Melanoma

Skin Neoplasia Naevi and Melanoma 

Naevi = hamartoma of the skin.

With respect to melanocytes, a benign neoplasm

Melanoma

Risk Factors: 

• UV Exposure
  • Sun Exposure and history of Sunburns
  • Sun sensitivity
  • Regular tanning bed use before age 30 years
• Caucasian skin
  • Fair skin that burns easily
    • common in very fair skin (skin phototype 1 and 2)
    • may occur in those who tan quite easily (phototype 3)
    • rare in brown or black skin (phototype 4-6).
• Latitude related
• Immunosuppression
• Congenital Melanocytic Nevi
• Melanoma Family History
  • First degree relative increases risk 8-12 fold
• Blistering Sunburn more than once as child

VERY HIGH RISK:

1. Previous invasive melanoma or melanoma in situ(especially <40 years old)
2. Previous nonmelanoma skin cancer
3. Multiple (>5) atypical naevi (funny-looking moles or moles that are histologically dysplastic)
4. Strong family history of melanoma with 2 or more first-degree relatives affected
   • Atypical Nevus syndrome with Family History of Melanoma
5. Giant Congenital Melanocytic Nevi (>15-20 cm)
6. Precursor Lesions

• Lentigo maligna
• Congenital neoplastic nevi
• Clark’s melanocytic nevi (Dysplastic Nevus)

Less strong factors include 

• blue or green eyes
• red or blond hair
• indoor occupation with outdoor recreation
• signs of sun damage.

Extrinsic Risk Factors for Melanoma
Solar UV radiation		[8,11,12]
●   Intermittent sun exposure	RR: 1.61 (95% CI: 1.31–1.99)	[9,14]
●   Sunburn  (especially in childhood)	RR 2.03 (95% CI: 1.73–2.37)	[9,15,16,17]
●   Sunbathing (‘ever’ intentional sun exposure)	RR 1.44 (95% CI: 1.18–1.76)	[11,19]
Artificial UV radiation
●   ‘ever’ sunbed use <35 years old	RR: 1.2 (95% CI: 1.08–1.34) RR: 1.59 (95% CI: 1.36–1.85)	[17,19,20,21]
Lifestyle factors
●   High lifetime intake of spirits	HR: 1.47 (95% CI = 1.08–1.99)	[24,25]
Immunosuppression
●   HIV in Caucasians	IR > 10 fold increased	[26]
●   (renal) Transplant recipients	RR: 3.6 (95% CI: 3.1–4.1)	[27,28,29,30]
●   Non-Hodgkin’s lymphoma	RR: 2.4 (95% CI: 1.8–3.2)	[31]
●   Chronic lymphocytic leukemia	RR: 3.1 (95% CI: 2.1–4.4)	[31]

Intrinsic Risk Factors for Melanoma
Phenotype
●   Fitzpatrick phototype:		[33]
III vs. IV	RR: 1.77 (95% CI: 1.23–2.56)
II vs. IV	RR: 1.84 (95% CI: 1.43–2.36)
I vs. IV	RR: 2.09 (95% CI: 1.67–2.58
●   Light eye color:		[33]
blue vs. dark	RR: 1.47 (95% CI: 1.28–1.69)
green vs. dark	RR: 1.61 (95% CI: 1.06–2.45)
●   Light hair color:		[33]
red vs. dark	RR: 3.64 (95% CI: 2.56–5.37)
blond vs. dark	RR: 1.96 (95% CI: 1.41–2.74)
light brown vs. dark	RR: 1.62 (95% CI: 1.11–2.34)
●   Freckles	RR: 2.10 (95% CI: 1.80–2.45)	[34]
●   High nevi count (>100)	RR: 6.89 (95% CI: 4.63–10.25)	[35]
●   Presence of atypical nevi	RR: 6.36 (95% CI: 3.80–10.33)	[35]
Sex
●   Male sex	IR per 100,000: male vs. female 29.3 vs. 18.0	[40,41]
Medical history
●   Personal history of
melanoma	O:E: 8.61 (95% CI: 8.31–8.92)	[46,47]
BCC (yes vs. no)	2.46% vs. 0.37%	[46]
●   Family history of     melanoma	RR: 1.74 (95% CI: 1.41–2.14)	[34,48,50]
●   Preceding malignancy:		[65,66]
Breast cancer	SIR: 5.13 (95% CI: 3.91–6.73)
Thyroid cancer	SIR: 16.2 (95% CI: 5.22–50.2)
Head and neck cancer	SIR: 5.62 (95% CI: 1.41–22.50)
Soft tissue cancer	SIR: 8.68 (95% CI: 2.17–34.70)
Cervical cancer	SIR: 12.5 (95% CI: 3.14–50.20)
Kidney/urinary tract cancer	SIR: 3.19 (95% CI: 1.52–6.68)
Prostate cancer	SIR: 4.36 (95% CI: 2.63–7.24)
Acute myeloid leukemia	SIR: 6.44 (95% CI: 2.42–17.20)
Chronic lymphatic leukemia	SIR: 2.74 (95% CI, 2.43–3.08)	[67]
Genetic conditions and susceptibility genes
●   Familial melanoma		[52,53,54]
●   CDKN2A, CDK4, BAP1, MITF, TERT, ACD, TERF2IP, POT1 mutation		[56,57,59,60]
●   MC1R
one variant:	OR: 1.41 (95% CI: 1.07–1.87)
≥two variants	OR: 2.51 (95% CI: 1.83–3.44)
Mixed cancer syndromes
●   PTEN, BRCA1, BRCA2, RB1, BAP1, TP53 mutation		[56,61,62,63]

