DR ANA MANSOURI
Dr Ana Mansouri is an aesthetic doctor at Kat & Co in Birmingham. She has a Bachelor of Medicine & Bachelor of Surgery from Newcastle University Medical School and has completed a postgraduate diploma in Clinical Dermatology with Queen Mary University London. She is a member of the British Association of Dermatology (BAD), British Society for Dermatological Surgery (BSDS) and British Society of Aesthetic Examiners and Assessors (BSAEA). Follow her on Instagram: @doctor__ana
Primary cutaneous melanoma or malignant melanoma (MM) is an increasingly common malignant tumour arising from cutaneous melanocytes. MM is an uncommon cancer in the UK (≈4% of all new cancer diagnoses). 1 It has extremely high mortality, with over 2,000 deaths across the UK in 20111 and subsequently, a significant impact on the years of life lost in view of its occurrence in young people.2
MM occurs most frequently in fair-skinned individuals and is more common in women. Mean age of onset is 50 but ≈20% of patients are young adults. 2 The lifetime risk was estimated 1:120 for women and 1:150 for men in 2010 in the UK. The incidence varies greatly among countries; MM is the 15th most common cancer worldwide.3
The incidence of MM correlates closely with latitude and the causation of sun exposure in the development of MM is well documented. 2 UV light is the main environmental risk factor. Intense and intermittent UV exposure is associated with higher risks in contrast to chronic sun exposure. Exposure to over five episodes of sunburn during childhood or adolescence leads to a two-fold increased risk of developing MM. This also applies to sunbed users and psoriasis patients receiving UVA phototherapy.3
The majority of precursor melanocytes which develop into a benign nevus and subsequently into an atypical nevus will regress, however some undergo malignant transformation into MM. 2
The pathway where normal melanocytes undergo melanogenesis is not yet fully understood. 3 Major advances in the past decade have identified new predisposing gene alterations. The process is believed to rely on a complex interaction between environmental UV-exposure in combination with endogenous triggers (tumour-intrinsic and immune-mediated factors).3 37-50% of MM carry a mutation in the BRAF gene, the majority is the V600E type. BRAF mutation leads to unregulated activation of the mitogen-activated protein kinase (MAPK) pathway which is exhibited in up to 90% of MM cases. Activation of MAPK and thus RAS protein activation stimulates RAF (including BRAF) and subsequently MEK and ERK kinase phosphorylation. This process leads to cell cycle deregulation and inhibition of apoptosis.3
Xeroderma pigmentosum is a genetic disease where the DNA excision system is dysfunctional hence leading to a predisposition to MM. The familial atypical multiple mole-melanoma syndrome and its variant, the melanoma-astrocytoma syndrome has been associated with germline mutations in the high-penetrance melanoma genes CDKN2A or p16 and mutations in CDK4.3
Early diagnosis is essential due to MM’s typically slow early growth rate, as this may allow for detection and removal of curable lesions, hence a reduction in likeliness of mortality. 2,4
Most cases of MM are asymptomatic, however some patients experience pruritus, tingling or bleeding. These features are rarely helpful in diagnosis as they commonly occur in benign moles. 2 The majority of MM in the UK occur in the lower legs in women and on the back in men. Head and neck lesions commonly occur in people with chronic sun exposure.2
Table 1. Phenotypic risk factors for malignant melanoma. 2,4,3
*diameter of 20 cm and 5% of body surface area
**2% of the UK population have this phenotype
Table 2. Examples of signalling molecules and gene alternation involved in the malignant transformation of melanocytes. 3
Figure 1. The malignant transformation of MM; only 20-50% of MM develop on a pre-existing nevus, a significant number of MM develop de novo. 2,3
Figure 2. Malignant transformation of the melanocyte through the two processes of mutations affecting proto-oncogene/tumor suppressor genes (TP53, NF1, PTEN) and the BRAFV600E mutation which may undergo further UV mediated mutation (TERT and CDKN2A). 3
Table 3. Clinical subtypes of Malignant Melanoma. 1,2,5
MM can be classified into the four most commonly occurring clinical subtypes as per Table 3.
