title: EpCAM-based flow cytometry in cerebrospinal fluid greatly improves diagnostic accuracy of leptomeningeal metastases from epithelial tumors.
abstract: Moderate diagnostic accuracy of MRI and initial cerebrospinal fluid (CSF) cytology analysis results in at least 10%-15% false negative diagnoses of leptomeningeal metastases (LM) of solid tumors, thus postponing start of therapy. The aim of this prospective clinical study was to determine the diagnostic value of epithelial cell adhesion molecule (EpCAM)-based flow cytometry versus cytology in CSF for the diagnosis of LM in patients with epithelial tumors.
  
  
  
  Patients with a clinical suspicion of LM but a negative or inconclusive MRI in whom a diagnostic lumbar puncture has to be performed were included. At least 5 mL of CSF for cytology, 5 mL for flow cytometry, 2 mL for cell count and biochemistry, and 8 mL whole blood samples for circulating tumor cells measurements and biochemistry were drawn. Tumor cells in CSF and whole blood were detected by multiparameter flow cytometry using EpCAM antibody.
  
  
  
  In total 29 eligible patients were enrolled in the study. Thirteen patients were ultimately diagnosed with LM. The flow cytometry assay showed 100% sensitivity and 100% specificity for diagnosing LM, while sensitivity of CSF cytology was only 61.5%. Cell count or biochemical parameters in CSF were abnormal in 100% of patients with LM.
  
  
  
  Our results suggest that the EpCAM-based flow cytometry assay is superior to CSF cytology for the diagnosis of LM in patients with an epithelial tumor, a clinical suspicion of LM, and a nonconclusive MRI. Confirmation of these data is needed in a larger dataset to recommend dual CSF diagnostics for LM.
  
  
  
  NCT01713699.
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Bojana
authors.initials: B
authors.lastname: Milojkovic Kerklaan
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Dick
authors.initials: D
authors.lastname: Pluim
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Mijke
authors.initials: M
authors.lastname: Bol
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hofland
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Johan
authors.initials: J
authors.lastname: Westerga
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Harm
authors.initials: H
authors.lastname: van Tinteren
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Willem
authors.initials: W
authors.lastname: Boogerd
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, the Netherlands (B.M.K., D.P., I.H., J.H.M.S.); Department of Clinical Pharmacology, NKI-AVL, Amsterdam, the Netherlands (B.M.K., J.H.M.S.); Department of Pathology, NKI-AVL, Amsterdam, the Netherlands (M.B.), Core Facility Molecular Pathology & Biobanking (CFMPB), Department of Molecular Pathology, NKI-AVL, Amsterdam, the Netherlands (I.H.); Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands (J.W.); Biometric Department, NKI-AVL, Amsterdam, the Netherlands (H.v.T.); Department of Pharmacy and Pharmacology, NKI-AVL, Amsterdam, the Netherlands (J.H.B.); Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands (J.H.B., J.H.M.S.); Department of Neuro-oncology, NKI-AVL, Amsterdam, the Netherlands (W.B., D.B.).
authors.forename: Dieta
authors.initials: D
authors.lastname: Brandsma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008577:Meningeal Neoplasms / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D008875:Middle Aged; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000071858:Epithelial Cell Adhesion Molecule
keywords: carcinomatous meningitis; cerebrospinal fluid (CSF); circulating tumor cells (CTC); epithelial cell adhesion molecule (EpCAM); leptomeningeal metastases (LM)