Melanoma is a common cancer in Australia and is potentially life threatening. Despite the heightened awareness of sun protective measures in recent decades, the incidence of melanoma has increased steadily. With these increases in incidence, a need for a better understanding of melanoma pathogenesis is warranted. Recent studies have proposed that melanomas of different histological subtypes are distinct entities, and that melanomas from different anatomical sites arise through different pathogenic pathways. Exploring the aetiological differences between the various histological subtypes of melanoma and melanomas arising from different anatomical sites is one strategy toward increasing overall understanding of the pathogenesis of melanoma.
The primary aim of this thesis was to explore the issues of histological differences and causal heterogeneity in melanoma. Firstly, histological, epidemiological and immunohistochemical comparisons of melanomas of differing histological subtype arising on the same anatomical site were made. These were followed by histological, epidemiological and immunohistochemical comparisons of melanomas of a single histological subtype from two different anatomical sites.
A population-based case-case comparison study was conducted of 1 4 1 cases of lentigo maligna or lentigo maligna melanoma (LM/ LMM) and superficial spreading melanoma (SSM) diagnosed between January 1 998 and December 1 999 in Queensland, Australia. The epidemiological data were extracted from a dataset collected as part of a previous study in which participants completed a structured questionnaire and underwent a physical examination by a trained research nurse. Paraffin sections of tumour tissue from these patients were obtained and stained with haematoxylin and eosin for assessment of histological features. Expression of tumour suppressor genes p53 and p 16 was assessed by immunohistochemical techniques using DO-7 and G175-405 monoclonal antibodies respectively.
For head and neck melanomas, different associations with various histological features were found for SSMs and LM/ LMMs. For example, SSMs were more likely than LM/ LMMs to have no epidermal atrophy (OR= 1.8, 95% CI= 0.7-4.6) and to have less effacement of epidermal rete ridges (OR= 7.5, 95% CI= 2. 1 -27.0) and atypical melanocytes in the upper half of the epidermis (OR= 1 8.9, 95% CI= 5.4-66.5). SSMs were more likely than LMILMMs to be associated with a contiguous naevus (OR= 4.1, 95% CI= 1.2- 14.3) but were less likely to be associated with moderate or marked solar elastosis (OR= 0.1, 95% CI= 0.0-1.0).
For the subtype-specific site comparison, SSMs of the head and neck were less likely than SSMs of the back to arise in conjunction with a pre-existing naevus (OR= 0.5, 95% CI= 0.2- 1.2), but were more likely to be associated with moderate-marked solar elastosis (OR= 11.2, 95% CI= 3.3-38.0). Clinically, patients with head and neck SSMs were also less likely to have more than 60 naevi but were more likely to have a large number of SKs than patients with back SSMs.
Abnormal p53 expression was found in 13.5% of melanomas in our series. Although non-significant, it appeared that head and neck SSMs were more likely than head and neck LMILMMs to be p53-positive (OR= 2.5, 95% CI= 0.7-9.2), and SSMs on the head and neck were more likely than SSMs on the back to be p53-positive (OR=2.1, 95 % CI= 0.6- 6.8).
Expression of p 16 was lost in 64% of melanomas. Head and neck SSMs were more likely than back SSMs to have lost p16 expression (OR= 2.5, 95% CI= 1.0-6.4). Patients with complete loss of p 1 6 expression were less likely to have solar keratoses on clinical examination (OR= 0.5, 95% CI= 0.1 -1.8) but were more likely to report having some or many facial freckles as a teenager (OR= 2.5, 95% CI= 0.8-7.8).
This study has provided further histological, epidemiological and immunohistochemical evidence to support the notion that melanomas are not all the same. Differences in histological characteristics and p53 immunohistochemical expression exist for LM/ LMMs and SSMs arising from the head and neck. SSMs from the back and head/ neck differ in their histological, phenotypic and sun-exposure characteristics and their p53 and p16 immunoexpression, suggesting that these melanomas arise from different pathogenic pathways. Cumulative sun-exposure seems to play an important role in the pathogenesis of SSMs arising from the head and neck while increased naevogenesis is more important for SSMs arising from the back.