Continuing Professional Development: Malignant Melanoma of the Skin

Continuing Professional Development: Malignant Melanoma of the Skin

AUTHOR:Dr Emma Porter. Dermatology Registrar, University Hospital Limerick

60 Second Summary

Malignant melanoma is the fifth most common invasive cancer nationally, with rising incidence. The main risk factor for its development is ultraviolet radiation exposure, especially intense and intermittent exposures and sun burn in fair-skinned individuals. Most cases of melanoma affect middle-aged individuals, though a significant proportion affect young adults. Males over 50 tend to present with thicker tumours, often on the trunk, and have a worse prognosis than females. Most melanomas occur de novo, with approximately 30% arising within a pre-existing mole.

Early detection and prompt excision of melanoma remains the most important element of management, with rapidaccess pigmented lesions set up nationally for this purpose. Early stages of melanoma have excellent prognosis. Historically, the prognosis for advanced and metastatic melanoma was very poor, though dramatic improvements in the landscape of melanoma treatment have been made in the last decade with the advent of a variety of systemic therapies for advanced and metastatic disease. These include targeted therapies such as BRAF and MEK inhibitors for BRAF-mutated melanoma, and immunotherapy agents in the form of immune checkpoint inhibitors and programmed cell-death protein 1 (PD-1) inhibitors.

Primary prevention strategies and public health messaging emphasise the importance of adequately protecting skin from the sun and selfsurveillance for early detection of suspicious lesions.

Introduction

Malignant melanoma is the fifth most common invasive cancer in Ireland, with approximately 20 cases per 100,000 per year - one of the highest incidence rates globally - and rising incidence. 1 Ultraviolet (UV) radiation exposure is the main risk factor for development of melanoma, particularly intense and intermittent exposures in fair-skinned individuals. 2,3 Sun bed exposure is widely recognised to increased risk of melanoma, particularly when used in younger age groups. 4 Further risk factors include multiple melanocytic naevi, dysplastic naevus syndrome, a family history of melanoma, and immunosuppression. Familial genetic mutations with high penetrance are rare, with CDKN2A most frequently reported in these cases. In genome-wide association studies, single nucleotide polymorphisms in multiple genes related to nevogenesis and pigmentation have been associated with melanoma, including melanocortin 1 receptor, the gene which underlies red hair and freckles. 5

Median age at diagnosis was 64 years for melanoma between 2011 and 2015 in Ireland. Melanoma patients, particularly females, tend to have a younger age profile than those with non-melanoma skin cancers, with almost 31% of all female patients and 20% of males diagnosed before age 50. Paediatric melanoma is rare. 6 Males over 50 tend to present with thicker tumours, often on the trunk, and have worse prognosis. Epidemiological studies suggest that women with melanoma have a better prognosis, regardless of whether pre or postmenopausal and when adjustments for tumour characteristics are taken into account. 7,8

The majority of melanomas occur de novo, with 30% arising within a pre-existing naevus. There is emerging evidence suggesting differing characteristics of these melanomas, with naevusassociated melanoma associated with lower depth of invasion and similarities in body sites. 9 Histopathological subtypes of melanoma include superficial spreading, the most common, representing a radial growth phase, and nodular (vertical growth phase). Other types include acral (hands and feet), spitzoid and desmoplastic (spindle cells). In-situ melanoma is considered pre-cancerous, non-invasive and is limited to the epidermis, without evidence of dermal invasion on histology. Lentigo maligna is a subset of melanoma in situ with histological evidence of photodamage, typically seen on sun-exposed areas such as the face in elderly individuals.

