Cutaneous Melanoma
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. Newer treatments options that have become available
over the last 5 years have shown significant improvements and long term survival is
now more achievable for advanced melanoma.
Epidemiology skin cancer is responsible for approximately 1000 deaths 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 have 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).
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 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. Additionally, a high “mitotic
rate”, a measure of how fast the melanoma was growing, is an indicator of worse
prognosis.
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 evidence behind this are clearly laid out in the NH&MRC guidelines. No
advantage has been shown in any of the trials for 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 1520% 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
and colleagues. 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 person’s 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 xray 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 x-ray,
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
and colleagues in 2014 (New England Journal of Medicine 2014; 370:599-609). In
this study, 1200 patients (the multi-centre sentinel lymphadenectomy trial – 1), were
randomly assigned to have a wide local excision alone or a wide local excision with a
sentinel lymph node biopsy (SLNB) and their outcomes compared. The study
foundthat the addition of a SLNB 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 when
considering the entire study population of 1200. 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 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) and may
also be eligible for clinical trials. These options should be discussed with your Doctor.
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
sites 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).
A recent clinical study was conducted by the European Organization for Research and
Treatment of Cancer (EORTC) 18071, published online March 31 in the Lancet
Oncology, for high-risk patients with stage III melanoma who had undergone a
complete lymph node dissection. The interim results show that 3-year recurrence-free
survival was significantly higher in patients receiving ipilimumab than in those
receiving placebo (46.5% vs 34.8%; P = .0013). However, overall survival
information was not available from this analysis. These resultrs are promising but it is
not yet available as standard treatment. 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 reduce local recurrences such as
these but to date has no affect on overall survival.
Neck Dissection
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 gland (a salivary gland in front of the ear) is involved, it will 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
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
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. Where investigations
(CT or PET scans) have revealed lymph node involvement in the pelvis, or where
there are high risk features in the groin, then surgery is extended to included the
removal of lymph nodes in the pelvis. This is done by an incision through the lower
abdomen and the lymph nodes related to the pelvic blood vessels are removed. This
carries little additional long-term morbidity. 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 compression stockings.
In-Transit Disease
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, local treatment alternatives have been developed and
will be discussed on an individual basis.
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 used to be the
main stay of treatment for patients with stage IV disease, results were very poor.
However, in recent years new agents targeting a specific gene, BRAF, that is abnormal
in ~45% of melanomas (and is responsible for “driving” the melanomas aggressive
behaviour) have shown dramatically improved response rates and favourable long
term outcomes for ~10% of patients. In addition, drugs that activate the immune
system so that it can recognize a person’s melanoma as foreign and kill it, have shown
similar reponse rates 50% that are maintained in the long term for ~20% of patients.
These are great strides forward and ongoing clinical studies are continuing to redefine
the landscape for melanoma treatment. You should ask your treating Doctor about
clinical studies that might be suitable.