Australia, together with New Zealand, have the highest rates of melanoma in the world. The annual incidence is about 37/100,000 per year. It is the fourth most common cancer in men and the third most common in women. It is notable for a relatively higher incidence in younger people relative to other cancers, and can often lead to death if not detected early in development.
Elsewhere in the world, melanomas are seen more frequently in caucasian populations, such as North America and Europe. In general, the risk in Caucasians increases with proximity to the equator. Migrants adopt a risk midway between their home country and their destination.
Non-caucasians have much lower rates of melanoma (about 15 times less) which is thought to be due to a combination of increased pigmentation and different lifestyles. People of Asian descent have the lowest rates of melanoma. Most melanomas occur in the non-pigmented areas (palms/soles).
The incidence of melanoma changed during the 20th century. Incidence climbed steeply in the latter parts of the century, levelling off in the 1990s in Australia. It continues to increase in some other parts of the world.
Aetiology and Pathogenesis
UV Radiation is the main environmental factor associated with melanoma:
- It is particularly relevant for those with sun sensitive skin
- Exposure in childhood is more important than exposure in later life although there is still some contribution
- Sunburns also increase risk rather than simple sun exposure
UV radiation is more common with depletion of the ozone layer. Melanoma is also more common in those of higher socio-economic status, most likely due to higher levels of sun exposure in wealthier individuals.
An important concept in melanoma is radial versus vertical growth phase. Most melanomas undergo a period of radial growth with minimal dermal invasion that may last months to years. This is especially true of the superficial spreading and lentigo maligna types. Nodular melanoma has no radial growth phase.
Melanoma can spread to regional nodes or, less commonly with the absence of lymph node metastases, distantly to other sites (most commonly the skin, but also brain, liver, lung, kidney and any other site). Sentinel node biopsy is a useful means of excluding nodal metastases and survival for sentinel node negative patients is > 90% at 5 years.
A helpful mnemonic is ABCD.
- Indistinct Border
- Uneven Colour
- Diameter > 6 mm
Diagnosis can be difficult particularly in patients with dysplastic nevus syndrome. Small melanomas may have distinct borders and uniform pigment.
Advanced cases can be ulcerated which is a poor prognostic finding.
Malignant melanocytes have a broad range of microscopic appearances and melanoma can impersonate a number of other tumours on microscopy.
- Cell size ranges from small round blue cells to large mutlinucleated cells
- Cell shape ranges from round, oval, polygonal or spindle cells
- Many melanomas contain intracytoplasmic melanin pigment, but this is not always seen
- Mitotic figures are often present but are not diagnostic of melanoma over a benign nevus. Bizarre mitoses (eg. tripolar) may occur in melanoma.
Superficial Spreading Melanoma
This is the most common form (70%). The tumour is characterised by a long radial growth phase with minimal invasion beyond the epidermis. Melanocytes infiltrate in a Pagetoid manner through the epidermis. Invasion in the papillary dermis usually occurs in clusters of nests. This form is notable for a higher prevalance of the BRAF mutation which has therapeutic implications.
Nodular melanoma is characterised by vertical growth minimal intraepidermal growth. It is more aggressive than superficial spreading melanoma and is often present for a shorter time. It rarely arises from a pre-existing nevus. Cells are frequently polymorphic and there are frequent mitoses.
Lentigo Maligna and Lentigo Maligna Melanoma
Lentigo maligna is a non-invasive type of melanoma where there are nests of cells that grow along the basement membrane of the skin epithelium, often extending into the hair follicles and sweat glands. It is limited to the basal layer of the epithelium (junctional zone) which distinguishes it from superficial spreading melanoma which typically involves all layers of the epithelium with pagetoid spread. Unlike other melanomas, LM and LMM are associated with chronic sun damage to the skin rather than childhood sun exposure and sunburns.
Lentigo maligna melanoma is a more aggressive form where dermal invasion has occurred.
Acral melanoma occurs in non-hair bearing skin of the palms, soles and underneath the nails. It is a rare form (2% in caucasians) but and important type in those with coloured skin where it makes up 80% of melanoma diagnoses. It has characteristic features - expansion of the horny layer of the epidermis and elongation of the rete ridges relative to the non-involved areas.
Desmoplastic and Desmoplastic Neurotropic Melanoma
An important subtype of melanoma; it makes up about 2% of diagnoses. The macroscopic appearance is often non-pigmented and may seem to be a scar. Biopsy demonstrates malignant spindle cells surrounded by abundant mature collagen fibres. There is often a lymphocytic infiltrate. Neurotropism and perineural invasion are common features and spread may occur distantly from the macroscopic tumour along nerve sheaths. In contrast to other melanoma types, S100 is the only positive immunohistochemical marker and HMB45 and Melan-A are usually negative. Vimentin is often positive.
Immunohistochemistry is an enourmously helpful tool in the diagnosis of melanoma, particularly when metastatic deposits are found without a primary. The three common markers examined are:
Unfortunately not all melanomas express these markers but they remain helpful in the diagnosis of this tumour.
Staging / Classification
Melanoma of the skin is staged using the TNM system.
Tis: No dermal invasion (eg. lentigo maligna)
T1: < 1 mm invasion
T2: 1-2 mm invasion
T3: 2-4 mm invasion
T4: > 4 mm invasion
The number is followed by an 'a' or 'b' depending on:
- Mitotic rate
Disease free survival is strongly correlated with depth of invasion, with 96% 5 year survival for tumours < 0.5 mm and 56% survival for tumours > 4 mm invasion. Similar differences are seen for those with low mitotic rates versus high mitotic rates and with ulceration.
There are two additional staging systems based on the depth of tumour invasion which are not used for staging purposes with TNM.
- Stage I: < 0.75 mm
- Stage II: 0.75-1.5 mm
- Stage III: 1.5-2.25 mm
- Stage IV: 2.25 - 3 mm
- Stage V: > 3 mm
- Level 1: Confined to epidermis (melanoma in situ)
- Level 2: Invasion of papillary dermis
- Level 3: Invasion to junction of papillary and reticular dermis
- Level 4: Invasion into reticular dermis
- Level 5: Invasion into subcutaneous fat
N1a: Microscopic involvement of one node
N1b: Macroscopic involvement of one node
N2a: Microscopic involvement of 2-3 nodes
N2b: Macroscopic and microscopic involvement of 2-3 nodes
N2c: In transit metastases or satellite lesions alone
N3: > 3 nodes involved or involved nodes + in transit metastases
As nodal involvement increases, 5-year survival decreases (eg. 70% 5 year survival for N1a, 60% for N2a).
There are 3 M stages!
- M1a: Metastasis to skin, subcutaneous or distant lymph node sites and a normal LDH (best prognosis) ~ 65% 1 year survival
- M1b: Lung metastases and normal LDH
- M1c: Other visceral metastases or metastases with elevated LDH (worse prognosis) ~ 30% 1 year survival
|IB||T1b - 2a||N0||M0|
|IIA||T2b - 3a||N0||M0|
|IIB||T3b - 4a||N0||M0|
|IIIA||T1a - 4a||N1a / 2a||M0|
|IIIB||T1b - 4b
T1a -4 a
|N1a / 2a
N1b / 2b / 2c
|IIIC||T1b - 4b
|N1b / 2b / 2c
Stage I and II are local disease with varying depths of invasion (the 'b' counts as +1 for stage, eg. T1a is Stage IA, T1b is stage IB).
Stage III is lymph node disease of increasing severity but potentially curable.
Stage IV disease is metastatic.