What is metastatic melanoma?
Melanoma is a type of skin cancer that develops from the pigment-producing cells (melanocytes) of the skin, mucosa, eye, and rarely other sites. Metastatic melanoma is melanoma that has spread to other sites of the body. The spread occurs through the lymphatic system and/or the blood vessels. Melanoma can spread to the subcutaneous tissue which lies underneath the skin, the lymph nodes, and to other organs such as the lungs, liver, bone or brain.
Metastatic melanoma can be classified into local recurrence, in transit metastasis, nodal metastasis, and haematogenous spread.
Local recurrence of melanoma
Local recurrence is defined as a recurrence of melanoma within 2cm of the surgical scar of primary melanoma. It can result either from direct extension of the primary melanoma or from spread via the lymphatic vessels.
In transit melanoma metastases
In-transit metastases are melanoma deposits within the lymphatic vessels more than 2 cm from the site of the primary melanoma.
Nodal melanoma metastasis
Nodal metastasis is metastatic melanoma involving the lymph nodes. Every site on the body drains initially to one or two nearby lymph node basins. The lymph nodes first involved are the regional lymph nodes. Usually, the involved lymph nodes become enlarged and may be be felt as a lump through the skin.
Haematogenous spread of melanoma
Haematogenous spread is spread of melanoma cells in the bloodstream, which can happen either by a tumour invading blood vessels or secondary to lymph node involvement. Once in the bloodstream, melanoma cells can travel to distant sites in the body and deposit. It can proliferate in any tissue but most often grows in the lungs, in or under the skin, the liver and brain. Many patients also develop metastases in bone, gastrointestinal tract, heart, pancreas, adrenal glands, kidneys, spleen and thyroid.
Diffuse melanosis cutis
Diffuse melanosis cutis is a rare presentation of metastatic melanoma in which the entire skin surface changes colour.
Melanoma-associated leukoderma is depigmentation that occurs in patients with metastatic melanoma. It may present as white areas within a melanoma due to regression, halo melanoma, or as white patches resembling vitiligo distant from the melanoma. Leukoderma associated with metastatic melanoma is also known as melanoma-associated vitiligo.
Leukoderma can also be triggered by drugs used to treat metastatic melanoma, such as ipilimumab, immune checkpoint inhibitors (pembrolizumab, nivolumab), and BRAF inhibitors (vemurafenib, dabrafenib) [see also Drug-induced vitiligo].
Who gets metastatic melanoma?
Melanoma usually starts as a single lesion on the skin or mucous membrane. This lesion can progress to the formation of metastases if it is not recognised and treated effectively at an early stage.
Risk factors for the development of melanoma include:
- Age (risk increases with age)
- A history of previous skin cancer
- A family history of melanoma
- Having large numbers of moles especially atypical moles
- Having fair skin which burns easily
- Having sun-damaged skin.
The risk of melanoma metastasising is highest in an individual with an aggressive rapidly growing melanoma, an unrecognised melanoma, advanced primary melanoma, melanoma that was not completely excised (or not removed at all), and/or is immunosuppressed.
What do cutaneous melanoma metastases look like?
Cutaneous melanoma metastases usually grow rapidly within the skin (cutaneous metastases) or under the skin surface (subcutaneous metastases); dermal metastases are more common than subcutaneous. They are usually firm or hard in consistency. Cutaneous metastases may be any colour but are often black or red. They may also ulcerate and bleed.
Cutaneous metastatic melanoma
Epidermotropic metastatic melanoma is rare. In this case, the metastases develop more superficially than usual, within the epidermis. Epidermotropic metastatic melanoma is often initially misdiagnosed as the primary melanoma. The diagnosis of epidermotropic metastatic melanoma should be considered if multiple lesions arise with similar pathology.
Subcutaneous metastases are skin coloured or bluish lumps. They are usually painless.
Subcutaneous metastatic melanoma
Obstruction of lymphatic vessels due to melanoma in the lymph nodes or surgical removal of the lymph glands can result in swelling of the associated limb (lymphoedema).
How is metastatic melanoma diagnosed?
Metastatic melanoma may be diagnosed on the basis of characteristic skin lesions.
Other clues are enlarged lymph nodes and/or symptoms related to other organs. People with metastatic melanoma may feel tired, lethargic, and have weight loss prior to the diagnosis being made.
- Suspicious skin and subcutaneous lesions should be removed by excisional biopsy and will show characteristic features of metastatic melanoma pathology.
- A sentinel node biopsy is sometimes performed after a primary melanoma is diagnosed. This is a biopsy of a regional lymph node to determine whether there are occult (not palpable) lymph node metastases.
- The serum lactate dehydrogenase (LDH) is a marker for progressive metastatic disease at distant sites. When it is elevated it confers a worse prognosis, but often the LDH remains normal even in late-stage metastatic melanoma.
- Other laboratory tests are not routinely used because their value as pointers to the presence of metastases and/or prognosis is limited.
- In the future, blood-based melanoma detection tests (liquid biopsy) may become available.
- Chest x-ray — lung metastases may be visible on chest x-ray, but, as melanoma metastases resemble other types of lung lesion, there are also a significant number of false positives meaning that this is not a very helpful investigation.