Diagnosis

When diagnosed and treated early, melanoma has an excellent prognosis. Stage 1A carries a 5-year survival rate of 99%. Diagnostic and therapeutic advances contribute to further improvement in survival in all stages, though advanced melanoma still carries a poor prognosis and one fifth of patients are at stage III or IV at the time of diagnosis. 1

The National Cancer Control Programme (NCCP) has developed the National Melanoma GP Referral Guidelines (Figure 1) for assessment and referral of suspicious lesions via a standardised pathway to a dermatologist or plastic surgeon, the National Pigmented Lesion GP Referral form. 10,11 There are 14 rapid access centres nationally to where referrals can be sent. Standardised referral forms support inclusion of relevant clinical data for pigmented lesions including the ‘ABCDE’ system of lesion abnormalities (see Figure 1) and environmental and genetic risk factors.

Melanoma is usually clinically suspected before histopathological confirmation. The use of dermoscopy by dermatologists is used as standard in analysis of pigmented lesions and can facilitate differentiation from benign lesions, and prompt excision where atypical features are present. 12 In special cases and where available, confocal reflectance microscopy is a further diagnostic tool in improving clinical diagnosis.

The COVID-19 pandemic introduced unprecedented challenges to healthcare systems worldwide, and limited access to non-emergency services resulted in lower levels of referral, and later diagnosis of melanoma and skin cancer in general. 13,14 Many centres report more advanced tumours at diagnosis, though national figures are not currently available.

Figure 1. National Melanoma GP Referral Guidelines

Management

Primary excision

Early detection of melanoma and prompt, complete excision influences prognosis and survival and is the first line of management. A 2mm surgical margin around the lesions and a cuff of subcutaneous fat is taken on primary excision. Some centres offer same day excision where resources allow. After histopathological confirmation, cases are discussed at dedicated multidisciplinary meetings. The diagnosis of melanoma is explained in detail to patients in a clinic setting, and information provided, usually with support from a dedicated skin cancer clinical nurse specialist.

Following primary excision, histopathological findings are used to determine staging – based on the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, shown in Figure 2. 15 Breslow thickness, or the depth in millimetres of tumour invasion into the dermis, is the most important pathological feature, followed by the presence of ulceration. Tumours with a Breslow thickness of <0.8mm and without ulceration are pT1a, carrying an excellent prognosis (99% 5-year survival). In contrast, for example, a 50-year-old male with a melanoma with Breslow thickness >4mm with ulceration on an extremity, and no metastatic spread at diagnosis, has a 5-year survival rate of 70%. 16

Wide local excision

Wide local excision is performed for all melanomas, with the aim to reduce the risk of local recurrence.

Clinical margins as recommended by NICE Guidelines are 0.5cm for Stage 0 or in situ melanoma, 1cm for Stage I melanoma and 2cm for Stage II. 17 In some cases, topical imiquimod can be considered for melanoma in situ, for example if complete surgical excision would cause unacceptable morbidity or disfigurement.

Sentinel lymph node biopsy

Sentinel lymph node biopsy (SLNB) involves sampling of the first node(s) in the draining nodal basin of the melanoma, e.g. the axillary nodes for a melanoma on the upper limb. This is a prognostic or staging procedure rather than therapeutic, is typically carried out by plastic surgeons at the time of wide local excision, and requires general anaesthetic. This is offered to patients with tumours ≥0.8mm Breslow thickness, estimated to carry a 5% risk of sentinel lymph node positivity. Preceding 2017, the standard of care was complete lymph node dissection for those with a positive SLNB, however the landmark studies MSLT-I and MSLT-II showed that there is no melanoma-specific survival benefit for those that have SLNB, nor for those with a positive SLNB who undergo immediate lymph node dissection versus ultrasound surveillance. 18,19 However, identification of occult nodal metastasis with SLNB can allow consideration of systemic adjuvant therapy with an aim to reduce the risk of relapse and improve survival.

Radiological imaging

NICE Guidelines 2015 and European consensus guidelines from 2019 for the management of melanoma outline recommendations for baseline staging imaging for melanoma patients – including stage IIC melanoma and above. 12 A summary of these recommendations is illustrated in Table 1 (on page 34). These are general guidelines, and an individualised plan is made for each patient following multidisciplinary review.

