Cutaneous malignant melanoma is a malignant tumour of the skin. It is strongly associated with sun exposure. While representing a serious diagnosis, patients with early stage disease have a very good chance of cure. Patients diagnosed at a more advanced stage of disease have a more serious prognosis but curative treatment options are often available.
Epidemiology skin cancer is responsible for approximately 1000 deaths in per year in Australia. Melanoma represents 5% of all skin cancers in Australia but it counts for 800 of the 1000 deaths. It is the 5th leading cause of death from cancer in Australia. Australians has a significant lifetime risk of developing melanoma and this is more pronounced in Queensland. In Queensland, lifetime risk of developing melanoma for men is 1 in 14 and for women 1 in 18. As a result, significant effort has been focussed upon prevention strategies. The recent analysis of trends in the incidence of melanoma in Queensland has shown annual increase in the incidence of melanoma for both males and females with the incidence for males rising faster. The majority of the increased incidence has been accounted for by very thin or in-situ lesions. There appears to be stabilization in the incidence of melanoma in the younger age group of people less than 35. Similarly the mortality rate overall seems to have stabilised. Early detection may be responsible for the stable mortality despite the increase of incidents. Moreover primary prevention with sun protection may be one explanation for the stabilization of incidents in the less than 35 year age group.
Risk Factors for Melanoma
Several risk factors for melanoma have been identified. These include light skin pigmentation, excessive exposure to sun light (UVB), living close to the equator and previous skin diseases such as atypical moles (dysplastic naevi) or zero dermopigmentosim.
Diagnosis of Melanoma
The majority of melanomas are pigmented and of these approximately half arise in a pre-existing mole. The diagnosis of melanoma can be challenging but clinicians who use a number of methods to differentiate moles that may be malignant melanomas from those that are entirely benign. Clues that a mole may be a melanoma include an asymmetrical appearance in the lesion, an irregular border, variable colour throughout the lesion, larger sized lesions, elevated components to the lesion or if there has been any change seen in the lesion over time. In addition to naked eye examination, clinicians may use skin surface microscopy otherwise known as dermatoscopy. This provides significant level of magnification and permits detailed examination of the pigment patterns of the lesion. Lesions suspected of being melanomas should undergo biopsy to confirm the nature of the lesion. In the majority of cases this would involve removing the entire pigmented lesion (excision biopsy). This may not be possible for larger lesions and in such settings shave or punch biopsies may be used to make the diagnosis. There is no evidence that one biopsy technique is inferior to the other with respect to cancer survival. Excision biopsies are typically performed under local anaesthetic and a simple elliptical excision with a narrow margin is achievable.
Prognosis of Melanoma
For patients presenting with a primary malignant melanoma of the skin, the chances of cure are related to the depth of the lesion and a presence or absence of ulceration. Patients with a level I (in-situ melanoma) are typically cured by there definitive surgery. For patients with primary melanoma invading beyond level I their prognosis is dictated by the depth of the lesion in millimetres (breslow thickness). This is further modified by the presence of or absence of ulceration. Melanoma depths are broken up into thin melanomas (melanomas less than 1mm in depth), intermediate thickness 1-4mm in depth or thick melanomas (greater than 4mm in depth). The majority of patients will have thin or intermediate thickness melanomas. The patients with thin melanomas, the chances of cure are in excess of 90%. For those with intermediate thickness melanomas cure rates vary from 70-90%. Thick melanomas carry a more serious prognosis with chances of cure approximately 60%. The presence of ulceration in the lesion is associated with behaviour more consistent with the next level of thickness. For example, and intermediate thickness melanoma with ulceration would behave more like a thick melanoma.
Presence or absence of malignant melanoma in regional lymph node has an even stronger prognostic indicator than tumour depth or ulceration. In this setting cure rates are 50% or below. The likelihood of cure in the setting of involved lymph nodes is related to the number of lymph nodes positive and whether they are microscopic or large deposits. This is referred to as stage III disease. Malignant melanoma may spread beyond the primary lesion and the regional lymph nodes to involve any distant organs such as the liver, brain and lungs. Melanoma spread such as this is referred to as stage IV or metastatic disease. Stage IV melanoma is associated with a cure rates of less than 10%.
Treatment of Primary Melanoma
Melanoma’s are associated with local or recurrence (that is tumour growing back within 5cm of the original lesion) if inadequate amount of skin is removed around the melanoma. For level I or in-situ lesions the recommended excision margin is 5mm. For invasive melanoma the recommended excision margins are 1cm for lesions up to 4mm in depth and 1-2cm for lesions greater than 4mm in depth. For variance of malignant melanoma such as desmoplastic melanoma a minimum 2cm margin is advocated. These margins have been established on the basis of several large clinical trials. The events behind this are clearly laid out in the NH and MRC guidelines. No advantage has been shown in any of the trials before removing more than 1-2cm of skin around the primary melanoma. This substantially reduces the risk of local recurrence but does not make that chance zero. Recurrences after definitive excision are the result of more aggressive tumour types.