Epidemiology:

• 1 – 3% of childhood cancers
• Females 14/100,000, males 9/100,000. Difference is in the distribution on the legs

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Skin Cancer Risk Assessment – Routine History Questions

When assessing a patient’s skin cancer risk (e.g. in general practice or skin check clinic), include the following key history domains:

🔹 1. Personal History of Skin Cancer

• Have you ever been diagnosed with:
  • Melanoma?
  • Basal cell carcinoma (BCC)?
  • Squamous cell carcinoma (SCC)?
  • Solar keratoses (actinic keratoses)?

🔹 2. Family History

• Any first-degree relatives with melanoma or other skin cancers?
  • Ask about age of onset and number of family members affected.

🔹 3. Phenotypic Risk Factors

• What is your natural skin type? (e.g. Fitzpatrick I–VI)
• Do you have:
  • Fair skin that burns easily?
  • Red or blonde hair?
  • Blue or green eyes?
  • Freckles?
• How do you react to sun exposure (burn vs tan)?

🔹 4. Naevus Profile

• Do you have a large number of moles (>50)?
• Do you have any atypical/dysplastic moles?
• Any congenital large naevi?

🔹 5. UV Exposure History

• Have you had significant sun exposure, especially:
  • As a child?
  • During outdoor work or hobbies?
• Have you ever had blistering sunburns, particularly in childhood or adolescence?
• Any solarium or tanning bed use?

🔹 6. Immunosuppression

• Are you on immunosuppressive medications?
• Any organ transplant, HIV, or hematological malignancy?

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Examination Findings

• A: asymmetry
• B: border irregular – e.g. growing a peninsular
• C: colour – 3 or more, colour not symmetrical, areas of black, variegated
• D: dimension > 0.6 cm (although you can get smaller melanomas, and most larger lesions aren‟t melanomas
• E: elevated  – dermal penetration (but most are initially flat – superficial spreading melanomas)
• Usually asymptomatic: don‟t bleed until late (ie take bleeding seriously) and don‟t usually itch

Watch out for:

• Changes: but moles can change for lots of reasons. And patients aren‟t good at detecting changes (either miss them or think they‟ve changed when they haven‟t)
• Bleeding, itching and halo (although can get two tone moles – OK if symmetrical)

Progression:

• Radial Growth Phase: initially growth is along the dermo-epidermal junction and within the epidermis
• Vertical Growth Phase: Growth into the dermis  malignant cells in contact with lymphatics and capillaries  metastasis
• Nodular melanoma: bad news
• Acral Letigenous Melanoma: on palms and soles

Differential:

• Benign mole
• BCC
• Seborrheic keratosis: stuck on appearance, monotone and symmetrical, greasy surface, numerous
• Angiokeratomas
• Dermatofibroma: firm, round, monotone
• Any lesion under a nail (usually thumb) is a melanoma or SCC until proven otherwise

Pathology:

• Features of malignant cells: irregular, hyperchromatic, large N:C ratio, mitoses (blackberry nuclei), abnormal number of mitosis
• Radical/Superficial/Horizontal growth phase: cells in contact with dermis, don‟t metastasise
• Vertical growth: mass of atypical melanocytes infiltrating dermis, lymphocytes, not necessarily pigmented, metastasises
• Will always have junctional activity. If they only exist deeper in the dermis then they‟re not malignant.

