Melanoma: The Definitive Guide

It is the third most common type of skin cancer after basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). In New Zealand is the fourth most common reported cancer overall.

MM can invade into the surrounding tissues and spread to regional sites. About 4-8% of them spread (metastasise) to distant sites of the body. Melanomas are primarily treated by surgical removal. More advanced melanomas are also treated with medications.

How common is melanoma (Epidemiology)?

In New Zealand, there were 2,730 melanomas (55 / 100,000 population) diagnosed during 2019. Different countries have markedly different rates.

While it’s generally more common in regions closer to the equator, this only holds true for individuals with fair skin. Darkly pigmented people do not have higher rates of MM in lower latitude regions.

Country	Incidence (per 100,000)
New Zealand	55
Australia	63
United States	27
Europe	15

Melanoma rates are continuing to increase mostly in people over the age of 40 whereas rates among younger people are declining. This is likely to be due to better sun protection education during their lifetimes. Overall, the mortality rate is declining, probably due to earlier detection.

Melanomas are approximately 20% more common amongst men, compared to women. Presumably, this is because of better sun protection behaviours by women.

Who gets melanoma (risk factors)?

Sun exposure is by far the most important risk factor for developing melanomas. Ultraviolet radiation causes damage to the DNA in the skin and over time this can progress to developing MM.

• In 2009, the World Health Organisation (WHO) classified tanning beds as a Group 1 Carcinogen (the same grouping as cigarette smoking). Several studies have shown that tanning beds confer an increased risk of melanoma and for some groups, their risk is more than six-fold.
• Fair skin increases the risk of development by about three times overall. Hair colour is a proxy for fair skin:
  • Blondes have a 2 times increased risk.
  • Redheads are 3.6 times more likely to develop.

Viagra

Various studies have suggested a link between sildenafil (Viagra) and melanoma, reporting an increased risk of 14-84%. However, most of these studies did not control for lifestyle factors e.g., sun exposure, medical conditions, etc. We are not convinced by this association.

Endometriosis

Some small studies have also seen an increase in those with endometriosis (60% increase) and prostate cancer (83% increase), however further studies are required to confirm the association.

While only 29.1% of melanomas develop from existing naevi (moles), having many naevi increases the risk.

• 16 naevi: 47% increased risk.
• > 100 naevi: 600% increased risk.

A family history also increases the risk:

• One first-degree relative with melanoma results in about a three-times risk.
• Two first-degree relatives with melanoma confer a 9-times risk for an individual developing melanoma.

Another melanoma risk factor is having previously had one:

• One previous melanoma results in a 2-3 times risk of developing another.
• Two melanomas result in a 72% risk of developing another within 5 years.

Some common risk factors are summarised in the following table:

Risk factor	Relative Risk
Previous melanoma	2-3
Previous NMSC	4.3
1+ parent	2.4-4.4
Sibling	3-4.4
Two first degree relatives	8.9
Naevi 0-15	1.0
Naevi 16-40	1.5
Naevi 41-100	2.2-4.7
Naevi 101-120	6.9
Red hair	3.6
Blond hair	2
Transplant recipient	3.6
Moderate alcohol	1.2

Immunosuppression

Those who are chronically immunosuppressed have an increased risk of developing melanoma. Transplant recipients have 3.6 times increased risk.

Diet

Several studies have reported protective or harmful associations with melanoma (caffeine, citrus fruit). However, these studies have not completely controlled for confounding factors so it is difficult to draw meaningful conclusions.

How does a melanoma develop (Pathogenesis)

Melanomas develop from a complex interaction of genes and environmental influences, in particular UV-induced DNA damage.

It is important to realise that even tanning (without burning) results in UV-induced damage of keratinocyte DNA damage and induction of p53-mediated stimulation of melanocytes (pigment cells). Interestingly, this process involves the proopiomelanocortin (POMC)/melanocyte-stimulating hormone (MSH) which contains endorphins, leading to the hypothesis that this could be a pathway for sun addiction.

Almost all melanomas develop through activation of the mitogen-activated protein kinase (MAPK) pathway. This pathway promotes cellular growth and survival. Mutations in several of these proteins and receptors can lead to uncontrolled cellular growth and development. In melanomas, the most common are mutations affecting BRAF (45%) and NRAS (18%).

Understanding this pathway has resulted in the development of several medical medications (small molecule inhibitors) targeting BRAF, MEK, and KIT mutations. Inhibitors of extracellular signal-regulated kinase (ERK) are currently in development.