Atypical moles and melanoma in situ are considered pre-malignant lesions and often show marked variation in shape and colour and may have an inflamed appearance. 1,2 It is important to note that MM can rarely arise from any melanocytic origin including gastrointestinal tract, ears and eyes, oral and genital mucosa as well as leptomeninges.1
Clinical assessment tools
A number of assessment tools are used to identify high-risk lesions. The Glasgow 7-Point Checklist outlines minor and major clinical features as per Table 4. The ABCDE rule is another commonly used tool for early detection of MM as per Table 5.
These tools are considered more sensitive than specific; however, they may be less accurate in identifying nodular and amenlanocytic subtypes. 4 The “ugly duckling” sign may be more useful in these cases whereby the melanoma can be recognised as an “outlier”. It is also important to note the majority of MM cases develop de novo.1,6 It is well documented that some melanomas will have no major features, the cue in identifying MM may therefore lie only in the history.
Any suspicious lesion should be referred for local specialist MDT input, in particular any individual classed at high risk (see Table 1). 1,2,4 A moley patient should be referred for a 13-week specialist assessment including risk estimation and patient education. 2
Table 4. The Glasgow 7-Point Checklist system. Referral to secondary care is recommended for a lesion with the presence of any major feature or a lesion scoring at least three points. The presence of minor features should increase suspicion. 1,6
Table 5. The ABCDE rule of diagnosing melanoma. The presence of any feature is an indicator for referral. 1,2,4,6
Dermatoscopy is a useful tool in assessment and monitoring of atypical melanocytic lesions as well as in improving early detection of MM as it can increase diagnostic accuracy in the use of trained clinicians. 4
The differentials of the MM diagnosis include a wide range of conditions as per Table 8. Subungual MM may in particular be misdiagnosed as a fungal infection or pyogenic granuloma. 1
Histological classification and risk calculation determine subsequent treatment options.
Breslow thickness is measured as millimeters of depth from the granular layer of the epidermis to the deepest part of the tumour. This describes the anatomical level of invasion and makes part of the AJCC staging system (as per Table 11) as it correlates strongly with survival. 4
Pre-operative staging CT is recommended for stages IIC and III in view of the higher likelihood of distant metastases, whereas stage IV disease should be imaged based on SSMDT outcome. 4,6 Once melanoma has spread it typically becomes life-threatening rapidly and prognosis is therefore poor.4
Local skin cancer MDTs should identify patients who would benefit from specialist skin cancer MDT (SSMDT) evaluation such as advanced or metastatic MM and rare subtypes of MM. 4,6
Surgical excision of primary melanoma
Suspected MM should undergo excision biopsy with a 2mm margin of normal skin to confirm the diagnosis. 4 Surgery is the only curative treatment; wide local excision with recommended margins (Table 13) is the mainstay of treatment to reduce the risk of loco-regional recurrence. The decision of appropriate margin will be determined in MDT with consideration of functional and cosmetic. The histology should be reviewed again following WLE to ensure adequacy of excision. 4,6
Table 6. Indications for urgent two-week referral to local specialist
MDT assessment. 1,2,4
Table 7. Classical dermatoscopical features of MM subtypes. 1,5
Table 10. The four main histological subtypes and their histological patterns. 5
Table 11. The 2009 American Joint Committee (AJCC) Cancer staging system for MM expressed as TNM.
Thickness measured using the Breslow system. 4
Figure 4. Therapeutic approaches for the medical treatments for MM. 3 Monoclonal antibodies improve the efficacy of the immune system to identify and destroy malignant cells. Dabrafenib/vemurafenib: selective RAF inhibitors; Cobimetinib/rametinib: selective MEK inhibitors; Ipilimumab: monoclonal antibody IgG1k anti- CTLA-4; Nivolumab/pembrolizumab are PD-1 monoclonal antibodies IgG4 and IgG4k anti-PD-1.
