What is melanoma?
Melanoma is a potentially serious type of skin cancer, in which there is uncontrolled growth of melanocytes (pigment cells). Melanoma is sometimes called malignant melanoma.
Normal melanocytes are found in the basal layer of the epidermis (the outer layer of skin). Melanocytes produce a protein called melanin, which protects skin cells by absorbing ultraviolet (UV) radiation. Melanocytes are found in equal numbers in black and in white skin, but melanocytes in black skin produce much more melanin. People with dark brown or black skin are very much less likely to be damaged by UV radiation than those with white skin.
Non-cancerous growth of melanocytes results in moles (properly called benign melanocytic naevi) and freckles (ephelides and lentigines). Cancerous growth of melanocytes results in melanoma. Melanoma is described as:
- In situ, if the tumour is confined to the epidermis
- Invasive, if the tumour has spread into the dermis
- Metastatic, if the tumour has spread to other tissues.
Who gets melanoma?
The highest reported rates of melanoma in the world are in Australia and New Zealand. About one in 15 white skinned New Zealanders are expected to develop melanoma in their lifetime. In 2012, invasive melanoma was the third most common cancer in males (after prostate and colorectal cancers) and in females (after breast and colorectal cancers).
Melanoma can occur in adults of any age but is very rare in children. In New Zealand in 2012:
- 1% occurred in those under 24 years
- 10% occurred in people 25 to 44 years
- 38% in those aged 45 to 64 years
- 25% in those aged 65 to 74 years
- 27% in those aged older than 75 years
According to New Zealand Cancer Registry data, 2366 invasive melanomas were diagnosed in 2013; 53% were in males. There were 354 deaths from melanoma in 2012 (63% were male).
The main risk factors for developing the most common type of melanoma (superficial spreading melanoma) include:
- Increasing age (see above)
- Previous invasive melanoma or melanoma in situ
- Previous basal or squamous cell carcinoma
- Many melanocytic naevi (moles)
- Multiple (>5) atypical naevi (large or histologically dysplastic moles)
- Strong family history of melanoma with 2 or more first-degree relatives affected
- White skin that burns easily
These risk factors are not important for rare types of melanoma.
What causes melanoma?
Melanoma is thought to begin as uncontrolled proliferation of melanocytic stem cells that have undergone genetic transformation.
Superficial forms of melanoma spread out within the epidermis (in situ). A pathologist may report this as the radial or horizontal growth phase.
Further genetic changes promote the tumour to invade through the basement membrane into surrounding dermis, when it becomes an invasive melanoma.
Nodular melanoma has a vertical growth phase, which is potentially more dangerous than the horizontal growth phase. It may arise within a previously healthy dermis, or within the invasive portion of a pre-existing more superficial kind of melanoma.
Once the melanoma cells have reached the dermis, they may spread to other tissues via the lymphatic system to the local lymph nodes or via the blood stream to other organs such as the lungs or brain. This is known as metastatic disease or secondary spread. The chance of this happening mainly depends on how deep the cells have penetrated into the skin.
Melanoma can arise from otherwise normal appearing skin (in about 75% of melanomas) or from within a mole or freckle, which starts to grow larger and change in appearance. Precursor lesions include:
- Benign melanocytic naevus (normal mole)
- Atypical or dysplastic naevus (funny-looking mole)
- Atypical lentiginous junctional naevus (flat naevus in heavily sun damaged skin)
- Large or giant-sized congenital melanocytic naevus (brown birthmark)
What are the clinical features of melanoma?
Melanomas can occur anywhere on the body, not only in areas that get a lot of sun. In New Zealand, the most common site in men is the back (around 40% of melanomas in men), and the most common site in women is the leg (around 35% of melanomas in women).
Although melanoma usually starts as a skin lesion, it can also rarely grow on mucous membranes such as the lips or genitals. Occasionally it occurs in other parts of the body such as the eye, brain, mouth or vagina.
The first sign of a melanoma is usually an unusual looking freckle or mole. A melanoma may be detected at an early stage when it is only a few millimetres in diameter, but it may grow to several centimetres in diameter before it is diagnosed.
- A melanoma may have a variety of colours including tan, dark brown, black, blue, red and, occasionally, light grey.
- Melanomas that are lacking pigment are called amelanotic melanoma.