Symptoms & appearance of melanoma (clinical features)

Melanomas can develop anywhere on the skin – even where the sun doesn’t shine! But it usually develops in areas exposed to the sun. In those with darkly pigmented skin, melanomas are actually more common in non-sun-exposed areas. It is important to realise that two-thirds arise de novo (without an indefinable preceding naevus).

The ‘ugly duckling’ sign describes the observation that most people with numerous moles have a few signature naevus types. The ugly duckling lesion that is different from the others should be considered suspicious.

Adjusted for surface area, the face, head, and neck are the most common sites for MM, followed by the trunk.

Subtypes of melanoma

Melanomas mostly develop as superficial lesions of the epidermis (top layer of skin) and can remain as such for several years. This is known as the radial or horizontal growth phase.

Once melanomas invade the dermis, they enter their vertical growth phase which also gives them the potential to spread to distant sites (metastasise). Some (nodular) melanomas start with a vertical growth phase and as a result, are considered more aggressive. The strongest predictor of metastasis is the (Breslow) depth of the tumour.

• Superficial spreading makes up about 70% of melanomas with 60% being diagnosed with a Breslow thickness of ≤ 1 mm and therefore highly treatable. Classically they appear as dark macules or patches, irregular borders, and potentially different colours.
• Nodular comprise about 15% of melanomas and typically appear as dark papules or nodules. Most nodular melanomas are already > 2 mm at the time of diagnosis.
• Lentigo maligna makes up about 10% and usually appears in older people with chronic sun damage. It typically presents as a dark macule or patch that grows over years.
• Acral lentiginous comprise less than 5% of melanomas but is the most common type in those with darker skin. They appear on the palms and soles of the hands and feet as well as underneath the nail (subungual). They appear as dark macules or patches.
• Amelanotic lack pigment and make up about 2% of cases. Any of the above subtypes can present as an amelanotic melanoma. They can present as pink, red, or flesh-coloured macules, papules or nodules making them very difficult to detect.
• Spitzoids are uncommon and they usually present as a papule or nodule that is either red or dark in colour.
• Desmoplastics are also rare and typically located in areas of chronic sun exposure. They present as an amelanotic nodule or scar.
• Melanocytomas are rare darkly pigmented and slow-growing nodules.

ABCDE criteria for melanoma

Specialist dermatologists tend not to use these criteria and rely more on pattern recognition as they are able to draw from their extensive experience. Furthermore, they will also often use dermoscopy to assist with diagnosis.

How is a melanoma diagnosed?

All suspected melanomas should have confirmation by laboratory analysis (histology) which involves a surgical procedure to obtain the tissue sample. In most situations, an excisional biopsy should be performed – meaning the entire lesion is surgically removed with a narrow (2 mm) margin. While this may seem redundant, full lesion sampling is the standard recommendation to avoid the risk of a sampling error which can occur when taking a small (partial) biopsy.

Sampling errors arise when a biopsy is taken from a small part of the lesion. The analysis could be reported as benign when the biopsy has simply missed the melanoma. This is one of the worst errors to occur as the patient may avoid getting the lesion checked again while it continues to grow as they have been falsely reassured that it is benign.

However, in very large or difficult lesions an incisional biopsy can be performed with care. This should ideally be taken across a full diameter of the lesion and include the most significant area to minimise the risk of a sampling error.

After the biopsy, the sample is fixed in formalin, stained with haematoxylin and eosin (H&E), and prepared on slides. The pathology team may use a range of immunohistochemical stains to help confirm the diagnosis.

The pathologist will then examine these slides under a microscope and issue their report. There is no single diagnostic feature of melanoma. The diagnosis is made from a combination of characteristics. Often the diagnosis is straightforward, however, it can be difficult in some cases which results in an amount of pathologist discordance. Difficult-to-diagnose cases may require special immunohistochemical stains or molecular techniques to determine the diagnosis. This can delay the biopsy results, but the delay should not be interpreted as bad news.

The pathology report

• Breslow thickness: this is the single most important prognosticator and at a minimum determines how wide the subsequent formal excision margin should be.
• Ulceration: present/absent.
• Mitoses: number per mm squared. This is a measure of how rapidly the cells are dividing/replicating resulting the tumour growth.
• Microscopic satellites: present/absent.
• Vascular invasion: present/absent.
• Clark level: this is the anatomical level of invasion:
  • Level 1: Confined to the epidermis: in situ melanoma.
  • Level 2: Invasion into the papillary (superficial) dermis.
  • Level 3: Invasion to the junction of the papillary and reticular dermis.
  • Level 4: Invasion into the reticular dermis.
  • Level 5: Invasion into the subcutaneous tissue (fat).