Lymph node management
The presence of nodal involvement is the most important clinical predictor of prognosis. Patients with primary melanoma of stage IB-IIC with Breslow thickness >1mm should be referred to SSMDT if this provides a SLNB service for the purpose of contributing to the staging process. 4,6
Radical dissection of the entire lymph node basin is now only indicated where metastases is confirmed. Patients needs to be counselled carefully on the risks and benefits of this in view of a lack in good quality evidence for its effect on survival. 6
Advanced and unresectable melanoma
Treatment for all advanced cases of MM or loco-regional recurrence should be evaluated by SSMDT. Options are generally palliative in nature and include surgical excision, CO2 laser or isolated limb infusion or perfusion. 4
The benefits for radio and chemotherapy are limited. Radiotherapy may be considered in cases of doubt of the adequacy of surgery following recurrence or concerns regarding the feasibility of salvage surgery. 4 Chemotherapy may be indicated for patients otherwise unsuitable for targeted treatments, metastatic cases or disease progression despite surgery or laser. Adjuvant chemotherapy lacks evidence in regard to survival benefit.4
Significant progress in the biological understanding of MM during the last decade has contributed to the development of new targeted treatment options for advanced MM. This includes BRAF inhibitors as single agents, or in combination with a MEK inhibitor as well as novel single or combinational agent immunotherapies. 6
These recent advances have improved outcomes for advanced stage MM patients significantly although the immunotherapies are associated with severe complications such as autoimmune toxicity. All patients with advanced MM should therefore be tested for BRAF mutations and discussed in SMDT. 6
Table 8. Differential diagnoses of MM. 1
Table 12. Prognostic histological markers for MM. 4
Table 13. Recommended margins for wide local excision as recommended by the BAD guidelines 2010. 4 Thickness measured using the Breslow system.
Table 14. New treatment modalities for MM 3,4,6
A number of complementary and alternative medicine treatments are available for MM including nutrition therapy, neuropathic medicine, herbal medications, acupuncture and acupressure, hydrotherapy and meditation. 7 The evidence base to support their use is sparse.
PREVENTION AND FOLLOW-UP
The general public – in particular, children – should be advised to avoid sunburn. Patients identified at risk of MM are advised of life-long sun avoidance. This should be targeted to patients particularly at risk (see Table 1) in view of the suggested role of vitamin D deficiency in the prevention of other types of cancer as well as for general health. At-risk patients should be advised to supplement Vitamin D. 2,4 Patients at high risk should be referred for risk assessment and education including monthly selfexamination but regular follow up is not required.4
Patients at greatly increased risk should receive life-long follow-ups by a specialist due to the risk of malignant change. 4
The psychosocial implications of MM often significantly affect patients’ and families’ quality of life. The prevalence of anxiety and depression in skin cancer patients has been reported at between 11- 23%. A holistic needs assessment is recommended at each point in the journey to identify particularly vulnerable patient groups. The specialist MDT can be a useful resource in identifying vulnerable patients as well as facilitating referral to local support services.8
MM is an important condition with increasing incidence and high burden on years of life lost. The importance of patient education, prevention of risk factors and early recognition of suspicious lesions is therefore great. Recent breakthroughs of MM’s complex molecular aetiology has thankfully lead to the development of new therapies which have improved the outlook for advanced MM. Mapping of further genotypes is under investigation which is promising for the future of MM.
Table 15. BAD guidelines for follow-up of MM patients. 4
Table 16. Psychosocial factors to consider when assessing patients with MM. 8
1. McCourt C, Dolan O, Gormley G. Malignant melanoma: a pictorial review. Ulster Med J. 2014;83(2):103-10.
2. Royal College of Physicians and British Association of Dermatologists. The prevention, diagnosis, referral and management of melanoma of the skin: concise guidelines. Concise guidance to good practice series, No 7. London: RCP, 2007.
3. Leonardi GC, Falzone L, Salemi R, et al. Cutaneous melanoma: From pathogenesis to therapy (Review). Int J Oncol. 2018;52(4):1071-1080.
4. Marsden JR, Newton-Bishop JA, Burrows L et al. BAD Revised U.K. guidelines for the management of cutaneous melanoma 2010. BrJ British Journal of Dermatology. 2010; 238–56.
5. www.dermnetnz.org (Accessed on 10th February 2019 and 19th February 2019).
6. Brown ESR, Fraser SJ, Quaba O, Simms A, Stein A. Clinical Cutaneous melanoma: an updated SIGN guideline. Journal of the Royal College of Physicians of Edinburgh. 2017;47(3); 214-217.
7. https://www.healthline.com/health/melanomaalternative-treatments#alternative-treatments (Accessed 1st February 2019).
8. Hansen E. London Cancer North and East: Psychosocial support for adult skin cancer patients. 2013. www.londoncancer.org/media/76385/london- cancer-skin-psychosocial-support-guidelines-2013- v1.0.pdf