The incidence of melanoma in North America is higher today than ever in the past. Clinicians play an important role in the early assessment and recognition of suspicious moles and lesions which may represent a cutaneous malignancy. It’s imperative to perform investigations on atypical moles to exclude malignant changes. Clinicians need to know and educate their patients about primary prevention and recognition of risk factors. Early detection of thin cutaneous melanoma is the best way to reduce mortality and improve long-term patient outcomes.

Melanoma is a malignancy of pigment-producing cells (melanocytes) located predominantly in the skin, but also found in the eyes, ears, GI tract, leptomeninges, and oral and genital mucous membranes. Melanoma accounts for only 4% of all skin cancers, but causes the greatest number of skin cancer-related deaths worldwide¹.

How common is melanoma in Canada?

Given the lack of mandatory reporting in most provinces, incidence rates of melanoma in Canada are estimates. The majority of malignant melanoma patients aren’t seen in regional cancer centres, and melanoma in situ isn’t included in provincial or Canadian Cancer Statistics. A population-based study of cutaneous melanoma in Alberta reports age-standardized rates per 100,000 person-years ranging from 11.1-15.9 among men and 9.8-14.1 among women². These rates are considerably higher than the previously reported (1976) highest Alberta incidence of 4.1 and 4.8 in men and women, respectively. This study didn’t include melanomas in situ. According to Canadian Cancer Society Statistics 2009, melanoma incidence increased in men and women by 1.6% and 1.0% per year, respectively, between 1996 and 2005. Invasive melanoma is estimated to be the 7^th most common cancer in Canada.

What’s the pathophysiology of melanoma?

Melanocytes arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. They reside in the skin within the basal layer of the epidermis, at the junction of the dermis and epidermis, where they produce a protective melanin³.

Ultraviolet solar radiation promotes malignant change in the skin by having direct mutagenic effects on DNA, by stimulating the cellular constituents of the skin to produce growth factors, by reducing cutaneous immune defences, and by promoting reactive oxygen species of melanin that cause DNA damage and suppress apoptosis^3,4.

Melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocyte. Many genes are implicated in this disease, including CDKN2A (p16), CDK4, RB1, CDKN2A (p19), PTEN/MMAC1, and ras8. CDKN2A (p16) appears to be especially important in both sporadic and hereditary melanomas. This tumour suppressor gene is located on band 9p21, and its mutation plays a role in several cancers.

These abnormalities promote cell proliferation and prevent normal pathways of apoptosis in response to DNA damage. The altered melanocyte is thereby predisposed to cumulative DNA damage, resulting in the selection for genetic mutations that allow all aspects of the malignant phenotype, including stimulation of blood vessel growth, evasion of the immune response, tumour invasion, and metastasis⁵.

What’s the patient’s prognosis after being diagnosed with melanoma?

If detected early, melanoma can be cured with surgical excision. Stage 1 lesions (melanoma in situ) confer a 5-year survival rate of 95%, whereas stage IV melanoma metastatic to skin, subcutaneous tissue or lymph nodes with normal LDH has a 5-year survival rate of 19%⁶. A stage IV melanoma that has metastasized to lungs has a 5-year survival rate of 7%⁶.

Can micrometastases of the melanoma occur after it’s biopsied?

It’s imperative that a diagnosis of melanoma be made prior to wide excision, but due to the size of some lesions, a full excisional biopsy may not be feasible. A large retrospective case control study set out to investigate the effect of incisional biopsy on melanoma prognosis. Data were obtained from the database of the Scottish Melanoma Group; the database was set up in 1979 to follow all patients diagnosed with melanoma in Scotland⁷.

Each incisional biopsy case was matched against 2 excisional biopsy cases controlling for age, sex, sites, and Breslow thickness. The main outcome measures were time from initial biopsy to recurrence and to melanoma related death. This study is the largest series on the effect of incisional biopsy on melanoma prognosis to date and the first to include matched controls. The study concluded that melanoma prognosis is not influenced by incisional biopsy before definitive excision. There was no difference in survival outcomes between melanoma patients who had incisional vs excisional biopsies⁷.

What are the recommendations for removing cutaneous melanomas?

The narrowest effective margins for cutaneous melanoma have yet to be determined. Surgical margins of 5 mm are currently recommended for melanoma in situ, and margins of 1 cm are recommended for melanomas up to 1 mm in depth (low-risk primaries). In some settings, tissue sparing may be critical and Mohs margin-controlled excision may be appropriate⁸.

Randomized prospective studies suggest that 2-cm margins are appropriate for tumours of intermediate thickness (1-4 mm Breslow depth), although 1-cm margins have been proven effective for tumours of 1- to 2-mm thickness. Margins of 2 cm are recommended for cutaneous melanomas greater than 4 mm in thickness (high-risk primaries) to prevent potential local recurrence in or around the scar site⁹.

Mohs micrographic surgery has also been proposed for cutaneous melanoma and has the advantage of providing visualization of 100% of peripheral and deep margins microscopically¹. Mohs surgery may have certain “niche” indications, including melanomas located on the head, neck, hands, or feet. Mohs surgery may prove useful in completely removing subclinical tumour extension in certain subtypes of melanoma in situ, such as lentigo maligna and acral lentiginous melanoma in situ.

