Melanoma is a unique type of cancer normally arising in the skin arising from melanocytes. Melanocytes make a cell pigment melanin; this is present to protect the skin from ultraviolet damage. A melanoma may begin in a mole but can also begin in other pigmented tissues such as in the eye or the intestines.
Causes of melanoma
Repetitive scorching burning by sunshine/ultraviolet light particularly when suffered by fair skinned individuals in youth, is a predisposing factor for the development of melanoma. This explains why the disease is more common in Caucasian races living nearer the equator, and the lower incidences in black races. There are some data that suggest that ultraviolet dependent melanoma has a slightly better prognosis than other types. Studies from Western Canada and other regions of the world strongly suggest that intermittent burning exposure of unacclimatised Caucasian skin is a major risk factor for the development of melanoma.
Other predisposing factors are the dysplastic naevus syndrome, a familial condition of multiple congenital dysplastic naevi (‘moles’) and the cancer predisposition syndrome, the Li Fraumeni syndrome, which runs heavily in families and runs to multiple other primary cancers. There are three genes currently identified which influence melanoma risk. The majority of cases arise in patients with no obvious predisposing cause.
Malignant melanoma is a relatively uncommon cancer in the UK where it comprises only 1% of cancers and only 1200 deaths per year; however, there are some data to suggest that the incidence is rising. By contrast, the incidence in Queensland, Australia, where a Caucasian population are heavily exposed to sunlight, is 5 per 1,000 of the population indicating the breadth of incidence of this highly fatal cancer across the globe. Whilst the incidence of melanoma is highest in Australia, there is good evidence that the incidence in Europe and America is rising. In the European population, the increase in incidence has been linked to a greater opportunity for foreign travel and sunbathing holidays. This increased chance of taking holidays in the sun may in part explain why there is a higher incidence of the disease in higher social classes In America, the Surveillance, Epidemiology and End Results (SEER) study showed a steady increase in incidence of cutaneous melanoma at various latitudes, again reinforcing the sunshine exposure risk factor. The disease is more common in women by a factor of approximately twofold – in Europe and America (but not in Australia). Also, there is a tendency for melanoma to occur on the trunk in men and extremities in women; facial melanoma tends to be a disease of the elderly. Mucosal melanoma is relatively more common in dark skinned races, in whom the incidence of skin melanoma is less frequent.
Symptoms & diagnosis: Melanoma
The most characteristic feature associated with a melanoma is the black colour of the skin lesion. Whilst some malignant melanomas arise from benign naevi (‘moles’) the majority arise from normal skin. The development of a black skin lesion must never be ignored and the changes within a pre-existing skin lesion, particularly of its size, shape and colour should all alert the patient and doctors. The development of bleeding, crusting and a change in sensation or inflammation in a skin lesion merits further assessment.
A proportion of patients may present with signs or symptoms of disseminated melanoma. These may include the development of lymph nodes or skin nodules; pain from metastases, weight loss or neurological symptoms if there has been spread to the brain or spine.
There are several clinically recognised types of presentation: the first is the superficial spreading type of melanoma (up to 2/3 of cases) where a flat, coloured skin lesion progressively grows irregularly in the skin, typically on the limbs.
The nodular melanoma has more substance to it, is frequently faster growing and tends to be a rounder nodular skin lump, such nodular cases account for up to 20% of all cases.
The rarer types of melanoma are the lentigo maligna melanoma which is a very slow growing flat skin lesion growing on the face of typically elderly and female patients and the acral type which is found on the palms and soles and mucosal membranes and typically encountered in Asian and black peoples.
To determine if the abnormality is a melanoma, a small piece of the area (or if it is small, the entire area) is removed and examined under a microscope to determine if precancerous or cancerous cells are present.
The staging for melanoma will include assessing the local extent of the primary tumour, whether there is further spread to the local skin or lymph node areas and the presence of metastatic disease.