Pathology report

1. Diagnosis of primary melanoma
2. Breslow thickness to the nearest 0.1 mm
3. Clark level of invasion
4. Margins of excision i.e. the normal tissue around the tumour
5. Mitotic rate – a measure of how fast the cells are proliferating
6. Whether or not there is ulceration

Evaluation

• Melanoma metastases
  • Lymph Node exam
  • Full skin exam
• Chest XRay
• Labs considered above stage IA (and in all cases of Stage III and IV)
  • Complete Blood Count (CBC)
  • Liver Function Tests (LFT or hepatic panel)
  • Lactate Dehydrogenase (LDH)
• Advanced imaging (indicated for stage III, IV)
  • CT Head, chest and Abdomen and/or
  • PET Scan (eyes to thighs)

Prognosis:

• Breslow tumour thickness
  • a strong predictor of outcome; the thicker the melanoma, the more likely it is to metastasise (spread).
    • > 0.76 cm bad
    • 5year survival related to tumor depth
    • Survival 99%: Depth < 0.85mm
    • Survival 80%: Depth 0.85 to 1.69mm
    • Survival 70%: Depth 1.70 to 3.64mm
    • Survival 40%: Depth > 3.65mm
• Clarke‟s levels
  • deeper the Clark level, the greater the risk of metastasis
  •     Level 1: Epidermis
  •     Level 2: Reaches papillary Dermis
  •     Level 3: Fills papillary Dermis ~ Breslow 0.76, bigger = worse
  •     Level 4: Enters reticular Dermis
  •     Level 5: Penetrates subcutaneous fat
• Ulceration > 3 mm (bad)
• High mitotic rate (bad)
• Regression an indication of metastasis (bad)
• Tumour infiltrating lymphocytes (bad)

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Treatment: surgical excision

Summary: Early 2 mm excision biopsy for diagnosis → WLE margins matched to Breslow → consider SLNB >1 mm or high-risk thin lesions → stage-appropriate imaging and MDT-guided systemic therapy → structured long-term surveillance and sun-safety counselling.

1. Initial Diagnosis: Excisional Biopsy

Purpose: Confirm melanoma diagnosis and determine Breslow thickness for treatment planning.

Preferred Technique: Elliptical Excision Biopsy

• Margin: 2 mm peripheral margin.
• Orientation: Along relaxed skin tension lines.
• Deep margin: Includes upper subcutis.
• Benefits: Enables accurate Breslow depth, margin assessment, and histological staging.

Why Shave or Punch Biopsies Are Less Preferred

• Risk of under-sampling (misses depth).
• Inaccurate Breslow thickness if base is transected.
• Higher false-negative rate and margin positivity.
  • Punch: 23% false negatives
  • Shave: 4.5%
  • Elliptical excision: 1.7%

When Shave/Punch May Be Acceptable

• If full-thickness lesion removal is achieved.
• Scenarios:
  • Small, thin, or flat lesions (e.g. suspected melanoma in situ).
  • Acral or cosmetically sensitive sites (e.g. face, eyelid, nail, lip).
  • Large lesions unsuitable for elliptical excision in one stage.

Technique Requirements (If Used):

• Aim for full-thickness removal:
  • Margins: ~1–3 mm in all directions.
  • Depth: to upper subcutis, not just dermis.
  • Do NOT do superficial shaves or partial punches.
  • Label clearly as “excisional biopsy” on pathology request form.
  • Ensure timely wide local excision (WLE) is arranged if melanoma confirmed.

Guideline Evidence:

• Grade C: Deep shave (saucerisation) or full-thickness punch acceptable in selected cases.

Bottom Line:

• “Avoid shave/punch biopsy” = partly true.
• Gold standard = elliptical excisional biopsy.
  • Deep shave or full-thickness punch is acceptable if:
    • Whole lesion is removed.
    • Depth and margins are preserved.
    • Pathology can confidently stage.

