is mandatory to prevent/delay resistance and reduce toxicity (paradoxical MAPK activation with BRAF inhibitor monotherapy).

1. Dabrafenib + Trametinib

• Evidence: COMBI-d and COMBI-v trials: ORR 69%, median PFS 11-12 months, median OS 25-26 months, 5-year OS 34%. [27]
• Dosing: Dabrafenib 150mg PO BID + trametinib 2mg PO daily; continue until progression
• Adverse events: Pyrexia (60%, may be severe/recurrent), fatigue, nausea, chills, rash, arthralgia, peripheral oedema; cutaneous SCC (7%), uveitis (rare)

2. Vemurafenib + Cobimetinib

• Evidence: coBRIM trial: ORR 70%, median PFS 12.3 months, median OS 22.3 months
• Dosing: Vemurafenib 960mg PO BID + cobimetinib 60mg PO daily (21 days on, 7 days off)
• Adverse events: Photosensitivity (prominent with vemurafenib), rash, arthralgia, elevated LFTs, diarrhea, pyrexia

3. Encorafenib + Binimetinib

• Evidence: COLUMBUS trial: ORR 63%, median PFS 14.9 months, median OS 33.6 months (longest OS of BRAF/MEK combinations to date). [28]
• Dosing: Encorafenib 450mg PO daily + binimetinib 45mg PO BID
• Adverse events: Similar spectrum; possibly better tolerated (lower pyrexia rate than dabrafenib, lower photosensitivity than vemurafenib)

Sequencing Strategy: Immunotherapy vs Targeted Therapy First

For BRAF V600-mutant metastatic melanoma, both immunotherapy and targeted therapy are options. Sequencing considerations:

Data on Sequencing:

• Targeted → Immunotherapy: Response rate to subsequent immunotherapy 15-30% (lower than treatment-naïve)
• Immunotherapy → Targeted: Response rate to subsequent targeted therapy 40-50% (minimally impacted)
• Emerging data suggest starting with immunotherapy may yield better long-term OS, but prospective RCTs lacking

Triple Therapy (Investigational): Anti-PD-1 + BRAF + MEK combination (e.g., atezolizumab + vemurafenib + cobimetinib in IMspire150 trial): Improved PFS but unacceptable toxicity (grade 3-4 AEs in 79%); not FDA-approved.

Management of Brain Metastases

Brain metastases occur in 40-50% of stage IV melanoma patients. Prognosis historically poor (median OS 4-6 months), but improved with modern therapies.

Treatment Modalities:

Multimodal Approach (Preferred): SRS for 1-3 lesions + systemic immunotherapy or targeted therapy yields best outcomes (median OS 18-24 months in selected patients).

Other Systemic Therapies

Interleukin-2 (High-Dose IL-2):

• Historic immunotherapy; FDA-approved 1998
• Complete response rate 5-10%, but durable
• Severe toxicity (capillary leak syndrome, ICU admission required)
• Rarely used now; superseded by checkpoint inhibitors

Chemotherapy (Dacarbazine, Temozolomide):

• ORR 10-15%, no OS benefit
• Historical standard; now reserved for patients failing immunotherapy and targeted therapy, or in resource-limited settings

Oncolytic Virotherapy (Talimogene Laherparepvec, T-VEC):

• Intralesional injection of modified herpes simplex virus
• For unresectable stage IIIB-IVM1a (injectable cutaneous/nodal disease)
• ORR 26% (injected and non-injected lesions); durable responses
• Often combined with systemic immunotherapy (synergistic; under investigation)

Isolated Limb Perfusion/Infusion:

• Regional chemotherapy (melphalan +/- TNF-alpha) for unresectable in-transit metastases confined to limb
• ORR 60-80%; limb salvage in 80%
• Morbidity: Compartment syndrome (5%), amputation (1%)

---

8. Complications

Disease-Related Complications

Treatment-Related Complications

Surgical Complications:

• Wound infection: 5-10%
• Seroma/haematoma: 10-15%
• Skin graft/flap failure: 5%
• Nerve injury (CLND): 10-20% (sensory more common than motor)
• Lymphoedema (CLND): 20-30% (axillary), 30-40% (inguinal)

Immune-Related Adverse Events (irAEs) from Checkpoint Inhibitors:

Management Principles for irAEs:

