Pathology - Theses
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ItemClinical implications of melanin expression in melanoma and molecular drivers of cutaneous squamous cell tumours( 2013)Melanomas are derived from melanocytes – highly specialized pigment-producing cells residing in the basal layers of the skin. The majority of melanomas continue to produce melanin, presenting a potential disease specific biomarker, so far largely unexplored. This thesis begins by examining how melanin might be exploited as a melanoma specific target for molecular based imaging. The novel fluorinated, melanin-binding radiopharmaceutical, MEL050, is tested as a PET-tracer in ten patients with advanced melanoma. We establish MEL050 safety, and detail metabolism, radiopharmacokinetics and normal biodistribution. Diagnostic parameters are compared with a gold-standard of FDG PET/CT. Excellent specificity of 100% but more variable sensitivity is demonstrated. Overall sensitivity was 47%. In a subset of five patients who underwent resection of all known disease sites, histological assessment of tumour melanin correlated with MEL050 PET signal: 100% for melanotic tumours but 0% for amelanotic tumours. These findings suggested a high frequency of amelanotic metastases – an aspect of melanoma not well detailed in the literature. In order to validate melanin as a suitable target for melanoma imaging, but also to determine if changes in its expression may reflect clinically meaningful differences in underlying biology, we next examined melanoma melanin in two distinct clinical cohorts. In the first, amelanosis was evaluated in tumours from 253 patients with primary melanoma. 20% were macroscopically amelanotic. These tumours had a higher Breslow thickness (p < 0.001), were more likely to be ulcerated (p = 0.002), have increased mitoses (p < 0.001) and be BRAF wild-type (p < 0.001). In a multivariate survival analysis, amelanosis was associated with worse disease free survival (HR 2.3, p = 0.031) and disease specific survival (HR 2.5, p = 0.033). The second cohort examined patients with more advanced melanoma. 142 patients with stage IIIa melanoma had sentinel node tumours examined for novel markers of melanin and Ki-67. 45% of tumours were amelanotic by H&E and mean Ki-67 score was 29%. Sentinel node tumour melanin outperformed existing prognostic factors, however, contrary to in primary tumours, persistent melanin was associated with worse disease free (HR 2.1, p = 0.002) and disease specific survival (HR 3.6, p = 0.009). Furthermore, in matched biopsies from primary, regional and distant metastatic sites, the frequency of amelanosis was shown to increase with disease progression – although bidirectional phenotype switching was also observed. Finally, an interaction between molecular targeted therapies and cutaneous squamous cells in a subset of melanoma patients was explored. Using mass-spectrometric genotyping, mutations in cutaneous squamous cell tumours developing in RAF-inhibitor treated patients were compared with similar tumours developing spontaneously or in patients requiring immunosuppression. Treatment related tumours were enriched for RAS mutations (OR 8.0, p = 0.007) supporting a hypothesized proliferative interaction between RAF-inhibitors and RAS primed cells. Amalgamated findings suggest dynamic changes in melanogenesis make melanin an unsuitable target for diagnostic imaging. Clinicopathological and prognostic associations of amelanosis in the context of known regulatory pathways support a distinct phenotype worthy of further clinical exploration and biological characterization. Confirmation of a clinical interaction between RAF inhibitors and RAS activated cells provides strategies for anticipating and managing treatment related toxicities.