The extent of the primary melanoma in terms of depth of invasion at microscopic assessment has a significant impact on outcome. Patients with stage 1 disease have a 90% ten year survival, stage 2 has a 60% and stage 3 has a 30% ten year survival. Only five per cent of patients with stage 4 disease survive five years.
The assessment of lymph nodes spread can be undertaken by clinical examination and imaging investigations. CT scanning of the body would be offered to patients with a medium to high risk of metastases. Other imaging tests including a Chest x-ray, liver ultrasound may also be used to identify disease. PET scanning may be considered in selected cases. The assessment of urinary melanogen and a serum protein S100 remain poorly validated.
Thus the staging is based on the depth/thickness of invasion for stages 1-2 disease; the overall staging is thus:
Stage 1A. Localised: Less than 0.75mm depth
Stage 1B. Localised: 0.76-1.5 mm depth
Stage 2A. Localised: 1.5 – 4mm depth
Stage 2B. Localised: More than 4mm depth
Stage 3. Nodal metastases in the regional draining nodes
Stage 4. Metastatic disease to other organs
Treatment and outcomes: Melanoma
In most patients, surgery is required to remove (or excise) the entire tumour. Generally, one to two centimetres of normal skin surrounding the lesion must also be removed. Occasionally, skin grafting may be necessary to promote healing and replace skin that has been removed.
If an enlarged lymph node (or gland) is present, it may be biopsied at the time of the wide local excision. Even if enlarged lymph nodes cannot be detected, the lymph nodes may be evaluated during or after the surgical removal of the melanoma.
In the majority of cases, enlarged lymph nodes are not visible, and the only way to determine if they are affected is to take a sample of the lymph node during surgery. The sample is then examined under a microscope to determine if abnormal cells are present. This is typically accomplished with a surgical technique known as sentinel lymph node (SLN) biopsy.
The sentinel lymph node (SLN) technique is based upon the theory that when tumour cells migrate, they spread to one or a few lymph nodes before involving other nodes. Further, these nodes can be identified by injecting a blue dye or radioactive material around the primary tumour before the wide local excision, and then searching for the node that has taken up the dye or the radioactive tracer at the time of surgery.
SLN biopsy has become the standard technique for assessing the status of regional lymph nodes and is recommended for staging of most patients with newly diagnosed primary melanomas. However, patients whose melanomas are less than 1 mm in thickness (thin melanomas) may not require SLN, since the likelihood of tumour spread to the regional lymph nodes is less than 10 percent.
In contrast, SLN biopsy may be advised for thin melanomas with other high-risk features, such as ulceration, Clark’s level IV or V (the tumour has invaded deeper levels of the skin), or if there are significant areas of regression (spontaneous loss of tumour cells).
Based upon the pathologic disease stage, the optimal treatment is chosen. For patients with localized disease who have no evidence of distant metastases, the goals of treatment are:
- Complete surgical removal of the primary melanoma
- Evaluation of regional lymph nodes for evidence of tumour involvement
- Preventing further spread or disease recurrence
With regard to the prevention of further spread comes the use of ‘upfront’ systemic (i.e therapy that travels all around the body) in the post-operative period to reduce the chance of further appearance of disease in the future – this is called adjuvant therapy. For patients with stage three disease (in particular) and a high chance of life-threatening relapse, the need for effective adjuvant therapy is paramount.
Melanoma is not very responsive to chemotherapy and so adjuvant chemotherapy has not been demonstrated to be effective in this disease.
However, it has long been observed that he body may be mounting its own attack’ on melanoma, with observed spontaneous regressions of this disease being well documented. This has engendered interest that the body’s immune system may be trying to mount an attack on this ‘foreign’ (due its genomically mutated phenotype) tissue. Immune vaccines have been tried for several decades but it was really only in the early 2000’s that some evidence arose that interferon could be useful in the therapy of melanoma and also adjuvantly.