1. Early recognition: Baseline labs before each infusion (CBC, CMP, LFTs, TSH)
2. Grading: Use CTCAE v5.0
3. Hold vs Discontinue:
   • Grade 1: Continue therapy, symptomatic treatment
   • Grade 2: Hold therapy, oral steroids (0.5-1mg/kg prednisone)
   • Grade 3-4: Permanently discontinue therapy (exception: endocrinopathies can often continue with hormone replacement); high-dose IV steroids (1-2mg/kg methylprednisolone)
4. Rechallenge: May consider restarting anti-PD-1 after resolution of Grade 2 events; DO NOT rechallenge after Grade 3-4 events (except endocrine with replacement)

BRAF/MEK Inhibitor Adverse Events:

---

9. Prognosis and Outcomes

Survival by AJCC 8th Edition Stage

Based on international melanoma database (over 46,000 patients): [20]

Prognostic Factors: Multivariable Analysis

Favourable Prognostic Factors:

• Low Breslow thickness (less than 1mm)
• Absence of ulceration
• Low mitotic rate (less than 1/mm²)
• SLNB negative
• Brisk tumour-infiltrating lymphocytes (TILs)
• Female sex
• Younger age (less than 60 years)
• Superficial spreading subtype
• Extremity location (vs trunk, head/neck)
• Good performance status (ECOG 0)

Unfavourable Prognostic Factors:

• High Breslow thickness (greater than 4mm): Single most important factor
• Ulceration present
• High mitotic rate (greater than 5/mm²)
• SLNB positive (micrometastases confer Stage III)
• Microsatellites present
• Male sex
• Advanced age (greater than 70 years)
• Nodular subtype
• Head/neck or acral location
• Elevated serum LDH (Stage IV only)
• Brain metastases (vs other visceral sites)
• BRAF wild-type (fewer targeted options, though immunotherapy effective)

Molecular Prognostic Markers (Emerging):

• Gene expression profiling (GEP): DecisionDx-Melanoma (31-gene signature) stratifies risk; Class 1A/1B (low), Class 2A/2B (high)
• Circulating tumour DNA (ctDNA): Detectable ctDNA post-surgery predicts recurrence; under investigation
• Tumour mutational burden (TMB): High TMB associated with better immunotherapy response

Surveillance Recommendations (NCCN Guidelines)

Post-treatment surveillance aims to detect recurrence early (when potentially curable) and identify second primary melanomas.

Patient Education - Self-Skin Examination:

• Monthly self-examination of entire skin surface (use mirrors, involve partner for back/scalp)
• Photograph baseline naevi if multiple atypical naevi
• "ABCDE" and "Ugly Duckling" rules
• Report any new or changing lesions immediately

---

10. Prevention and Screening

Primary Prevention

Sun Protection Strategies:

1. Sunscreen: Broad-spectrum SPF 30+ (UVA and UVB protection); apply 15-30 minutes before exposure; reapply every 2 hours and after swimming
2. Protective clothing: Long sleeves, wide-brimmed hat (7.5cm brim), UV-blocking sunglasses
3. Avoid peak UV hours: 10am-4pm; seek shade
4. Avoid indoor tanning: WHO Group 1 carcinogen; banned for minors (less than 18 years) in many jurisdictions
5. Childhood protection: Blistering sunburns in childhood/adolescence confer 2-3x melanoma risk; prioritise sun protection for children

Evidence for Sun Protection Efficacy:

• RCT in Australia (Green et al., J Clin Oncol 2011): Daily sunscreen use reduced melanoma incidence by 50% over 10-year follow-up. [29]

Chemoprevention (Investigational):

• Nicotinamide (Vitamin B3): Reduces NMSC (basal cell and squamous cell carcinoma) by 23%, but no proven melanoma benefit
• Aspirin/NSAIDs: Observational data suggest reduced melanoma risk, but insufficient evidence for recommendation

Secondary Prevention: Screening

Population-Based Screening: Systematic reviews and modelling studies show insufficient evidence for whole-population screening in low-incidence populations (e.g., UK, USA). Targeted screening for high-risk groups is preferred.

