Circulating tumor cells (CTCs) have long been recognised as potentially important aids to clinical decision-making, and as important targets for anticancer treatment. However, recent work has revealed the limitation of relying of currently accepted CTC markers for non-epithelial cancers. This has confounded attempts to expand the clinical utility of CTCs assays. MicroRNAs (miRNAs) have emerged as potentially important diagnostic markers, as they are key regulators of disease progression. Here, we describe a robust in situ hybridization (ISH) protocol, incorporating the ScreenCell® CTC filtration system. This enables the investigation of potentially important malignancy linked miRNAs such as miR-10b on a cell-by-cell basis without relying on current CTC cell surface markers. We have applied this method to the liquid biopsy from patients with aggressive nonmelanoma skin cancer, including those with the rare genetic disease, Epidermolysis Bullosa (EB), where CTC detection using established markers is confounded by disease specific conditions, such as the differential expression of cytokeratin.