- Ultrasound scanning — can reveal liver metastases and lymph node metastases.
- CT and MRI — can show metastatic deposits in most body sites.
- Positron emission tomography (PET) scanning – this is an important advance in imaging for metastatic disease. It shows up 'hot spots' of tissue that are metabolising faster than normal tissue. It has been found to have good diagnostic accuracy for metastatic melanoma.
What treatments are available for metastatic melanoma?
In some cases, a deposit of metastatic melanoma can be surgically removed. This is an appropriate treatment option with the aim of cure when there is a solitary metastasis of the skin, in the subcutaneous tissue or of a lymph node. Sometimes surgery is done when there is felt to be one metastasis to another organ such as the liver. Surgery may also be helpful in reducing symptoms and improving quality of life, even if it will not be expected to cure the disease.
Chemotherapy for melanoma
Chemotherapy can slow the rate of progression of metastatic melanoma but it does not cure it. Agents such as dacarbazine, temozolomide and combinations of other agents are used. A chemotherapy agent is sometimes successfully infused into a limb to treat in-transit metastases (isolated limb perfusion) but this technique can have serious complications.
Adjuvant therapy for melanoma
High dose interferon-α is proven to improve survival and lower relapse rate in high-risk melanoma. Side effects can be difficult to tolerate for many people and can even be fatal. They include flu-like symptoms, tiredness, depression and rhabdomyolysis (destruction of muscle tissue). See Adjuvant therapies for melanoma.
Radiotherapy for melanoma
Radiotherapy can be useful for improving symptoms caused by metastatic disease and along with surgery is the mainstay of treatment of brain metastases.
Immunotherapy for melanoma
Immunotherapy for melanoma includes interleukin-2, which is given intravenously. Side effects include fever, low blood pressure and irregular heart rhythms.
Interferon alfa 2b is delivered by subcutaneous or intravenous injection. Side effects include 'flu-like symptoms, depression, and depression cell counts.
Topical imiquimod is an immune modifier that has been used alone or in combination with intravenous interleukin-2 treatment. Imiquimod cream is applied directly to melanoma metastases to enhance an immune response to the tumour. The encouraging response of in-transit metastases has been reported in some cases.
Topical diphencyprone for melanoma
Topical diphenylcyclopropenone or diphencyprone in various concentrations (0.0001% to 10%) in solution or cream may be useful for small cutaneous melanoma metastases. The first application sensitises the patient to the chemical over about 10 days. Further applications applied to the lesions at weekly intervals cause allergic contact dermatitis, which can be very itchy and uncomfortable and may generalise. When effective, existing treated lesions stop enlarging and may shrink or disappear. Dramatic responses have been reported including regression of involved lymph nodes.
Intralesional immunotherapy for melanoma metastases using talimogene laherparepvec (T-VEC), Allovectin-7® and Rose Bengal is under investigation.
Molecularly targeted therapy for melanoma
- Ipilimumab is a monoclonal antibody that targets CTLA-4. It can increase survival in metastatic melanoma.
- Vemurafenib, sorafenib and dabrafenib target the BRAF protein which is mutated in some metastatic melanomas. Trametinib inhibits the MAPK signalling pathway in melanoma with BRAF mutations. Cobimetinib is a MEK inhibitor that is taken in combination with vemurafenib. These new drugs can lead to a very good initial improvement but eventually, the metastatic melanoma progresses.
- Pembrolizumab targets the programmed death 1 (PD-1) receptor and can be used in patients with all forms of melanoma. Favourable response rates were demonstrated in clinical trial data from 173 patients with melanoma in the KEYNOTE-001 study.
- Nivolumab is a human programmed death receptor-1 (PD-1)–blocking antibody. The Check-Mate studies indicated clinical benefit in metastatic melanoma.
- Therapies which block the formation of new blood vessels can also be helpful as additional treatments.
- A number of vaccines for melanoma have been developed with the aim of stimulating the immune system to fight the melanoma cells. Unfortunately, these have had disappointing results to date.
With a range of new therapies being developed and studied for melanoma, some patients choose to participate in a clinical trial. This can mean having access to a treatment that wouldn’t otherwise be possible.
A 2018 Cochrane report confirmed that immune checkpoint inhibitors and small-molecule targeted drugs have significantly improved patient prognosis, especially combinations of immune checkpoint inhibitors and combinations of small-molecule targeted drugs, but toxicity is common.
A small, preliminary study suggested that beta-blockers may prevent or delay the recurrence of melanoma.
Palliative care for melanoma
Palliative care focuses on quality of life rather than the length of life. It includes control of pain and other uncomfortable symptoms and provides support for patients and their families.
What is the outlook for patients with metastatic melanoma?
In most instances, it is not possible to cure metastatic melanoma entirely because it tends to spread to multiple sites. Treatment is focussed on improving the quality of life and the length of survival.
The prognosis of melanoma depends on the disease staging, which is based around characteristics of the primary tumour, nodal and distant metastases. The prognosis is poorer with higher numbers of involved nodes and with metastases to internal organs and distant sites.