2. Definitive Treatment: Wide Local Excision (WLE)

Breslow Thickness Determines Excision Margins

Breslow Thickness	Lateral WLE Margin	Deep Margin
Melanoma in situ	5 mm (up to 10 mm for lentigo maligna)	To fascia
≤ 1 mm	1 cm	To fascia
1.01 – 2 mm	1–2 cm (aim for 2 cm)	To fascia
2.01 – 4 mm	2 cm	To fascia
> 4 mm	2 cm	To fascia

3. Sentinel Lymph Node Biopsy (SLNB)

When to Offer:

• Breslow >1.0 mm (standard recommendation).
• Breslow 0.8–1.0 mm with high-risk features:
  • Ulceration
  • Clark level IV/V (less commonly used)
  • Mitotic rate ≥1/mm²
  • Lymphovascular invasion
  • Younger patients

Procedure:

• Timing: Prior to or at same time as WLE.
• Involves radioactive tracer or dye for lymphatic mapping.
• Purpose: Prognostic and staging value, not therapeutic.
• Positive SLN: Upgrade to Stage III; triggers staging and MDT input.

SLNB Positivity Rates by Thickness:

Melanoma Thickness	Node Involvement Risk	SLNB Indicated?
In situ	Negligible	No
< 0.75 mm	<5%	No
0.75–1.0 mm	5–10%	Yes, if high-risk
1.0–4.0 mm	15–25%	Yes
> 4.0 mm	25–40%	Yes

4. Regional Lymph Node Assessment & CLND

Complete Lymph Node Dissection (CLND):

• Indications:
  • SLNB positive.
  • Clinically apparent lymph node disease.
• Aim: Regional control; reduces recurrence.

Prognosis by SLN Status:

Condition	5-Year Survival	Prognostic Value
SLN Negative	90.2%	High
SLN Positive	72.3%	Moderate
CLND at detection	72.3%	Early advantage
CLND when clinical	52.4%	Worse outcome

5. Staging Investigations

Stage	Routine Imaging
In situ	Not required
IA	Not required
IB–IIA	No routine imaging; consider nodal US if concern
IIB–IIC	CT chest/abdomen/pelvis, +/- brain MRI or PET/CT
III	PET/CT, brain MRI, serum LDH
IV	PET/CT, brain MRI, serum LDH

• PET/CT has better whole-body sensitivity compared to CT for Stage III/IV.
• Brain MRI is more sensitive than CT for CNS metastases, and is preferred over CT brain in advanced stages.
• LDH is not diagnostic, but included as a prognostic marker in AJCC staging for Stage IV.

6. Adjuvant & Systemic Therapy

Stage III / resected IIB–IIC:

• Immunotherapy: Nivolumab or Pembrolizumab.
• BRAF mutation: BRAF + MEK inhibitors.

Stage IV / unresectable:

• First-line: Immunotherapy.
• BRAF-mutant: Consider targeted therapy.
• Enrolment in clinical trials encouraged.

7. Follow-Up & Surveillance

Stage	Clinical Exam Schedule	Imaging
In situ	Yearly with GP/Derm	None
IA	Yearly	None
IB–IIA	6–12 monthly (years 1–5), then yearly	Consider node US
IIB–IIC	3–6 monthly (years 1–5), then 6–12 monthly	Annual PET/CT/CT + brain MRI
III	3–4 monthly (years 1–2), 6 monthly (years 3–5), then yearly	PET/CT or CT every 6–12 months
IV	Individualised	As per MDT/oncologist

Components of Follow-Up:

• Examine scar and regional nodes.
• General skin check.
• Full physical exam.
• Mole mapping for high-risk patients.

8. Sun Protection & Patient Education

Avoid peak UV hours (10 a.m. – 4 p.m.).

• Seek shade; wear protective clothing and wide-brimmed hats.
• Use wrap-around sunglasses.
• Apply broad-spectrum SPF ≥ 30 sunscreen.
• Avoid tanning and solariums.
• Promote regular self-examination and professional skin checks.