Sentinel Lymph Node Biopsy
Melanoma recurrence in the regional lymph nodes (neck, armpit, groin) affect 15-20% of patients with intermediate thickness melanoma’s and some patients with high risk thin melanoma’s (Clark’s level IV, ulcerated, high mitotic rate). Regional lymph node recurrence is higher risk in patients with melanoma’s greater than 4mm although these patients are equally likely to suffer from more distant recurrence. In an attempt to identify a patient at risk for regional lymph node recurrence and improve their chances of a cure, the sentinel lymph node biopsy technique was devised by Morton et al. Essentially the technique is aimed at identifying the lymph gland or node responsible for the piece of skin in which the melanoma developed. It is this lymph node that would be the first site of melanoma spread if a patients melanoma has acquired the capacity to spread. The technique involves an x-ray called lymphoscintigraphy. This uses a radio labelled dye that is a very low dose injected in the skin around the site of the melanoma. An x-ray is taken soon after to identify the sentinel lymph node. The lymphoscintigraphy x-ray is typically done in the morning before the surgery or the afternoon before a morning surgery. A lymphoscintogram x-ray is a valuable guide to the surgeon to help identify the position of the sentinel lymph node. When a patient has elected to undergo a sentinel lymph node biopsy, the procedure is performed in the operating theatre typically under general anaesthesia. It is preferable to be done at the same time as the definitive wide excision. Once the patient is asleep, the surgeon will inject a blue non radioactive dye around the site of the melanoma. This blue dye helps facilitate identification of the sentinel lymph node. The surgeon then makes an incision over the area indentified by the radiologists either in the neck, armpit or groin and look for the sentinel lymph node marked by the blue dye and the presence of radioactivity using a gamma probe. Using this technique, sentinel lymph nodes are identified 95% of the time or more. The wide excision is then performed and the patient may go home on the same day. The sentinel lymph node is then analysed by the pathologists and this usually takes a couple of days and special stains are done to increase the accuracy of the test.
Sentinel Lymph Node Biopsy and Survival
While sentinel lymph node biopsy provides accurate prognostic information and staging, it’s role in respect to improving a patients chances of survival are controversial. To date only one randomised control trial has been published with respect to the use of sentinel lymph node biopsy in addition to a wide local excision compared with a wide local excision alone. These results were published by Morton ET AL in 2006. In this study of 1200 patients (the multi-centre sentinel lymphadenectomy trial – 1) that randomly compared patients to a wide local excision alone versus a wide local excision with a sentinel lymph node biopsy and found that it improved disease free survival (that is how long it took the melanoma to recur) but sentinel lymph node biopsy did not improve overall survival (that is the number of patients actually dying from melanoma) compared with wide local excision and delayed treatment of any recurrence in lymph nodes. Further analysis reported by the authors has shown that for patients with a negative sentinel lymph node, there is no difference in survival between this group and those that did not undergo a sentinel lymph node biopsy and did not subsequently develop recurrence in their lymph nodes. However analysis of patients with a positive sentinel lymph node suggests the possibility of a survival benefit in this group of patients over those that did not undergo a sentinel lymph node biopsy but subsequently developed melanoma in their lymph nodes. While the impact of sentinel lymph node biopsy on overall survival remains controversial, the removal of the nodes does reduce the risk of recurrence in lymph nodes from 20% to less than 4%.
For a patient with a negative sentinel lymph node no further treatment is required at the time. These patients will continue to undergo routine follow up in the clinic on a 3 – 6 monthly basis. Patients with a positive sentinel lymph node, the current standard of care is to remove all of the remaining lymph nodes from the area that the sentinel lymph node was removed from. This is recommended on the basis that up to one in five patients with a positive sentinel lymph node will have other lymph nodes with melanoma remaining in the area. See stage III disease below for the side effects of such surgery. It is not known whether all patients require a completion lymph node dissection in the setting of a positive sentinel lymph node and a new clinical trial is underway to examine the role of close follow up in the setting of a positive sentinel lymph node without further surgery (multi-centre lymphadenectomy trial – 2 or MSLT 2). In addition to further surgery patients with a positive sentinel lymph node biopsy qualify for extra treatment with Interferon (see Interferon section).
Stage III disease (Melanoma in lymph nodes)
Melanoma can recur in the lymph nodes of any patient with invasive melanoma and can affect more than 15% of patients with melanoma’s greater than 1mm in thickness. Occasionally a melanoma will be detected first in the lymph nodes with no preceding history of a skin melanoma (unknown primary). The treatment for the lymph nodes is the same in any case. When melanoma is suspected in lymph nodes typically a fine needle biopsy would be performed to obtain a tissue diagnosis so the treatment can be planned. Once a firm diagnosis of stage III melanoma has been obtained, further staging would be arranged in the form of a CT scan of the chest, abdomen and pelvis to exclude the possibility of other sites of melanoma (stage IV disease). Once these studies have been done the main stay of the curative treatment is surgery. The typical science of surgery for patients with stage III melanoma are lymph nodes in the neck, the arm pit (axilla) or the groin. Surgery in each of these areas will be discussed below. While stage III disease carries a more serious prognosis than primary melanoma, a substantial proportion of these patients are still cured by their surgery. In addition to surgery outpatients may elect to have Interferon therapy post operatively (see below). Despite the surgery to remove the lymph nodes in certain circumstances where the tumour appears to be more aggressive radiotherapy may be offered in an attempt to reduce the risk of further lymph node recurrences in the area. Radiation has been shown to effect local recurrences such as these but to date has no affect on overall survival.