- There may be areas of regression that are the colour of normal skin, or white and scarred.
During its horizontal phase of growth, a melanoma is normally flat. As the vertical phase develops, the melanoma becomes thickened and raised.
Some melanomas are itchy or tender. More advanced lesions may bleed easily or crust over.
Most melanomas have characteristics described by the Glasgow 7-point checklist or by the ABCDE’s of melanoma. Not all lesions with these characteristics are malignant. Not all melanomas show these characteristics.
Glasgow 7-point checklist
- Change in size
- Irregular shape
- Irregular colour
- Diameter >7 mm
- Change in sensation
The ABCDEs of Melanoma
B Border irregularity
C Colour variation
D Diameter over 6 mm
E Evolving (enlarging, changing)
Subtypes of melanoma
Melanomas are described according to their appearance and behaviour. Those that start off as flat patches (ie, they have a horizontal growth phase) include:
- Superficial spreading melanoma
- Lentigo maligna melanoma and lentiginous melanoma (in sun-damaged sites)
- Acral lentiginous melanoma (on soles of feet, palms of hands or nails)
These superficial forms of melanoma tend to grow slowly, but at any time, they may begin to thicken up or develop a nodule (i.e. progress to a vertical growth phase).
Melanomas that quickly involve deeper tissues include:
- Nodular melanoma
- Spitzoid melanoma
- Mucosal melanoma
- Neurotropic and desmoplastic melanoma
- Ocular melanoma
Classification by age, sun exposure and number of naevi
Melanoma is also classified according to its relationship with sun exposure, age and number of melanocytic naevi.
Childhood melanomas (below 10 years of age):
- Extremely rare
- Infrequently associated with excessive sun exposure
- Compared to melanoma in adults, they are more often amelanotic (flesh coloured, pink or red), nodular, bleeding and ulcerated
- May arise within giant congenital melanocytic naevi > 40 cm diameter
- More common in women than in men
- Most common clinical subtype is superficial spreading
- Associated with many melanocytic naevi
- Tend to be seen on lower extremity
- Tends to have BRAFV600E genetic mutation
- Associated with intermittent sun exposure
- More common in men than in women
- Most common clinical subtype is lentigo maligna
- Often occur on head and neck
- Associated with accumulated, lifelong sun exposure
Melanoma is usually epithelial in origin, i.e. starting in the skin, or, less often, mucous membranes. But very rarely, melanoma can start in an internal tissue such as the brain (primary CNS melanoma) or the back of the eye (see ocular melanoma).
Lentigo maligna melanoma
Acral lentiginous melanoma
How is melanoma diagnosed?
Melanoma may be suspected because of a lesion’s clinical features or because of a history of change. The dermatoscopic appearance is helpful in the diagnosis of featureless early melanoma. Some melanomas are extremely difficult to recognise clinically.
The suspicious lesion is surgically removed with a 2 to 3-mm clinical margin for pathological examination (diagnostic excision). Partial biopsy is best avoided, but may be considered in large lesions.
The pathological diagnosis of melanoma can be very difficult. Histological features of superficial spreading melanoma in situ include the presence of buckshot (pagetoid) scatter of atypical melanocytes within the epidermis. These cells may be enlarged with unusual nuclei. Dermal invasion results in melanoma cells within the dermis or deeper into subcutaneous fat.
Immunohistochemical stains may be necessary to confirm melanoma.
The pathologist's report should include a macroscopic description of the specimen and melanoma (the naked eye view), and a microscopic description. The following features should be reported if there is invasive melanoma.
- Diagnosis of primary melanoma
- Breslow thickness to the nearest 0.1 mm
- Clark level of invasion
- Margins of excision i.e. the normal tissue around the tumour
- Mitotic rate – a measure of how fast the cells are proliferating
- Whether or not there is ulceration
The report may also include comments about the cell type and its growth pattern, invasion of blood vessels or nerves, inflammatory response, regression and whether there is associated in-situ disease and/or associated naevus (original mole).
The Breslow thickness is reported for invasive melanomas. It is measured vertically in millimetres from the top of the granular layer (or base of superficial ulceration) to the deepest point of tumour involvement. It is a strong predictor of outcome; the thicker the melanoma, the more likely it is to metastasise (spread).
What is the Clark level of invasion?
The Clark level indicates the anatomic plane of invasion.