Educate on monthly skin self-checks using the ABCDE approach:

• Asymmetry
• Border irregularity
• Colour variation
• Diameter >6 mm
• Evolution (changing in size, shape, colour, or symptoms)

Encourage checking:

• Back (use mirror or partner)
• Scalp
• Soles of feet
• Under nails

Professional Skin Checks

Advise:

• At least annual full-skin checks by a GP or dermatologist if moderate-to-high risk
• More frequent reviews if:
  • Multiple atypical naevi
  • Personal/family history of melanoma
  • History of high UV exposure

Patient Education & Resources

• Provide brochures or links to:
  • Cancer Council Australia – Skin Cancer Prevention
  • SunSmart program
• Reinforce that early detection = high cure rates in melanoma

9. When to Refer to Specialist or MDT

• Lesions in cosmetically or functionally complex areas.
• Large lesions requiring grafts or flaps.
• Positive or incomplete biopsy margins.
• Breslow > 1 mm (for SLNB and MDT planning).
• Stage IIB or higher, nodal involvement, or metastases.
• Patients requiring systemic therapy or trial enrolment.

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Superficial spreading melanoma

• grows outward in epidermis
• lots of colour variation in lesion
• 70% melanomas
• the malignant cells tend to stay within the tissue of origin, the epidermis, in an ‘in-situ’ phase for a prolonged period (months to decades).
  • At first, superficial spreading melanoma grows horizontally on the skin surface (radial growth phase. ), 
  • An unknown proportion of superficial spreading melanoma become invasive,
    • melanoma cells cross the basement membrane of the epidermis and malignant cells enter the dermis. 
  • A rapidly-growing nodular melanoma can arise within superficial spreading melanoma and start to proliferate more deeply within the skin.

• The most frequently observed dermoscopic features of superficial spreading melanoma are:

• Asymmetric structure and colours
• Atypical pigment network
• Blue-grey structures
• Multiple colours (5-6)

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Lentigo maligna

• “Hutchinson melanotic freckle”
• Malignant change of melanocytes along the epidermis border but no infiltration. 
• slow growing, intraepidermal, Takes years to become invasive
• multicoloured in time
• sun exposed areas in elderly
  • commonly face
  • tan macule
  • slowly enlarges and develops a geographic shape
• Now showing up on younger people – excise before they get too big

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Nodular melanoma

• trunk and limbs, young adult to middle age
• “blueberry” like nodule may be associated
• Isolated globules
• Blue-grey veil
• White streaks
• Irregular linear or dotted vessels
• Elevated, Firm, Growing
• Early: symmetrical, non-pigmented, even colour, small diameter, grows vertically, often mistaken for haemangioma or pyogemnic granuloma

Acral lentiginous melanoma

• -palms, soles and distal phalanges
• tends to be much deeper than is suspected from its flat nature. 
• Dermoscopically
  • broad parallel ridge pattern rather than the benign parallel furrow pattern
  • asymmetry and other features of superficial melanoma may be present.
  • Little white dots on the ridges are sweat ducts (acrosyringia)
• -poor prognosis
• -more common in dark skin

Desmoplastic melanoma

• rare, aggressive
• often ooks like a scar
• most non-pigmented

Amelanocytic melanoma

• odd-looking pink lesion. 
• small amount of focal and irregular pigmentation, often on the periphery of the lesion. 
• Atypical vascularity may be a clue, with linear, dotted, corkscrew or polymorphous vessels

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Melanocytic Naevi

• Normal skin: epidermal cells, plus melanocytes, Langerhans cells (Antigen Presenting Cells –APC), prickle cells and merkel cells (sensory receptors)

• Benign melanocytic naevi:
  • Junctional:
    • epidermis only
    • early active growth to <0.5 cm
    • Can be non-pigmented
    • Overgrowth of  melanocytes in nests along the junction of the dermis and epidermis.
  • Compound:
    • epidermis and dermis
    • older active growth (moles on palms, soles and genitalia stay junctional)
  • Intradermal:
    • stopped growing, loss of tyrosinase
    • small and pale. 
    • Don‟t have contact with the epidermal junction (ie are deep). 
    • Don‟t become malignant – must have junctional activity to do this

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Dysplastic melanocytic naevi (Atypical Mole Syndrome):

