Melanoma

Skin Neoplasia Naevi and Melanoma 

Naevi = hamartoma of the skin.

With respect to melanocytes, a benign neoplasm

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

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

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

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

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

Spotting them:

• 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)

Treatment: surgical excision

AFP > 2012 > July > Melanoma guide Volume 41, Issue 7, July 2012 Melanoma A management guide for GPs

Initial Excision Biopsy

• Purpose: Confirms melanoma diagnosis and aids in planning definitive treatment.
• Excision Biopsy with 2 mm Margins:
  • A narrow-margin excision biopsy (2 mm) is preferred for initial diagnosis rather than a wide excision.
  • Allows for histological confirmation of melanoma, precise measurement of Breslow thickness, and planning of further treatment.
• Partial Biopsies (e.g., punch, shave):
  • These are generally not recommended as they may miss parts of the tumour, leading to misdiagnosis.
  • However, for very large pigmented lesions, a partial biopsy may be taken from the most suspicious area if complete excision is challenging.

Histological Confirmation

• Ensures accurate diagnosis and facilitates rational planning of treatment:
  • Determines appropriate width and orientation of excision margins.
  • Helps decide on the necessity of sentinel lymph node (SLN) biopsy.

Definitive Treatment by Wide Excision

• Breslow Thickness:
  • Primary Measure for determining excision margin and prognosis.
  • Defined as the vertical depth of tumour invasion from the epidermis down into the dermis or subcutaneous tissue.
• Recommended Excision Margins:
  • Melanoma in situ: 5 mm margin.
  • Melanomas <1 mm: 1 cm margin.
  • Melanomas 1.0–4.0 mm: 1–2 cm margin, with 2 cm preferred for thicker melanomas within this range.
  • Melanomas >4 mm: 2 cm margin.

Sentinel Lymph Node Biopsy (SLNB)

• Indications:
  • Provides important prognostic information for patients with intermediate thickness melanomas (1–4 mm).
  • Offers a probable survival benefit.
  • Not recommended for thin melanomas (<0.8 mm) without high-risk features.
• Procedure:
  • Performed after primary tumor excision but before wide excision.
  • Involves lymphatic mapping and injection of a radioactive tracer or dye to identify sentinel lymph nodes.

Assessment of Regional Lymph Nodes in Melanoma

Melanoma Thickness	Risk of Spread to Regional Lymph Nodes	Recommended Treatment	Consider Sentinel Lymph Node Biopsy (SLNB)
In Situ	Negligible	Wide local excision with 5 mm margins	No
<0.75 mm	Very low (<5%)	Wide local excision	No
0.75–1.0 mm	Low (5–10%)	Wide local excision	Yes, if histological features (ulceration, elevated mitotic rate) are present
1.0–4.0 mm	Intermediate (15–25%)	Wide local excision	Yes
>4.0 mm	High (25–40%)	Wide local excision	Yes

Guidelines and Recommendations for Sentinel Lymph Node Biopsy (SLNB)

• Guidelines:
  • Australian and New Zealand guidelines recommend discussing SLN biopsy with patients who have melanomas ≥1 mm in thickness.
• Techniques and Expertise:
  • Lymphatic mapping, SLN biopsy, and histological SLN assessment are specialised techniques.
  • Best performed by individuals with appropriate training and experience.
• Lymphatic Mapping:
  • May be inaccurate after wide excision.
  • Consider direct referral of patients who might benefit from SLN biopsy to a melanoma centre or surgical oncologist.
• Intermediate Thickness Melanomas:
  • Approximately 15–25% of patients with intermediate thickness melanomas are SLN positive.
  • Immediate Complete Lymph Node Dissection (CLND) for patients with SLN positive results.

Survival and Prognostic Information

Condition	SLN Negative	SLN Positive	Early CLND	CLND when Metastasis Clinically Apparent
5-Year Survival	90.2%	72.3%	72.3%	52.4%
Prognostic Information	–	–	Provides significant survival benefit when performed early	–

Staging Tests

• Not indicated for patients with clinically localized primary melanomas.
• SLNB provides adequate staging information for most patients.

Complete Lymph Node Dissection

• Indications:
  • Required if microscopic or macroscopic disease is present in regional nodes identified by SLNB.
  • May involve removing all lymph nodes in the affected basin to reduce the risk of regional recurrence.

Management of Intransit Metastases

• Best managed at specialist melanoma treatment centers.
• Treatment options include surgery, local therapies, and systemic treatments depending on the extent of metastases.

follow-up for patients with invasive melanoma

• Advise
  • Avoid sun when strongest – UV rays are strongest from 10 a.m. to 4 p.m.
  • Stay in the shade.
  • Wear clothing that covers your arms and legs.
  • Wear a hat with a wide brim to shade your face, head, ears, and neck.
  • Wear sunglasses that wrap around and block both UVA and UVB rays.
  • Use a broad spectrum sunscreen with a sun protection factor (SPF) of 30 or higher
  • Avoid tanning, and never use UV tanning beds
  • Regular Self skin examination
  • skin checks by health professional
  • Follow-up intervals are preferably
    • 6monthly for five years for patients with stage 1 disease
    • 3-4 monthly for five years for patients with stage 2 or 3 disease
    • and yearly thereafter for all patients.

• Follow-up appointments may include:
  • A check of the scar where the primary melanoma was removed
  • A feel for the regional lymph nodes
  • A general skin examination
  • A full physical examination
  • In those with many moles or atypical moles, baseline whole body imaging and sequential macro and dermoscopic images of melanocytic lesions of concern (mole mapping)

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)

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

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

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

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.