Melanoma

Introduction

Melanoma is a malignant tumour of melanocytes, the melanin-producing neural crest-derived cells of the body. Melanoma commonly arises from melanocytes in the stratum basale of the epidermis, but can also arise from melanocytes at other sites.

In the UK, melanoma has an incidence of approximately 17 per 100000 people, most commonly on the trunk or legs, with incidence rising with age. They metastasise early (relative to other tumour types), partly due to their vertical growth (as opposed to radially) and can spread to nearly every tissue and organ in the body

The four main histological subtypes of melanoma are superficial spreading, nodular, lentigo maligna melanoma*, and acral lentiginous (Table 1). Melanin itself is produced in response to UV radiation exposure and acts to protect against DNA damage by dissipating >99.9% of absorbed radiation.

*Lentigo maligna is a macular lesion containing an increased number of abnormal melanocytes, confined to epidermis (aka melanoma in situ), whilst lentigo maligna melanoma are when these abnormal melanocytes invade the dermis

Table 1 – Main subtypes of skin melanoma

Pathophysiology

The definite pathophysiology of melanoma remains unclear, however the main contributor is ultraviolet (UV) radiation exposure. Specifically, UVB radiation (315–280nm wavelength light) from the sun is absorbed by the skin and causes direct DNA damage (through the creation of cyclobutane pyrimidine dimers).

Genetic mutations may also increase the susceptibility to carcinogenic effects of UV radiation; two main mutations include:

• MAPK pathway – mutations to proto-oncogenes, such as BRAF and NRAS, which normally promote cell proliferation and survival, result in activation of MAPK pathway, which causes uncontrolled cell proliferation*
• CDKN2A/RB1 pathway – CDKN2A encodes the p16 and p14ARF proteins, both of which act as tumour suppressors by regulating the cell cycle (specifically, by blocking transition from the G1 to S-phase); mutation to CDKN2A can result in unregulated cell growth and neoplastic progression.

*Approximately 50% of melanomas are BRAF positive, specifically NRAS mutations are present in ~20% of melanomas

Risk Factors

There are multiple risk factors for the development of melanoma. The most important risk factor is UV exposure (either sun exposure or artificially exposure through sunbeds).

Other risk factors include (using the mnemonic PPARENTS) Pre malignant lesions, Previous melanoma, Age, Race, Economic status, Naevi numbers*, or FAMM syndrome (familial atypical mole and melanoma syndrome), Type 1 or tyoe 2 skin (Fitzpatrick skin types), or Sunbed use

*More than 50 normal naevi confers an increased risk of melanoma

Clinical Features

Early melanomas are often asymptomatic. Patients usually present having noticed a new naevus or changes in an existing mole, such as change in size, shape, colour.

In such cases, history should focus on the risk factors. In more locally advanced cases, there may be evidence of bleeding or ulceration

On examination*, the ABCDE rule is helpful:

• Asymmetry
• Border irregularity
• Colour uneven
• Diameter >6mm
• Evolving lesion

The patient should be fully examined for features of spread, including regional lymph node involvement.

*Dermoscopy can help triage pigmented lesions, and may show features specific to melanoma

By Stevenfruitsmaak, Public domain, via Wikimedia Commons

Figure 1 – Melanoma (left) compared to simple naevi (right)

Differential Diagnosis

The main differential diagnoses are melanocytic naevi (darkly pigmented moles), pigmented basal cell carcinoma (an uncommon variant of basal cell carcinoma), dermatofibroma, subungual haematoma, or tinea nigra.

Regardless, any suspected melanoma or suspicious lesion should be referred urgently via the relevant cancer pathway to avoid delay in diagnosis.

Investigations

Diagnosis is made through excision biopsy*, requiring a 2mm peripheral margin and a cuff of subcutaneous fat at the deep margin. Histopathological features guide further management in the context of the Multidisciplinary Team (MDT). Definitive excision margins and further investigations/treatment will be decided after histopathology.

*Incision or punch biopsies may be acceptable in very large lesions; shave biopsies or curettage should not be performed

Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy (SNLB) aims to identify whether or not there is any melanoma in the primary draining lymph node(s) within a regional lymph node basin, when the nodes are not clinically or radiologically suspicious.

Current NICE guidelines recommend offering SLNB to patients with melanoma with a Breslow thickness >1 mm, without clinically apparent nodal or metastatic disease. SLNB has a high sensitivity and specificity for subclinical regional lymph node involvement, and can give prognostic information.

If the lymph nodes are clinically or radiologically suspicious, then fine needle aspiration cytology (FNAC) should be performed.

Staging

Imaging should be performed in patients with stage IIc melanoma who have not had SLNB, or stage III and IV melanoma. Typically this involves a CT chest-abdomen-pelvis and MRI brain, or whole body PET-CT with additional imaging of the brain.

Melanoma is staged using the TNM classification; the clinical TNM (cTNM) stage is then updated with information after surgery to give the pathological stage (pTNM).

The AJCC staging (Table 2) groups the TNM stages to guide treatment and prognosis.

Table 2 – The AJCC staging system

Management

Wide Local Excision

After melanoma is confirmed, the biopsied area should undergo a wide local excision (WLE). The aim of WLE is to improve locoregional control by removing micrometastases.

The peripheral margins taken are guided by the Breslow thickness (Table 3) and the deep margins should always be down to the deep fascia.

Table 3 – Peripheral Margins Required for WLE

The wide local excision is usually performed at the same time as the sentinel node biopsy. Any confirmed lymph node metastasis from positive SLNB or FNAC is treated by completion lymphadenectomy.

Metastatic Disease

Unfortunately metastatic disease is common. Systemic metastases can be treated using various immunotherapies and chemotherapies.

The immunotherapy agents most commonly used are:

• Ipilimumab – a monoclonal antibody that inhibits cytotoxic T lymphocyte antigen 4 (CTLA 4), which would normally down regulate T cell activation
• Pembrolizumab and Nivolumab – monoclonal antibodies that attach to the PD1 receptor on T cells so that the T cells cannot be switched off and remain active
• Vemurafenib and Dabrafenib – both are BRAF kinase inhibitors that block the activity of the BRAF V600E mutation which otherwise causes persistent MAPK pathway activation leading to uncontrolled cell proliferation
• Talimogene laherparepvec (TVEC) – an oncolytic immunotherapy derived from herpes simplex virus type-1 which causes tumour lysis and the release of tumour-derived antigens; it is injected directly into the metastasis

One of the main chemotherapeutic agent used for melanoma is dacarbazine, an alkylating agent; it has short lived response rates, however does not provide overall survival benefits.

Any recurrent locoregional melanoma is often treated palliatively.

Prognosis

Melanoma survival is strongly correlated with histopathological and individual features. Approximate 5-year survival, based on disease stage are:

• Stage 1 – 100%
• Stage 2 – 80%
• Stage 3 – 70%
• Stage 4 – 30%

Prevention is the best management option through education encouraging reducing exposure to UV light through sun-protection and avoidance of sun beds, and self-checking for new or changing moles. Patients at high risk for melanoma should receive annual screening.