Next came the realisation that the body’s immune system did recognise cancers as foreign bodies (antigens) that should be eliminated (and the more mutated the more they appeared foreign to the immune system and hence antigenic) but that the cancer/melanoma could put up a ‘smokescreen’ against the potential attack by purporting to be normal tissues that the immune system tolerated. The mechanism of this is of interest: ‘T’ lymphocytes patrol the body looking for foreign tissues (germs, parasites, transplants etc.) which they recognise as not normal (the ‘normal’ being what was in the foetus when the immune system was laid down). The recognition system depends on attack lymphocytes etc and suppressor lymphocytes (which inhibit the immune attack). The PD1 receptor on lymphocytes is the “check-point” which helps screen whether a tissue is foreign or not. If foreign then immune attack is signalled. Normal (non-foreign tissues) signal normality via a PDL1 receptor that they express on their surfaces. The PD1/PDL1 interaction signals normality and prevents immune attack. (This description is grossly over-simplified but suffices for this purpose). The ability of cancer cells to express PDL1 (and interesting signalled to do so by various cytokines including gamma-interferon) appears to be the major mechanism by which cancer cells put up the ‘smokescreen’ against immune attack and the amount of expression on a cnace is used to help the oncologist to predict how effective immunotherapy will be against a cancer (interestingly less so for melanoma).
The introduction of PD1 inhibitors (and then PDL1 inhibitors) into mainstream Onocology practice has allowed the interference of the PD1-PDL1 interaction such that the immune system is not inhibited by the cancer’s potential immunogenicity/antigenicity. Drugs such as : nivolumab and pembrolizumab have become front line therapy for metastatic melanoma with great success in many patients. Now, the there is evidence for these type of drugs being so useful that they can be moved up into the adjuvant setting for stage 3 cases and usually now the use of regional node dissection is no longer required.
These checkpoint inhibitors carry with them different side effects from chemotherapy. As might be predicted from the description above, on could envisage this type of therapy also destroying the tolerance of normal tissues in the body which depends on the PD1-PDL1 interaction on their tissue surfaces to prevent an ‘auto-immune’ attack on these normal tissues. This is indeed possible and severe auto-immune reactions on normal tissues (thyroid, gut, liver lungs, skin etc..) have been encountered and these can occasionally become serious. –
At present, these immune ‘check-point’ inhibitors are the most exciting immunotherapy potential in cancer and melanoma in particular.
CTL4 is another lymphocyte protein which also functions as an immune checkpoint to mediate and down-regulate the immune attack on normal (and ‘foreign’) antigenic expressing tissues. It is constitutively expressed in regulatory T lymphocytes but only upregulated in conventional lymphocytes after activation – it acts as an inhibitory ‘switch’. The CTL4 blocking antibody: ipilumumab, has also been shown to be useful in down-regulating the immune attack but has not been shown to be as useful as the PDI/PDL1 inhibitors as far as adoption into adjuvant therapy. However, further research into the whole system that the body utilises to mediate immune attack or not – is fertile ground for new discoveries.
Suffice to say that check-point inhibitors represent an exciting immunotherapy for melanoma and have moved up into adjuvant herapy for stage 3 disease as well as being important in advanced/metastatic disease therapy.
However, there has been another and equally exciting avenue of research in melanoma that has brought breakthroughs of equal magnitude to the immunotherapy and has relevant to adjuvant therapy, viz. genomics.
It is known that cancers arise from the mutations in the cells which often involve activated oncogenes (which stimulate cells to go on dividing outwith the needs of the body and outwith the normal regulatory [homeostatic] systems in place to allow stability – that is what a cancer is!! or tumour suppressive genes (whose function is to put the breaks on mitotic activity).
A major research interest in cancer is the discovery of the key mutated ‘driver’ genes in each cancer and the quest to discover drugs that can block the down-stream effector pathways (the consequence of the mutation) that lead to this uncontrolled cell division that is the ‘cancer’.