High-Risk Individuals Requiring Surveillance:

• Personal history of melanoma (4-8% risk of second primary)
• Familial melanoma syndrome (CDKN2A mutation, BAP1 mutation)
• Greater than 50 atypical naevi or greater than 100 total naevi
• Giant congenital naevus (greater than 20cm)
• Immunosuppression (transplant recipients, HIV)
• Previous NMSC (indicates UV exposure and genetic susceptibility)
• Xeroderma pigmentosum

Screening Modalities:

• Total body skin examination by dermatologist annually
• Total body photography for monitoring naevi over time
• Sequential digital dermoscopy imaging for high-risk atypical naevi

---

11. Guidelines and Evidence

Key International Guidelines

Landmark Clinical Trials

1. MSLT-I (Multicenter Selective Lymphadenectomy Trial I, 2014)

• Question: Does sentinel lymph node biopsy improve survival compared to nodal observation?
• Design: RCT, 1,269 patients with intermediate-thickness melanoma (1.2-3.5mm), SLNB vs observation
• Results: No overall survival difference at 10 years (OS 62% vs 60%, p=0.42); disease-free survival improved in SLNB arm (HR 0.73); SLNB provides accurate staging
• Conclusion: SLNB is for staging, not therapeutic benefit
• PMID: 24553149 | DOI: 10.1056/NEJMoa1310460 [11]

2. MSLT-II (Multicenter Selective Lymphadenectomy Trial II, 2017)

• Question: For SLNB-positive patients, does completion lymph node dissection improve survival compared to nodal observation?
• Design: RCT, 1,934 patients with positive SLNB, CLND vs observation with ultrasound surveillance
• Results: No melanoma-specific survival difference at 3 years (86% vs 86%, p=0.42); disease-free survival slightly higher in CLND arm (68% vs 63%, HR 0.80), but distant metastasis-free survival identical
• Conclusion: Observation with ultrasound is safe alternative to CLND; CLND does not improve survival
• PMID: 28552318 | DOI: 10.1056/NEJMoa1613210 [12]

3. CheckMate 067 (Nivolumab + Ipilimumab in Metastatic Melanoma, 2015-2019)

• Question: Is combination immunotherapy superior to monotherapy in metastatic melanoma?
• Design: RCT, 945 patients, nivolumab+ipilimumab vs nivolumab vs ipilimumab
• Results: 5-year OS 52% vs 44% vs 26%; 5-year PFS 36% vs 29% vs 8%; ORR 58% vs 44% vs 19%; Grade 3-4 AEs 59% vs 21% vs 28%
• Conclusion: Combination therapy offers highest survival but with increased toxicity; transformed melanoma from fatal to chronic disease
• PMID: 26027431 (initial), 31562797 (6.5-year update) | DOI: 10.1056/NEJMoa1504030 [4]

4. KEYNOTE-054 (Adjuvant Pembrolizumab in Stage III, 2018)

• Question: Does adjuvant pembrolizumab improve recurrence-free survival in resected Stage III melanoma?
• Design: RCT, 1,019 patients, pembrolizumab vs placebo for 12 months
• Results: 12-month RFS 75% vs 61% (HR 0.57, p less than 0.001); 3.5-year RFS 59% vs 41%; distant metastasis-free survival improved
• Conclusion: Adjuvant pembrolizumab is standard of care for Stage III melanoma
• PMID: 29658430 | DOI: 10.1056/NEJMoa1802357 [22]

5. COMBI-AD (Adjuvant Dabrafenib + Trametinib in BRAF-Mutant Stage III, 2017)

• Question: Does adjuvant BRAF/MEK inhibitor combination improve outcomes in BRAF-mutant Stage III melanoma?
• Design: RCT, 870 patients, dabrafenib+trametinib vs placebo for 12 months
• Results: 3-year RFS 58% vs 39% (HR 0.47, p less than 0.001); 3-year OS 86% vs 77% (HR 0.57); Grade 3-4 AEs 41% vs 14%
• Conclusion: Adjuvant targeted therapy is effective option for BRAF-mutant melanoma, though toxicity significant
• PMID: 29028924 | DOI: 10.1056/NEJMoa1708539 [25]

6. COLUMBUS (Encorafenib + Binimetinib in BRAF-Mutant Metastatic Melanoma, 2018)

• Question: Is encorafenib+binimetinib effective in BRAF-mutant melanoma?
• Design: RCT, 577 patients, encorafenib+binimetinib vs vemurafenib vs encorafenib monotherapy
• Results: Median PFS 14.9 vs 7.3 vs 9.6 months; median OS 33.6 vs 16.9 months (longest OS of BRAF/MEK combinations); ORR 63% vs 40%
• Conclusion: Encorafenib+binimetinib is highly effective BRAF/MEK combination with favourable survival
• PMID: 29573941 | DOI: 10.1016/S0140-6736(18)30142-6 [28]