Systemic therapy in advanced/ metastatic disease

Metastatic disease has historically been associated with poor survival. 20 Ten years ago, median overall survival of those with advanced-stage melanoma was 6-9 months. 21 With the advent of targeted therapy and immunotherapy for the treatment of metastatic melanoma in the last decade, outcomes are dramatically improving. 22 In 2010, targeted treatment for BRAFmutated melanoma was groundbreaking. 23 This has evolved to treatment with a combination of BRAF and MEK inhibition, to reduce resistance seen in BRAF inhibitor monotherapy. 24 However, less than 25% of melanomas in Ireland are BRAF-mutated, lower than other countries where this figure is closer to 40%. 25 Melanoma is an immunogenic tumour, and a BRAF mutation is not required for immunotherapy. Agents include immune checkpoint inhibitors including anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, and programmed cell-death protein 1 (PD-1) inhibitors such as pembrolizumab and nivolumab. 26 Toxicity with treatment, however, is a significant factor considered by oncologists when exploring options with patients with advanced melanoma, and not all patients will be suitable or have a preference for treatment. Several of the immunotherapy agents are approved for reimbursement by the HSE, including pembrolizumab, ipilimumab, nivolumab, along with multiple agents for BRAF mutation-positive unresectable or metastatic melanoma. 27

Figure 2: AJCC 8 th edition melanoma staging system. Source: Keung E, Balch C, Gershenwald J, et al. Key changes in the AJCC eighth edition melanoma staging system. Melanoma Lett. 2018;36(1): 1–9

Adjuvant treatment of stage III melanoma

Adjuvant therapy in melanoma aims to reduce the risk of relapse and improve overall survival in patients with moderate to high risk resected melanoma. Funding was made available for nivolumab in February 2021 as monotherapy for the adjuvant treatment of adults with stage III melanoma and lymph node involvement who have undergone complete resection, and pembrolizumab in May 2021. It is anticipated that licensing and funding for further agents will continue to expand in the near future.

Clinical follow up

Patients with melanoma are followed up in a dermatology clinic with full skin examination and assessment of draining lymph node basins on a regular basis, frequency and duration depending on clinical stage. The first five years are most important, as this is the period in which 90% of metastases occur. 12 Early stage melanoma, such as melanoma in situ and Stage IA melanoma, may only require a small number of clinic reviews over the space of the first year before discharge, as risk of recurrence is much lower. 13 Regular clinical review facilitates identification of recurrent disease, and monitors for development of a second primary melanoma (which can occur in up to 10% of patients) or a non-melanoma skin cancer. It also provides the opportunity for further patient education regarding photoprotection and selfsurveillance, and psychological support. Patients with later stage melanoma may require surveillance imaging (see Table 1).

Vitamin D

Following a diagnosis of melanoma, the change in behaviour in reducing sun exposure is likely to result in lower levels of vitamin D synthesis over time, with suboptimal levels common in the general population at a baseline. 28 There is some evidence that vitamin D plays a role in melanoma survival; higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. 29 Serum 25-hydroxyvitamin D3 levels are typically measured for melanoma patients to allow advice on supplementation, with an ideal range considered to be 60-85 nmol/L.

Primary Prevention

Public health campaigns for prevention of melanoma, and skin cancer in general, focus on safe sun practices of avoiding sun burn, seeking shade, covering up, using sunscreens and avoiding the use of sun beds. The SunSmart campaign, with the ‘5 S’s’ of Slip, Slap, Slop, Slide and Seek shade, has been most widely adopted, introduced first in Australia over 30 years ago where it has been shown to have a positive impact on sun-related behaviours. 30 This is the primary messaging used in Ireland, promoted by Healthy Ireland, and emphasised each year typically beginning in May with media campaigns. These sun protection practices are recommended especially between 11am and 3pm from April to September even on a cloudy day in Ireland, and when the UV Index is 3 or greater. Children and outdoor workers should have b. Stage IIAc. Stage IICd. Stage IIIA particular care taken in these measures. Furthermore, healthcare professionals can play an important role in further promoting these primary prevention practices for all patients we encounter.

References available on request