A mutation that occurs and appears to be the key ‘driver’ in many melanoma is the BRAF, V600E mutation. In melanoma patients with this mutation the downstream effector pathways are effectively ‘permanently turned on’ in terms of constant stimulatory signals for the cells to divide. Fortunately, there have been discovered drugs which inhibit those downstream effector pathways – vemurafenib and dabrafenib in particular. So effective are these drugs that they have become front-line therapy in melanoma patients who develop metastatic disease (first line over the immunotherapy that I have outlined above) and are being trialled as adjuvant therapy in stage 3 disease.
However, whilst the melanoma can respond for long periods to the inhibition of the V600E mutation by these two drugs, eventually (as it is inherent in cancers that they have an unstable genome and are always mutating) that, by Darwinian selection) pressured by the inhibition of the key driving V600E mutation) that the cells escape the therapy. For reasons that we do not understand, this is often by the development of the MEK mutation. There is an inhibitor of the downstream effector pathways of the MEK mutation: trametinib leads the field here.
What has been shown is that, if a MEK inhibitor is given at the same time as the V600E inhibitor for patients with advanced melanoma, there is a more durable advantage to these patients and a survival advantage. Therefore, nowadays, in V600E cases, the two drugs e.g. Dabrafenib and trametanib are given together.
However, the expense of giving these two drugs together is very high and the ability to monitor the evolution of the different driving genetic mutations for cancer using cell-free DNA (as all cancers release their turning-over DNA into the blood stream) from simple blood draws – to watch for the evolution of new cancer driver mutations . This may allow us to discover the time that the MEK (or other) escape mutation is taking over the continued growth stimulation of the cancer and allow us to know the time to bring in the alternative drug.
The drugs do have some activity against brain metastases, although this important complication of melanoma must be proactively watched- for by scanning and radiosurgery (Gamma Knife or Cyberknife) employed if there is progression; Surgery is reserved for large brain metastases with pressure effects.
Treatment of advanced metastatic melanoma focuses on shrinking or eliminating the metastatic lesions and preventing further spread of the disease, and ensuring patient comfort. In most cases, it is not possible to completely eliminate the cancer.
Depending on the location and extent of the metastases, treatment may involve the use of medical treatments (genomically targeted treatments and immunotherapy – vide supra or chemotherapy – drugs such as a platin plus a taxane – e.g. carboplatin plus taxotere, or dacarbazine are commonly used chemotherapy agents but hampered the innate relative chemoresistance of this cancer type). Surgery and radiotherapy have limited use in metastatic disease except to forestall local complications e.g. spinal cord compression.
Brain metastases are relatively common in melanoma and the use of radiosurgery – focal radiation therapy with Gamma Knife or Cyberknife has greatly increased the control rates in this relatively common situation. Where the metastases are large, and particularly where there is pressure, then surgical debulking should preceded the radiation therapy.
What to do if the melanoma becomes resistant to the foregoing therapies?
There are new and alternative immunotherapy options and anecdotal vaccine therapy success.
However, it is worthwhile getting a fresh biopsy of the melanoma at this time point to explore the new nutations htat have occurred – by next generation sequencing (NGS) – as it is possible that, like the new evolutionary appearance of the MEK mutation (vide supra), there might be a new and actionable mutation – if the patient was not already on it in combination.
The alternative to a new biopsy if to take a blood draw for cell-free DNA (cfDNA) as it is now possible to do NGS on this and analyse the melanoma DNA at any timepoint – we even follow the genomnc evolution over time by serial blood draws. The cfDNA option also has the advantage of looking at the mean composition of the melanoma as it is not constrained by a single site biopsy result.
Credit: P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics; tel: +44-2076311632)
The vast majority of early, thin (stage 1) melanomas are cured by the surgical excision described above. The prognosis for patients who have thicker tumours or who have relapsed is much more uncertain, but, with the availability now of effective adjuvant therapy, this will hopefully improve the outlook for patients with higher risk melanomas.
There is no formal screening programme in the UK (‘Mole Hunt), but in Australia and other areas where the incidence is high, a very extensive public awareness programme is present which, through script and graphics, demonstrates to the population what to report immediately if found on the skin.