• Uncontrolled proliferation without malignancy 
• (> 100 with at least one Dysplastic more or a mole > 0.5 cm)  
• Mostly benign with possibility of malignancy
• If have > 100 moles, 100 to 200 times normal risk
• Risk of melanoma proportional to the number of moles, plus family history and degree of atypia
• Management:
  • Self checking each month
  • Annual doctor check (to make sure they’re self checking)
  • Most moles that change aren’t melanoma, but if suspicious need to remove it

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Halo naevi

• Fairly common, especially in kids. 
• Depigmented symmetrical halo around the mole, but the mole is normal (cf depigmented melanoma where pigmented lesion is not normal and not central)
• Can occur more frequently when has melanoma elsewhere or when being treated for advanced melanoma. – do a full skin check
• Unknown trigger, immune system attacks the naevus and de-pigments the surrounding skin also
• Halo is 0.5 – 1cm wide, symmetrical
• No treatment required unless atypical features
• Pathogenesis: ?Somatic mutation 
• Differential:
  • Melanoma
  • Dermatofibroma: feels firm
  • Seborrheic keratosis: altered texture

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Blue naevus

• Melanocytic naevus where the naevus cells are located deep within the dermis
• Incomplete migration of the melanocytes – appears blue due to scattering of light
• More common in Asians and women
• Common blue naevus 0.5-1cm, never becomes malignant
• Cellular blue naevus is nodular at least 1cm diameter, rarely can become malignant
• Usually develop late childhood or adolescence, rare at birth
• Diagnose clinically, can excise if unsure , changing appearance, older adult

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Atypical/dysplastic melanocytic naevus

• People with 5 or more clinically atypical naevi have a higher risk than the general population of developing melanoma
• An atypical naevus may exhibit the following characteristics:
  • Size greater than 5 mm in diameter
  • Ill-defined or blurred borders
  • Irregular margins resulting in an unusual shape
  • Varying shades of color (mostly pink, tan, brown, black)
  • Both flat and bumpy components
• Demographics:
  • Sporadic Atypical Naevi:
    • Affect fair-skinned individuals with light-colored hair and freckles (phototype 1 or 2).
    • More common with frequent sun exposure.
    • Develop mostly within the first 15 years of life.
    • Typically, individuals have 1 to 10 moles larger than 6 mm in diameter.
  • Familial Atypical Naevi: Associated with FAMMM syndrome (Familial Atypical Multiple Mole and Melanoma). Characteristics include:
    • A first or second-degree relative diagnosed with melanoma at a young age (< 40 years)
    • A large number of naevi (often more than 50), some atypical
    • Histopathologically dysplastic naevi
    • Several hundred atypical naevi may be present.

Importance of Atypical Naevi

• Individuals with 5 or more clinically atypical naevi have a sixfold increased risk of melanoma.
• FAMMM syndrome significantly increases melanoma risk.

Management

• Suspicious or changing naevi should be removed by excision biopsy.
• should be taught how to self-examine their skin for new skin lesions and for changes to existing moles 
• numerous moles should visit their family doctor or dermatologist regularly for a thorough skin check.
• keep photographic records of melanocytic naevi
• Careful sun protection
  • Avoid excessive sun exposure and sunburn
  • dress up
  • use a SPF50+ sunscreen when outdoors in the middle of the day or for prolonged periods

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Epidermal Naevi

• Defined according to their predominant cell type
• Circumscribed distribution over a part of the body surface, usually dermatomal
• Any size, never cross the midline, uncommon on face and head

• Sebaceous Naevi: hamartomas of predominantly sebaceous glands. Usually on scalp (lesion is bald). Raised, velvety surface, present at birth, usually small. Risk of basal-cell carcinoma, but no longer prophylactically excised
• Dermal Melanocytic naevus (Mongolian spot): macular blue-grey pigmentation present at birth, over sacral area in Mongoloid and some other races. Looks like a large bruise. Rarely persist into adulthood.
• Congenital naevocellular naevus:
  • Small is < 1.5 cm, intermediate = 1.5 – 20 cm, large is > 20 cm.
  • If over lower sacrum –> spinabifida occulta.
  • May arise or darken in puberty. Large ones have risk of melanoma
• Spitz naevus:
  • appears in early childhood as a firm, round red or reddish brown nodule.
  • May bleed and crust. Benign. Local excision.