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Prevalence and heterogeneity of circulating tumour cells in metastatic cutaneous melanoma

Khoja, Leilaa,b,c; Shenjere, Patrickb; Hodgson, Clarea; Hodgetts, Jackieb; Clack, Glend; Hughes, Andrewd; Lorigan, Paulc; Dive, Carolinea,c

doi: 10.1097/CMR.0000000000000025
ORIGINAL ARTICLES: Translational research

We previously demonstrated that circulating tumour cells (CTCs) are detectable by the MelCAM and high molecular weight melanoma-associated antigen (HMW-MAA)-dependent CellSearch platform. However, CTCs which do not express these capture and detection markers are not detectable by CellSearch. Consequently, we explored the use of isolation by size of epithelial tumour cells (ISET), a marker independent, filtration-based device to determine the prevalence and heterogeneity of CTCs in metastatic cutaneous melanoma patients. Ninety patients were prospectively recruited and blood samples taken before treatment. Patients’ blood was filtered using the ISET platform. CTCs were enumerated using dual immunohistochemistry with positive selection by S100 expression and exclusion of leucocytes and endothelial cells expressing CD45 or CD144, respectively. A panel of markers (Melan-A, MITF, MelCAM, high molecular melanoma-associated antigen, CD271 and MAGEC) was also examined. Fifty-one patients (57%) had CTCs (range 1–44 CTCs/4 ml blood) and 12 patients also had circulating tumour microemboli. Seven patients had S100− CTCs, 11 patients’ CTCs were S100+ and 33 patients had S100+ and S100− CTCs. Substantial intrapatient and interpatient heterogeneity was observed for all other melanoma-associated markers. CTCs in metastatic cutaneous melanoma are detectable using the flexible marker-independent ISET platform. CTCs display significant marker expression heterogeneity implying that marker-dependent platforms would not detect all CTCs and multimarker assays are now required to reveal the biological significance of this CTC heterogeneity.

aClinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research

bThe Christie NHS Foundation Trust

cSchool of Cancer and Enabling Sciences, Manchester Cancer Research Centre and Manchester Academic Health Sciences Centre, University of Manchester, Manchester

dAstraZeneca Pharmaceuticals, Alderley Park, UK

All supplementary digital content is available directly from the corresponding authors.

Correspondence to Caroline Dive, PhD, Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 4BX, UK Tel:+44 161 446 3036; fax:+44 161 446 3019; e-mail: or Correspondence to Paul Lorigan, MD, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK Tel: +44 161 446 3000; fax: +44 161 446 3299; e-mail:

Received June 10, 2013

Accepted September 2, 2013

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins