A Report On Melanoma: Aetiology, Pathogenesis, Diagnosis And Current Treatment

Melanoma is a malignant neoplasm of melanocytes that has seen a steady rise in incidence globally over the past 50 years. Malignant melanoma accounts for only 1% of skin cancers diagnosed but causes 60% of mortality due to skin cancers. Australia has the world’s highest incidence of skin cancer globally, including melanoma, causing more than 1000 Australian deaths every year. This is due to a variety of factors including, a climate conducive to outdoor work and leisure activities, genetic susceptibility due to large migration of European, fair-skinned individuals, and national attitudes towards sun tanning being held in such high esteem, especially amongst teenage and adolescents. With its rising incidence and mortality, melanoma bears a heavy health and economic burden on Australia; it is considered a major public health concern. Nationally, the annual estimated cost for treatment of all new cases of in situ and invasive melanomas was AU$201 million. Melanoma can be considered a disease of great significance due to the social and economic burden placed on Australia, and individual lives each year.

In recent years, medical research in the field of melanoma diagnosis and treatment has significantly improved our understanding of the disease, in particular, the improvement of diagnostic techniques and surgical treatment of primary melanoma lesions. However, further research is still needed in order to improve clinical patient outcomes. One key area of interest for future research is determination of the metastatic behaviour of melanoma in order to help develop effective treatments.

This report serves to explore the aetiology, pathogenesis, diagnosis and current treatment of malignant melanoma. Additionally, this report details the way in which current research is progressing, the study of metastatic patterns in melanoma as well as current therapies in development. This report also identifies challenges stalling this progress and preventing the achievement of improved patient outcomes.

What is Melanoma?

Melanoma is a malignant neoplasm, usually of cutaneous origin, that originates from melanocytes. Melanocytes are cells that play the role of producing the skin's natural pigment, melanin, which also protects the body from damage caused by ultraviolet radiation produced by the sun. (Pluta, Burke, & Golub, 2011). When melanocytes transform into cancerous cells, and begin proliferating in an uncontrollable fashion, malignant melanoma tumours arise.

Aetiology

The aetiology of melanoma is, at present, incompletely understood, however it appears to be a result of damage to DNA caused by a complex interplay between environmental and genetic factors. Ultraviolet (UV) radiation from sunlight, is the most predominant environmental factor that contributes to the development of malignant melanoma skin cancer. Ultraviolet light is absorbed by skin cell DNA, resulting in direct DNA damage termed cyclobutane pyrimidine dimers. Dimers form between thymine and cystine residues by the joining of adjacent bases. If this damaged is induced to the point where DNA repair mechanisms cannot effectively repair the damage, mutations are induced, and melanoma may develop. Several genes have also been identified that greatly increase an individual's susceptibility to developing melanoma. Notably, variants of the melanocortin 1 receptor gene (MC1R) can prevent dark pigmentation from being produced. This association makes phenotypes of pale white, red, or blonde hair as well as freckled skin and a fair complexion, established risk factors for developing cutaneous melanoma.

Pathogenesis

On a molecular level, ultraviolet radiation from the sun, combined with genetic susceptibility, can cause malignant change in the skin by causing an accumulation of genetic mutations in cutaneous melanocytes, leading to the development of melanoma. The amassing of these mutations results in the activation of oncogenes such as BRAF and NRAS that cause deregulation of melanocyte growth by encouraging rapid cell proliferation. Mutations also cause the deactivation of tumour suppressor genes such as CDKN2A, which prevent the normal process of apoptosis, programmed cell death, from occurring in response to DNA damage. The altered melanocytes are then able to develop traits of malignancy such as increased blood vessel growth, resistance to the natural immune response, tumour invasion into neighbouring tissues, and metastasis (Thompson et al., 2005). Macroscopically, once melanocyte proliferation becomes uncontrolled, melanomas undergo two different growth phases. Radial growth, where melanocytes proliferate horizontally throughout the epidermal layer, followed by vertical growth in which malignant cells penetrate the basement membrane and grow vertically throughout the dermis, forming a true tumour (Urso, 2004). Melanomas then gain the potential to disseminate to other areas of the body such as lymph nodes, lungs and brain.

Diagnosis

Routine self-examination of the skin plays a critical in early detection and diagnosis of malignant melanom. The most common way that melanoma is currently detected remains through ‘naked eyes’ of the patient or physician, with approximately 53% of lesions being self-discovered. The 'ABCDE' criteria provides both patients and physicians with a memorable paradigm for early melanoma detection based on clinical features that are readily observable such as asymmetry, borders that are irregular, variegation in colour, a diameter larger than 6mm or evolution of a lesion over time. Recently, focus has shifted to computer-assisted diagnosis with systems being developed based on dermoscopic image recognition algorithms (Elbaum et al., 2001). Despite recent technological development, histopathological analysis remains the gold standard for definitive melanoma diagnosis. Following visual or dermoscopic examination, a biopsy may be taken, before undergoing histological analysis by viewing using haematoxylin and eosin stain. Upon confirmed diagnosis of melanoma, the lesion is subtyped and classified according to the American Joint Committee on Cancer (AJCC) TNM system for classification of malignant tumours.

Treatment

Early diagnosis of melanoma significantly increases the likelihood of effective surgical removal, preventing the potential for metastases to other organs. Melanoma that has metastasised to other areas of the body presents a significant clinical challenge that cannot be managed through surgery alone. Advanced malignant melanoma has a poor prognosis and chemotherapy is most of the times not effective because of the resistance of melanoma cells Thus, more effective strategies are continuously being sought. Currently, combinational therapy is the most common approach to treatment due to the high aggressivity of metastasised melanoma. Chemotherapeutic agents are used such as dacarbazine or temozolomide which can penetrate the central nervous system to treat brain metastases. Chemotherapy often shows a low response rate due to a natural resistance possessed by melanomas so other treatments such as immunotherapy that works to alter the patient's immune system, allowing them to better remover tumour cells are used. Targeted therapies such as BRAF inhibitors are currently, that act on specific molecular mechanisms of melanoma progression in order to halt or regress tumour development (Mishra et al., 2018).  To improve outcomes for patients with melanoma, there must be a continued focus on preventative awareness, early diagnosis, and enhanced treatment strategies.