---

12. Special Populations and Considerations

Pregnancy and Melanoma

• Incidence: Melanoma is the most common malignancy diagnosed during pregnancy (35% of cancers in pregnancy)
• Prognosis: Stage-adjusted survival equivalent to non-pregnant women; pregnancy does not worsen melanoma outcomes
• Diagnosis: Physiological changes (darkening naevi, linea nigra) complicate assessment; maintain low threshold for biopsy
• Management:
  • "Surgery: Wide local excision and SLNB safe in any trimester (avoid blue dye; technetium-99m low dose is safe)"
  • "Imaging: Ultrasound preferred; MRI without contrast safe; avoid CT (radiation exposure); PET-CT contraindicated"
  • "Systemic therapy: Chemotherapy and immunotherapy teratogenic; defer adjuvant therapy until postpartum if possible"
  • "Metastatic disease: Multidisciplinary decision; consider termination if early gestation and life-threatening disease"
• Placental metastases: Rare (less than 1%); requires placental histopathology examination; fetal metastases possible (poor prognosis)
• Lactation: Most systemic therapies excreted in breast milk; advise against breastfeeding during treatment

Paediatric Melanoma

• Incidence: Rare (less than 1% of melanomas); increasing incidence
• Risk factors: Giant congenital naevus, xeroderma pigmentosum, familial melanoma syndromes
• Clinical features: Often amelanotic, nodular subtype; ABCDE criteria less sensitive in children
• Differential diagnosis: Spitz naevus (benign mimicker); histopathological distinction challenging
• Prognosis: Better than adults at equivalent stage (thin tumours more common; host immune response stronger)
• Management: Same surgical principles; adjuvant therapy limited data in paediatrics

Elderly and Frail Patients

• Incidence: Peak incidence 65-75 years; head/neck melanomas more common
• Subtype: Lentigo maligna melanoma predominates
• Prognosis: Worse survival due to higher Breslow thickness at presentation, comorbidities, immunosenescence
• Management considerations:
  • "Surgery: Same principles, but higher perioperative risk; optimise comorbidities"
  • "SLNB: Consider omitting if advanced age (greater than 80 years) and comorbidities limit life expectancy (SLNB for staging only)"
  • "Adjuvant therapy: Toxicity tolerance lower; anti-PD-1 monotherapy preferred over combination; dose reductions often required"
  • "Metastatic therapy: ECOG performance status and comorbidities guide treatment intensity"

Immunocompromised Patients

• Transplant recipients: 3-8x increased melanoma risk; azathioprine exposure implicated; more aggressive melanoma behaviour
• HIV/AIDS: 2-3x increased risk; stage-adjusted outcomes similar to immunocompetent
• Immunotherapy paradox: Checkpoint inhibitors theoretically risky (rejection of transplanted organ), but case reports show feasibility with close monitoring; individualise decisions

---

13. Patient Education and Layperson Explanation

What is Melanoma?

Melanoma is a type of skin cancer that develops from melanocytes, the cells that give your skin its colour by producing melanin (the brown pigment). Melanoma is more serious than other common skin cancers (basal cell carcinoma and squamous cell carcinoma) because it can spread to other parts of the body if not caught early.

Why Does Melanoma Happen?

• Sun Exposure: The main cause is ultraviolet (UV) radiation from the sun or tanning beds. UV damages the DNA in skin cells, which can lead to cancer over time.
• Sunburns: Especially severe, blistering sunburns in childhood or teenage years significantly increase melanoma risk later in life.
• Fair Skin: People with pale skin, freckles, light hair (red or blonde), and blue or green eyes are at higher risk because they have less melanin protection.
• Many Moles: Having lots of moles (especially large or unusual-looking moles) increases risk.
• Family History: Melanoma can run in families due to inherited gene mutations.