- Level 1: In situ melanoma
- Level 2: Melanoma has invaded papillary dermis
- Level 3: Melanoma has filled papillary dermis
- Level 4: Melanoma has invaded reticular dermis
- Level 5: Melanoma has invaded subcutaneous tissue
Deeper Clark levels have a greater risk of metastasis. It is useful in predicting outcome in thin tumours. It is less useful than Breslow thickness for thick tumours.
What is the treatment for melanoma?
Following confirmation of the diagnosis, wide local excision is carried out at the site of the primary melanoma. The extent of surgery depends on the thickness of the melanoma and its site. Margins recommended in New Zealand are shown below.
- Melanoma in situ: 5 – 10 mm
- Melanoma <1 mm: 10 mm
- Melanoma 1–2 mm: 10 – 20 mm
- Melanoma >2 mm: 20 mm
Melanoma staging means finding out if the melanoma has spread from its original site in the skin. Most melanoma specialists refer to the American Joint Committee on Cancer (AJCC) cutaneous melanoma staging guidelines (2009). In essence, the stages are:
|Stage 0||In situ melanoma|
|Stage 1||Thin melanoma <2 mm in thickness|
|Stage 2||Thick melanoma > 2 mm in thickness|
|Stage 3||Melanoma spread to involve local lymph nodes|
|Stage 4||Distant metastases have been detected|
Should the lymph nodes be removed?
If the local lymph nodes are enlarged due to metastatic melanoma, they should be completely removed. This requires a surgical procedure, usually under general anaesthetic. If they are not enlarged, they may be tested to see if there is any microscopic spread of melanoma. The test is known as a sentinel node biopsy.
In New Zealand, many surgeons recommend sentinel node biopsy for melanomas thicker than 1 mm, especially in younger persons. However, although the biopsy may help in staging the cancer, it does not offer any survival advantage.
Lymph nodes containing metastatic melanoma often increase in size quickly. An involved node is usually non-tender and firm to hard in consistency.
If the melanoma is widespread, treatment is not always successful in eradicating the cancer. Some patients may be offered new or experimental treatments, such as:
- Immunotherapy: interleukin-2, interferon alfa 2b
- BRAF inhibitors: dabrafenib and vemurafenib
- MEK inhibitors: trametinib
- C-KIT inhibitors: imatinib, nilotinib
- CTLA-4 antagonist: ipilimumab
- PD-1 blocking antibodies: nivolumab, pembrolizumab
What happens at follow-up?
The main purpose of follow-up is to detect recurrences early (metastatic melanoma) but it also offers an opportunity to diagnose a new primary melanoma at the first possible opportunity. A second invasive melanoma occurs in 5-10% of melanoma patients, and melanoma in situ in more than 20% of melanoma patients.
The Australian and New Zealand Guidelines for the Management of Melanoma (2008) make the following recommendations for follow-up for patients with invasive melanoma.
- Self skin examination
- Regular routine skin checks by patient's preferred health professional
- Follow-up intervals are preferably six-monthly for five years for patients with stage 1 disease, three-monthly or four-monthly for five years for patients with stage 2 or 3 disease, and yearly thereafter for all patients.
- Individual patient’s needs should be considered before appropriate follow-up is offered
- Provide education and support to help patient adjust to their illness
The follow-up appointments may be undertaken by the patient's general practitioner and/or specialist.
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 dermatoscopic images of melanocytic lesions of concern (mole mapping)
In those with more advanced primary disease, follow-up may include:
- Blood tests, including LDH
- Imaging: ultrasound, X-ray, CT, MRI and/or PET scan.
Tests are not worthwhile for patients with stage 1 or 2 melanoma unless there are signs or symptoms of disease recurrence or metastasis. No tests are necessary for healthy patients who have remained well for 5 years or longer after removal of their melanoma.
What is the outlook for patients with melanoma?
Melanoma in situ is cured by excision because it has no potential to spread round the body.
The risk of spread and ultimate death from invasive melanoma depends on several factors, but the main one is the Breslow thickness of the melanoma at the time it was surgically removed.
Metastases are rare for melanomas <0.75 mm and the risk for tumours 0.75–1 mm thick is about 5%. The risk steadily increases with thickness so that melanomas >4 mm have a risk of metastasis of about 40%.