Prophylactic lymph node dissection for primary cutaneous melanoma of intermediate thickness was once believed to confer a survival advantage on patients with tumours of 1-4 mm in depth. Subsequently, prospective randomized clinical trials have shown no survival benefit for elective lymphadenectomy for melanomas of varying thicknesses on the extremities and marginal, if any, benefit for non-extremity melanomas.

After a melanoma is detected, should all moles on the body be removed?

It isn’t necessary to prophylactically remove all moles after the diagnosis of a melanoma. Patients should be monitored regularly after a diagnosis of cutaneous melanoma, particularly in the setting of thicker tumours, because most metastases occur in the first 1-3 years after treatment of the primary tumour. Annual skin examinations are recommended for life because an estimated 4-8% of patients with a history of melanoma develop new primary melanoma, generally within the first 3-5 years following diagnosis¹⁰.

However, the risk of new primary melanoma increases in the setting of multiple clinical atypical/dysplastic nevi, family history of melanoma, and atypical mole syndrome or familial atypical mole-melanoma syndrome. In such cases, it may be more common to follow-up with a dermatologist every 6 months for the first 3-5 years as opposed to yearly appointments.

What are the adjuvant therapies which are used for melanoma?

Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy and treatment of patients with advanced melanoma. Also, because fewer than one half of patients with deep primaries (> 4 mm) or regional lymph node involvement have long-term disease-free survival, these patients are considered high risk and should be considered for adjuvant therapy. Although controversy surrounds the use of adjuvant therapy in these patients, a recent, large, multi-centre study showed improvement in both long-term survival and disease-free survival using high-dose interferon-alpha-2b (IFN)¹¹. Based on this study, the Food and Drug Administration (FDA) approved IFN as adjuvant treatment after excision in patients who are free of disease but at high risk for recurrence.

Treatment of patients with advanced-stage melanoma (stage IV) hasn’t improved significantly in recent years. At this time, no combination chemotherapy regimen has proven to be significantly better than single-agent dacarbazine (DTIC), which yields only a 10-15% response rate¹². Two combination regimens commonly are used in the treatment of patients with advanced-stage melanoma. The first regimen is the cisplatin, vinblastine, and DTIC (CVD) regimen. The second commonly used regimen is the Dartmouth regimen, which is a combination of cisplatin, DTIC, carmustine, and tamoxifen. Biological therapies now are being used alone and with chemotherapy regimens.

What other investigations should be performed?

Sentinel lymph node biopsy (SLNB) for cutaneous melanoma was developed in the early 1990s to allow a selective approach to identifying individuals with occult regional nodal metastasis through localization of the first-draining, or sentinel, node. The success of the technique is based on the concept that cutaneous lymphatic flow is well-delineated in melanoma and that the histology of the sentinel node is characteristic of the entire lymph node basin (i.e. a negative sentinel node negates the need for further lymph node dissection)¹³. Sentinel node status (positive or negative) is the most important prognostic factor for recurrence and the most powerful predictor of survival in melanoma patients. SLNB is generally indicated for pathologic staging of the regional nodal basin(s) for primary tumours ≥ 1 mm depth and when certain high-risk histologic features (e.g. ulceration, extensive regression, high mitotic rate, angiolymphatic invasion) are present in thinner melanomas. It isn’t performed for most thinner melanomas such as melanoma in situ¹⁴.

Published data have shown that baseline and surveillance laboratory studies (e.g. lactate dehydrogenase [LDH] level, liver function tests), chest radiography (CXR), and other imaging studies (e.g. CT scanning, positron emission tomography [PET] scanning, bone scanning, MRI) are not typically beneficial for stage I/II (cutaneous) melanoma patients without signs or symptoms of metastasis. CT scanning, MRI, PET scanning, ultrasonography, and bone scanning have an extremely low yield in asymptomatic patients with primary cutaneous melanoma (AJCC stages I and II) and are generally not indicated. A metastatic workup should be initiated if physical findings or symptoms suggest disease recurrence or if the patient has documented nodal metastasis based on results from the SLNB. Baseline metastatic staging for melanoma patients with primary tumours > 1 mm in depth may include CXR, which typically is repeated every 6-12 months for routine surveillance (optional in the absence of signs or symptoms of metastatic disease)¹⁵.

How can melanoma be detected early?

A new or changing mole or blemish is the most common warning sign for melanoma. Variation in colour and/or an increase in diameter, height, or asymmetry of borders of a pigmented lesion are noted by more than 80% of patients with melanoma at the time of diagnosis¹⁶. Symptoms such as bleeding, itching, ulceration, and pain in a pigmented lesion are less common but warrant an evaluation. Again, because the majority of cutaneous melanoma arises de novo (i.e. not in association with a precursor nevus), the wholesale removal of melanocytic nevi isn’t warranted for melanoma prevention. Patients with numerous moles (common or dysplastic) or a family history of melanoma, however, should be educated regarding the importance of skin self-examination for early detection of skin cancer¹⁶.