MelanA is a known melanocyte marker and is important in melanoma diagnostics. Some tumours, however, show loss of MelanA expression and may therefore be difficult to distinguish from tumours of mesenchymal origin. Pure spindle-cell melanoma is a rare event, and little is known about its biological background and prognosis. However, morphological changes towards a more mesenchymal shape and cellular dedifferentiation may correlate with reactivation of important developmental programmes (epithelial-to-mesenchymal transition) and disseminative tumour cell properties. Inflammation and CD163+ macrophages have been shown to be important inducers of E-cadherin and cell-to-cell adhesion loss, a pivotal and final event of epithelial-to-mesenchymal transition. In a cohort of 385 patients with melanoma, we located nine tumours with a clonal MelanA expression, defined as a tumour section with a distinct MelanA-negative clone next to a MelanA-positive clone. Interestingly, MelanA-negative clones correlated significantly with an augmented inflammatory response of tumour-infiltrating macrophages (CD163+), complete loss of E-cadherin and a spindle-shaped morphology, irrespective of ulcerated status. These cases show the inflammatory heterogeneity of melanoma, which may have important diagnostic, prognostic and therapeutic implications for the patients. We show that melanomas harbour cell clones that bear strong resemblance to tumour-associated macrophages, a pivotal player in a tumour-supporting microenvironment. Interestingly, this distinct inflammatory phenotype is associated with loss of MelanA expression, the presence of spindle-shape morphology and complete loss of E-cadherin, considered as possible markers of poorly differentiated and more invasive tumour cells.