Warning Signs: How to Check Your Skin

Use the ABCDE rule to check your moles:

• A – Asymmetry: One half of the mole looks different from the other half
• B – Border: Edges are irregular, ragged, or blurred
• C – Colour: Multiple colours (brown, black, pink, red, white, or blue) instead of one uniform colour
• D – Diameter: Larger than 6mm (about the size of a pencil eraser), though smaller melanomas can occur
• E – Evolving: The mole is changing in size, shape, colour, or feel, or new symptoms like bleeding or itching appear

Also watch for:

• A new mole appearing after age 40 (unusual to develop new moles in adulthood)
• A mole that looks different from all your other moles (the "ugly duckling")
• Any mole that bleeds, itches, or doesn't heal

When to see a doctor immediately: If you notice ANY of the above warning signs, see your GP or dermatologist as soon as possible. Early melanoma is almost always curable with simple surgery.

How is Melanoma Diagnosed?

If your doctor is concerned about a mole, they will:

1. Examine your skin thoroughly, often with a special magnifying tool called a dermatoscope
2. Remove the mole (excision biopsy): The mole is completely cut out with a small margin of normal skin and sent to a laboratory
3. Analyse under a microscope: A specialist (pathologist) examines the mole to confirm if it's melanoma and, if so, how thick it is (Breslow thickness)

Breslow thickness is the most important measurement—it tells doctors how deep the melanoma has grown into the skin, which predicts the risk of it spreading and guides treatment.

How is Melanoma Treated?

Treatment depends on the stage (how advanced the melanoma is):

Stage 0-I (Early Melanoma):

• Surgery: The melanoma is removed with a wider margin of healthy skin (usually 1-2cm around the original site). This is called "wide local excision."
• Cure rate: Over 95% for early-stage melanoma

Stage II-III (Thicker Melanoma or Spread to Nearby Lymph Nodes):

• Surgery: Wide local excision, plus a "sentinel lymph node biopsy" to check if cancer has spread to nearby lymph nodes
• Additional treatment: If lymph nodes are involved or the melanoma is very thick, you may be offered additional treatment (called "adjuvant therapy") to reduce the risk of the cancer coming back:
  • "Immunotherapy (pembrolizumab or nivolumab): Drugs that help your immune system fight cancer cells (given as an IV infusion every 3-6 weeks for 12 months)"
  • "Targeted therapy (dabrafenib + trametinib): Pills that block specific mutations in the cancer (only if your melanoma has a BRAF mutation; taken daily for 12 months)"

Stage IV (Spread to Distant Parts of the Body):

• Immunotherapy: Very effective; combination therapy (nivolumab + ipilimumab) can lead to long-term survival in 50% of patients (this was unthinkable 15 years ago)
• Targeted therapy: For melanomas with BRAF mutations; works quickly but may stop working over time
• Other treatments: Radiation therapy for brain metastases, surgery to remove isolated metastases

What is the Outlook?

• Early detection is key: If melanoma is caught when it's thin (less than 1mm), the cure rate is over 98%.
• Advanced melanoma is now treatable: Even if melanoma has spread, new immunotherapy drugs have transformed outcomes—half of patients with advanced melanoma now survive 5 years or more, compared to less than 10% before 2011.
• Regular follow-up: After treatment, you'll have regular skin checks to detect any recurrence early and to find any new melanomas (people who've had one melanoma have a higher chance of developing another).

How to Prevent Melanoma

1. Protect your skin from the sun:

   • Use sunscreen: SPF 30 or higher, broad-spectrum (protects against UVA and UVB); apply 30 minutes before going outside and reapply every 2 hours
   • Wear protective clothing: Long sleeves, wide-brimmed hat, UV-blocking sunglasses
   • Seek shade between 10am and 4pm when the sun is strongest
   • Never use tanning beds: They dramatically increase melanoma risk and are banned for under-18s in many countries

2. Check your skin monthly: Look for new or changing moles using the ABCDE rule; use a mirror or ask a partner to check your back and scalp

3. Get professional skin checks: If you're at high risk (fair skin, many moles, family history, previous melanoma), see a dermatologist for a full-body skin exam once a year

4. Protect children: Childhood sunburns are particularly dangerous; always use sunscreen, hats, and protective clothing on children

Living with Melanoma

• Emotional support: A cancer diagnosis can be frightening; talk to your doctor, join a support group (Melanoma UK, Skin Cancer Foundation), and seek counselling if needed
• Skin self-examination: Continue monthly skin checks for life
• Sun protection: Essential even after melanoma treatment; wear sunscreen daily
• Follow-up appointments: Attend all scheduled follow-ups to detect recurrence early

Resources:

• Melanoma UK: https://www.melanomauk.org.uk
• Cancer Research UK: https://www.cancerresearchuk.org/about-cancer/melanoma
• American Academy of Dermatology (Skin Cancer Detection): https://www.aad.org

---

14. Viva and Exam Preparation

Common Viva Questions and Model Answers

Q1: "Tell me about melanoma."