Removing melanoma involving lymph nodes in the neck involves an operation called a neck dissection or modified radical neck dissection. This involves an incision in the neck on the affected side from the ear to the clavicle. At operation the surgeon will remove all of the lymph nodes on that side of the neck trying to preserve the main muscle on the side of the neck (sternocleidomastoid) as well as the jugular vein and the accessory nerve that supplies the trapezius muscle (responsible for the ability to shrug the shoulder). One or more of these structures may occasionally have to be removed if the melanoma involves them. After the surgery patients would expect to have a numb ear and much of the skin on the affected side of the neck. In addition the neck will appear thinner on the side where the surgery has been performed. In the immediate post operative period patients will have drains placed as the tissue fluid travels through the lymph nodes that are removed can collect under the wound in the early post operative period until this fluid has found a new route back into the circulation. After removal of the drains it is still possible to collect fluid under the wound and this is usually dealt with in the office by putting a needle under the skin and sucking the fluid out. This may need to be done on more than one occasion. Other side effects can include wound infection and scaring. Rarely bleeding occurs in the neck wound in the early post operative period requiring a re-operation.
If the parotid (asalivary gland in front of the ear) may also need to be removed. In this instance the main nerve at risk is the facial nerve responsible for the muscles in the face. This generally functions normally after the surgery but in a small number of patients may be temporarily or even permanently paralysed. If this affects the muscles around the eye this may require further surgery to make sure the eye is protected and can be closed.
Axillary dissection involves a transverse cut in the arm pit. At the surgery the surgeon removes all of the lymph gland material and fatty material in the arm pit through to the base of the neck (level III dissection). The surgeon aims to preserve all of the nerves to muscles in the armpit although occasionally these may be damaged giving some weakness to the shoulder stability. As with the neck dissection patients can expect to have some numbness in the armpit and on the inner side of the upper arm. Moreover patients will also have one or two drains placed in the armpit after the surgery. This is also to look after collections of lymphatic fluid (seroma) in the armpit after the operation. The drain may be in for several days up to weeks until the drainage stops. Once the drain has been removed fluid may still collect under the wounds requiring one or more visits to the office for this to be drained if it is uncomfortable. One of the most significant long term side effects of axillary dissection is lymphedema . This is less common in the arm than in the leg. A minor degree can be expected to happen in many patients but it is not usually problematic. The most severe lymphedema is relatively rare. Post operatively it is important to continue shoulder mobility and physiotherapy exercises are an important part of recovery. In addition physiotherapy can be helpful in reducing or treating lymphedema.
Groin dissection like axillary and neck dissection involves removing all of the glands in the groin. This is typically done through an incision that crosses the groin crease and removes all of the fat and lymph node tissue around the major vessels in the leg. This results in numbness in the inner part of the upper thigh. The groin by the nature of it’s site is associated with more wound complication then axillary or neck dissections. Wound infections are more common in this area as are persistent fluid collections requiring multiple drainages. Similarly the risk of lymphedema is increased in the leg because this area is more gravity dependent. In the post operative period in addition to physiotherapy, patients are encouraged to wear a compression stockings.
Approximately 4% of patients with melanoma will develop in-transit metastasis. These melanoma recurrences represent deposits of melanoma in the small lymphatic channels (like blood vessels) underneath the skin and the subcutaneous tissues. When they occur in small numbers these are often treated by simple excision alone. Where in-transit recurrences are not amenable to removal in surgery and occur on the limb, treatment with high dose chemotherapy in the limb may be offered. This is referred to as an isolated limb infusion and is performed through the melanoma clinic at the Princess Alexandra Hospital. This results in complete remission of the disease in 25 – 40% of patients and the melanoma does not recur in the majority of patients that get a good response. More recently we have a clinical trial open for a compound known as PV10 and if this is appropriate it would be discussed at the time of your consultation.
Stage IV disease
For the majority of patients who present with stage IV disease, their problem is not a curable one. However if the melanoma deposits are relatively few in number (less than 4) and in positions where they may be removed, then surgical removal is the best option and is associated with cure rates of 20-40%. For the majority of patients with stage IV disease this surgery is not appropriate. While chemotherapy is the main stay of treatment for patients with stage IV disease, a number of newer agents are under investigation. These compounds are being investigated through a number of clinical trials that are open and being discussed whenever they are thought to be an appropriate option.