Staging

Staging provides information on how extensive an MM has spread. It determines whether it is still in the skin (local) as spread to the nearest body region or to distant sites (metastatic). This information is then used to determine what treatment is appropriate.

It is important to realise that not all melanoma diagnoses require a complete staging work-up. This would potentially lead to a lot of unnecessary investigations and in particular unnecessary radiation exposure from scans.

Staging workup

Further imaging is recommended for tumours with a score of ≥ T3b (Breslow > 2mm with ulceration). Depending on the clinical situation, this may include:

• CT chest, abdomen, pelvis, or PET-CT.
• For tumours of the head and neck a CT neck.
• Stage IIIC or IIID an MRI of the brain.

Sentinel lymph node biopsy

Sentinel lymph node biopsies (SLNB) have been used to test for the microscopic spread of melanoma to the nearest (sentinel) lymph node. The procedure involves injecting a radioactive tracer to identify the first draining (sentinel) lymph node. This sentinel node is removed and sent for analysis to determine if it contains MM.

The theory is that if detected early, more aggressive treatments may result in better survival outcomes. Unfortunately, the study results have conflicted outcomes and treatments such as complete removal of the regional lymph nodes have not shown a survival benefit. Furthermore, some lymph node-positive patients may not be eligible for more aggressive treatments and some SLNBs are still often discussed as an option.

TNM staging system

The American Joint Committee on Cancer (AJCC) tumour, node, metastasis (TNM) system is used to score melanoma risk information and this is collated to classify according to the AJCC prognostic stage group.

T category	Thickness	Ulceration status
Tx: Thickness unknown	N/A	N/A
T0: No primary	N/A	N/A
Tis (in situ)	N/A	N/A
T1	≤ 1.0 mm	Unknown
T1a	< 0.8 mm	Nil
T1b	< 0.8 mm 0.8 – 1 mm	Ulcerated Either
T2	> 1 – 2 mm	Unknown
T2a	> 1 – 2 mm	Nil
T2b	> 1 – 2 mm	Ulcerated
T3	> 2 – 4 mm	Unknown
T3a	> 2 – 4 mm	Nil
T3b	> 2 – 4 mm	Ulcerated
T4	> 4 mm	Unknown
T4a	> 4 mm	Nil
T4b	> 4 mm	Ulcerated

Node category	Description	In-transit ± micro-satellite metastases
NX	Not assessed	No
N0	Nil	No
N1	1 node or satellite/transit
N1a	1 microscopic	No
N1b	1 clinical	No
N1c	Nil	Yes
N2	2-3 nodes or satellite/transit
N2a	2-3 microscopic	No
N2b	2-3, 1+ clinical	No
N2c	1	Yes
N3	4+ nodes or satellite/transit
N3a	4+ microscopic	No
N3b	4+, with 1+ clinical	No
N3c	2+	Yes

M category (M)	M criteria (metastasis location)
M0	Nil metastasis
M1	Distant metastasis present
M1a	Distant skin, muscle, nodes
M1b	Lung
M1c	Non-CNS viscera
M1d	CNS

Prognostic stage

Once a TNM score is determined, this will be used to determine the prognostic stage. An abbreviated staging score provides general information.

Stage	Description
0	In situ
1	< 2 mm Breslow
2	> 2 mm Breslow or > 1mm with ulceration
3	Regional lymph node involvement
4	Distant metastatic spread

However, specialists will often use the full AJCC prognostic staging system:

	N	M	Stage	Workup
Tis	N0	M0	0	Nil
T1a	N0	M0	IA	Nil
T1b	N0	M0	IA	Nil
T2a	N0	M0	IB	Nil
T2b	N0	M0	IIA	Nil
T3a	N0	M0	IIA	Nil
T3b	N0	M0	IIB	CT chest, abdomen, pelvis
T4a	N0	M0	IIB	CT chest, abdomen, pelvis
T4b	N0	M0	IIC	CT chest, abdomen, pelvis
T0	N1b, N1c	M0	IIIB	CT chest, abdomen, pelvis
T0	N2b, N2c, N3b, or N3c	M0	IIIC	CT CAP or PET-CT, MRI brain
T1a/b-T2a	N1a or N2a	M0	IIIA	CT chest, abdomen, pelvis
T1a/b-T2a	N1b/c or N2b	M0	IIIB	CT chest, abdomen, pelvis
T2b/T3a	N1a-N2b	M0	IIIB	CT chest, abdomen, pelvis
T1a-T3a	N2c or N3a/b/c	M0	IIIC	CT CAP or PET-CT, MRI brain
T3b/T4a	Any N ≥N1	M0	IIIC	CT CAP or PET-CT, MRI brain
T4b	N1a-N2c	M0	IIIC	CT CAP or PET-CT, MRI brain
T4b	N3a/b/c	M0	IIID	CT CAP or PET-CT, MRI brain
Any T, Tis	Any N	M1	IV

Treatment

Surgery

Surgery is an essential part of treatment as it provides diagnostic and staging information. Optimal treatment will require surgery to clear the tumour. While an excision with clear margins may have been achieved with the excisional biopsy, narrow margins are not considered adequate.

It is important to realise that histological analysis is not 100% accurate and the method used does introduce some uncertainty. Clear margins on a pathology report do not necessarily mean that the melanoma has been completely removed. We explain this further on our wide local excision (WLE) page.

Numerous national guidelines recommend further excision with wide margins to minimise the risk of recurrence or distant metastatic spread. These margins are determined by consensus and are partly based on previous studies comparing surgical margins with patient outcomes. In New Zealand, the recommended margins are described below:

Tumour score	Breslow thickness	Margin
Tis	(in situ	5 – 10 mm
T1	≤ 1 mm	10 mm
T2	1-2 mm	10-20 mm
T3/T4	> 2mm	20 mm

A wide local excision (WLE) is normally performed under local anaesthetic. The surgeon marks out the surgical site based on the previous scar (from the biopsy). The margins are determined from the above table and the excision is performed down to at least the fascia (the fibrous layer below the subcutaneous fat). The incision will be made in a 3:1 ellipse around this safety margin. So, a thin melanoma with a 1 cm diameter will result in a scar line approximately 9 cm long. On cylindrical areas e.g., the arm, the ratio may be 5:1, meaning a scar line of about 15 cm.

Mohs Surgery

In some situations, Mohs micrographic surgery (MMS) is sometimes performed on melanoma in situ of the head and neck although this is not routine.

Advanced stage melanomas

It is difficult to outline treatment options for advanced-stage melanomas (metastatic spread) as different jurisdictions and medical insurance companies will have different treatment options and eligibility criteria.

Furthermore, treatment regimens are normally tailored on a case-by-case basis. Some of these treatments may be used in combinations. We provide this information as a general information source for those who are interested:

• Surgical metastectomy is the surgical removal of metastases when there is a low burden of metastatic disease.
• Checkpoint inhibitor immunotherapy with PD-1 inhibitors: pemrolizumab, nivolumab.
• BRAF inibitors: dabrafenib and vemurafenib.
• MEK inhibitors: trametinib.
• c-KIT inhibitors: imatinib.
• Radiation therapy.

Surveillance

The objective of surveillance is to identify:

• New melanomas early.
• Local or regional recurrences that could be curable.
• A metastatic disease that can be treated with systemic therapies.

Surveillance regimens vary somewhat but in essence, higher risk/stages tend to have more frequent follow-up regimens:

• All patients should undertake a regular self-skin examination.
• Stage I & IIA: Every six months for two years, then annually for life.
• Stage IIB & III: Every four months for two years, every six months for five years, then annually for life.

Prognosis

Stage	5-year survival
Localised (Stage I & II)	99%
Regional (Stage III)	68%
Distant (Stage IV)	30%

Prevention

General sun protection advice includes:

• Avoiding sunburn and intentional tanning.
• Wearing sun protective clothing (hat, sunglasses, etc).
• Seeking shade where available.
• Taking extra care in highly reflective environments e(water, snow, and sand).
• Obtaining vitamin D through food and supplements if need be.
• Using a broad-spectrum, water-resistant sunscreen with a minimum SPF of 50+. Apply it 15-30 minutes prior to sun exposure and reapply every 2 hours or after sweating, swimming, or rubbing.

We have separate pages dedicated to sun protection and sunscreen. These pages cover controversial topics such as the impact of vitamin D, high-SPF sunscreens, and the absorption of sunscreen ingredients.

Other resources

• DermNetNZ
• Cancer Council of Australia
• American Academy of Dermatology

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