Model Answer: "Melanoma is a malignant neoplasm of melanocytes, the pigment-producing cells of the skin. It accounts for approximately 4% of skin cancers but causes 80% of skin cancer deaths due to its propensity for metastasis. [1] The global incidence is rising, with the highest rates in Australia and New Zealand exceeding 50 per 100,000 population. [2] The primary risk factor is ultraviolet radiation exposure, particularly intermittent intense exposure causing sunburns. Early detection and surgical excision of localised disease offer cure rates exceeding 95%, while metastatic disease has been transformed by immune checkpoint inhibitors and BRAF-targeted therapies, improving 5-year survival from 10% historically to 50-52% with combination immunotherapy. [4] Breslow thickness—the depth of tumour invasion in millimetres—is the most important prognostic factor and guides staging and treatment decisions."

Q2: "How would you assess a patient presenting with a suspicious pigmented lesion?"

Structured Answer: "I would take a systematic approach:

History:

• Duration of lesion and any recent changes (size, shape, colour, symptoms such as bleeding/itching)
• Personal history of previous melanoma or non-melanoma skin cancer
• Family history of melanoma
• UV exposure history (sunburns, tanning bed use, occupational exposure)
• Immunosuppression (transplant, HIV, immunosuppressive medications)

Examination:

• Assess the lesion using the ABCDE criteria: Asymmetry, Border irregularity, Colour variation, Diameter greater than 6mm, Evolution
• Dermoscopy if trained: Look for atypical network, blue-white veil, irregular dots/globules, regression structures
• Full-body skin examination to identify additional suspicious lesions or assess naevus pattern
• Regional lymph node examination for palpable nodes

Investigations:

• If suspicious: Excision biopsy with 2mm clinical margin, full-thickness skin to subcutaneous fat, for histopathological analysis including Breslow thickness, ulceration, mitotic rate
• Avoid shave biopsy as it precludes accurate Breslow depth measurement

Further Management:

• Depends on histopathology results; if melanoma confirmed, stage-appropriate definitive treatment including wide local excision and consideration of sentinel lymph node biopsy for Breslow ≥0.8mm."

Q3: "What are the AJCC TNM staging criteria for melanoma?"

Model Answer:

T staging is based on Breslow depth and ulceration:

• T1: ≤1mm; subclassified as T1a (≤0.8mm, no ulceration) or T1b (≤1mm with ulceration or 0.8-1mm)
• T2: greater than 1-2mm; T2a (no ulceration), T2b (ulcerated)
• T3: greater than 2-4mm; T3a (no ulceration), T3b (ulcerated)
• T4: greater than 4mm; T4a (no ulceration), T4b (ulcerated)

N staging incorporates number of involved lymph nodes, detection method (clinically occult vs detected), and presence of satellite/in-transit metastases:

• N1: 1 node or satellite/in-transit only
• N2: 2-3 nodes
• N3: ≥4 nodes
• Each subclassified by detection method (a: occult/SLNB+, b: clinically detected) and satellites (c: satellites/in-transit present)

M staging considers metastatic site and serum LDH:

• M1 a: Distant skin/soft tissue/non-regional nodes
• M1 b: Lung
• M1 c: Non-CNS visceral
• M1 d: CNS
• Elevated LDH upstages within each M category (suffix '1')

Staging combines T, N, M to determine Stage 0-IV, with 5-year survival ranging from 99% (Stage 0) to 32% (Stage IIID) to 50-52% (Stage IV with modern immunotherapy)."

Q4: "What is the role of sentinel lymph node biopsy in melanoma management?"

Model Answer: "Sentinel lymph node biopsy identifies occult regional lymph node micrometastases in clinically node-negative patients, providing accurate staging and prognostic information.

Indications: Breslow thickness ≥0.8mm, or less than 0.8mm with ulceration or high mitotic rate, in clinically node-negative patients.

Evidence: The MSLT-I trial demonstrated that SLNB provides accurate staging but does NOT improve overall survival compared to nodal observation with therapeutic dissection at recurrence. [11] Therefore, SLNB is performed for staging purposes, not as therapeutic intervention.

Management of positive SLNB: The MSLT-II trial showed that completion lymph node dissection does NOT improve melanoma-specific survival compared to ultrasound surveillance in SLNB-positive patients. [12] Current practice is ultrasound surveillance as an acceptable alternative to completion dissection, reserving therapeutic dissection for patients who develop nodal recurrence. SLNB positivity now triggers consideration of adjuvant systemic therapy (immunotherapy or targeted therapy) to reduce recurrence risk."

Q5: "Describe the management of Stage III melanoma."

Model Answer: "Stage III melanoma indicates regional lymph node involvement or presence of satellite/in-transit metastases.

Surgical Management:

• Wide local excision of primary (if not already performed) with stage-appropriate margins
• For positive SLNB: Either ultrasound surveillance (preferred) or completion lymph node dissection in selected cases (bulky nodes, multiple positive nodes)

Adjuvant Systemic Therapy: All Stage III patients should be considered for adjuvant therapy to reduce recurrence risk:

• Immunotherapy: Pembrolizumab or nivolumab (anti-PD-1 antibodies) for 12 months; KEYNOTE-054 trial showed 3.5-year RFS of 59% vs 41% with pembrolizumab vs placebo [22]
• Targeted Therapy: For BRAF V600-mutant melanoma, dabrafenib plus trametinib for 12 months; COMBI-AD trial showed 3-year RFS 58% vs 39% [25]
• Anti-PD-1 immunotherapy is generally preferred due to broader applicability and better tolerability

Surveillance: Clinical examination every 3 months for 2 years, then every 6 months; imaging (CT or PET-CT) every 6-12 months for first 3 years; lifelong dermatology follow-up."

Q6: "What is the role of immunotherapy in metastatic melanoma?"

Model Answer: "Immune checkpoint inhibitors have revolutionised metastatic melanoma treatment, transforming 5-year survival from less than 10% historically to 50-52% with modern combination therapy. [4]

Mechanism: Checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) block immune checkpoint proteins, unleashing T-cell-mediated anti-tumour immunity.

Evidence: The CheckMate 067 trial compared nivolumab+ipilimumab combination vs nivolumab monotherapy vs ipilimumab monotherapy, demonstrating 5-year overall survival of 52% vs 44% vs 26%, respectively, with combination therapy. [4]

Treatment Options:

• First-line for fit patients: Nivolumab + ipilimumab combination (highest response rate 58%, but grade 3-4 immune-related adverse events in 55-59%)
• First-line alternative: Pembrolizumab or nivolumab monotherapy (anti-PD-1); better tolerated with 5-year OS approximately 44%

Adverse Events: Immune-related adverse events affect multiple organ systems—dermatologic (rash, vitiligo), gastrointestinal (colitis), hepatic (hepatitis), endocrine (thyroiditis, hypophysitis), pulmonary (pneumonitis), cardiac (rare but serious myocarditis). Management involves holding therapy and corticosteroids for grade 2 or higher toxicity.

Patient Selection: Combination therapy is preferred for fit patients (ECOG 0-1) requiring high response rates; monotherapy for elderly, ECOG 2, or comorbidities."

High-Yield Facts for Exams

• Breslow thickness is the single most important prognostic factor
• SLNB is for staging, not treatment (MSLT-I/II trials)
• Completion lymph node dissection does NOT improve survival (MSLT-II)
• Adjuvant pembrolizumab or nivolumab reduces recurrence in Stage III (KEYNOTE-054, CheckMate-238)
• Combination nivolumab + ipilimumab achieves 52% 5-year OS in Stage IV (CheckMate 067)
• BRAF mutations occur in 50% of melanomas; enable targeted therapy with BRAF+MEK inhibitors
• Nodular melanoma often fails ABCDE criteria; use EFG (Elevated, Firm, Growing)
• Amelanotic melanoma (2-8%) frequently misdiagnosed; maintain high suspicion for persistent pink nodules
• Hutchinson's sign (periungual pigmentation) is specific for subungual melanoma
• Acral lentiginous melanoma accounts for 50-70% of melanomas in dark-skinned populations
• Ulceration worsens prognosis within each T stage; upstages T1a to T1b, etc.
• Excision margins: In situ 5mm, ≤1mm 1cm, 1-2mm 1-2cm, greater than 2mm 2cm
• Immune-related adverse events: Colitis, hepatitis, endocrinopathies; manage with steroids
• Brain metastases occur in 40-50% of Stage IV patients; SRS + systemic therapy is standard

---

15. References

1. Schadendorf D, van Akkooi AC, Berking C, et al. Melanoma. Lancet. 2018;392(10151):971-984. doi:10.1016/S0140-6736(18)31559-9

2. Arnold M, Singh D, Laversanne M, et al. Global Burden of Cutaneous Melanoma in 2020 and Projections to 2040. JAMA Dermatol. 2022;158(5):495-503. doi:10.1001/jamadermatol.2022.0160

3. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-492. doi:10.3322/caac.21409

4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836

5. Robert C, Grob JJ, Stroyakovskiy D, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059

6. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. doi:10.1038/nature00766

7. Abbasi NR, Shaw HM, Rigel DS, et al. Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA. 2004;292(22):2771-2776. doi:10.1001/jama.292.22.2771

8. Grob JJ, Bonerandi JJ. The 'ugly duckling' sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening. Arch Dermatol. 1998;134(1):103-104. doi:10.1001/archderm.134.1.103

9. Koch SE, Lange JR. Amelanotic melanoma: the great masquerader. J Am Acad Dermatol. 2000;42(5 Pt 1):731-734. doi:10.1016/s0190-9622(00)90128-1

10. Levit EK, Kagen MH, Scher RK, Grossman M, Altman E. The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol. 2000;42(2 Pt 1):269-274. doi:10.1016/s0190-9622(00)90137-2

11. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609. doi:10.1056/NEJMoa1310460

12. Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376(23):2211-2222. doi:10.1056/NEJMoa1613210

13. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer. 2005;41(1):45-60. doi:10.1016/j.ejca.2004.10.016

14. Olsen CM, Carroll HJ, Whiteman DC. Familial melanoma: a meta-analysis and estimates of attributable fraction. Cancer Epidemiol Biomarkers Prev. 2010;19(1):65-73. doi:10.1158/1055-9965.EPI-09-0928

15. Mervic L. Time course and pattern of metastasis of cutaneous melanoma differ between men and women. PLoS One. 2012;7(3):e32955. doi:10.1371/journal.pone.0032955

16. Stensheim H, Møller B, van Dijk T, Fosså SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol. 2009;27(1):45-51. doi:10.1200/JCO.2008.17.4110

17. Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251-263. doi:10.1016/j.cell.2012.06.024

18. Sample A, He YY. Mechanisms and prevention of UV-induced melanoma. Photodermatol Photoimmunol Photomed. 2018;34(1):13-24. doi:10.1111/phpp.12329

19. Vestergaard ME, Macaskill P, Holt PE, Menzies SW. Dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. Br J Dermatol. 2008;159(3):669-676. doi:10.1111/j.1365-2133.2008.08713.x

20. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-492. doi:10.3322/caac.21409

21. Sladden MJ, Balch C, Barzilai DA, et al. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev. 2009;(4):CD004835. doi:10.1002/14651858.CD004835.pub2

22. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378(19):1789-1801. doi:10.1056/NEJMoa1802357

23. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017;377(19):1824-1835. doi:10.1056/NEJMoa1709030

24. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016;375(19):1845-1855. doi:10.1056/NEJMoa1611299

25. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377(19):1813-1823. doi:10.1056/NEJMoa1708539

26. Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20(9):1239-1251. doi:10.1016/S1470-2045(19)30388-2

27. Robert C, Grob JJ, Stroyakovskiy D, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059

28. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603-615. doi:10.1016/S1470-2045(18)30142-6

29. Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol. 2011;29(3):257-263. doi:10.1200/JCO.2010.28.7078

30. National Institute for Health and Care Excellence. Melanoma: assessment and management (NG14). Published January 29, 2015. Updated December 15, 2022. Available at: https://www.nice.org.uk/guidance/ng14

31. Michielin O, van Akkooi AC, Ascierto PA, Dummer R, Keilholz U; ESMO Guidelines Committee. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(12):1884-1901. doi:10.1093/annonc/mdz411

32. Swetter SM, Tsao H, Bichakjian CK, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2019;80(1):208-250. doi:10.1016/j.jaad.2018.08.055

---

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances and be made in consultation with appropriate specialists. This content does not replace clinical judgment or individualised patient care.