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Hyaluronan (HA) and its major cell surface receptor, CD44, play an important role in tumor growth, proliferation, neovascularization, and invasion. CD44 is an integral transmembrane protein and exists in standard form (CD44s), as well as a myriad of CD44 variants isoforms (CD44v1-v10). Functional fragments of the CD44 can be released from the cell membrane by proteolytic cleavage of extracellular domain producing soluble CD44. Although studies have proposed the use of serum HA and soluble CD44, specifically soluble CD44v6 (sCD44v6) levels, as a tumor markers, its diagnostic utility in body fluid samples has not been clearly established. The purpose of this study was to correlate HA and sCD44v6 levels in effusions with the cytology diagnosis and to assess their usefulness in differentiating between malignant and nonmalignant effusions. In this retrospective study we evaluated HA and sCD44v6 contents in 20 effusions from cytologically positive samples and 10 effusions from cytologically negative samples. Corresponding cytopathology slides were reviewed to confirm the diagnoses. Malignant effusions included 18 cases of metastatic adenocarcinomas (9 ovarian, 3 breast, 3 pulmonary, 3 adenocarcinoma of unknown primary) and 2 cases of lymphomas. The level of HA and sCD44v6 were measured using a sandwich enzyme-linked immunoadsorbent assay. For HA, we used hyaluronic acid quantitative test kit (Corgenix, Denver, CO) and for sCD44v6 we used Human sCD44v6 Instant ELISA (Bender MedSystems, Vienna, Austria). HA concentrations (μg/mL) and sCD44v6 concentrations (ng/mL) were calculated and correlated with clinical data as well as cytodiagnosis. The mean concentration of HA (22.42 ± 5 μg/mL) and sCD44v6 (70 ± 42 ng/mL) in the cytologically positive samples was significantly higher than those in the cytologically negative samples for HA (5.5 ± 5 μg/mL, P < 0.01) and sCD44V6 (17 ± 10 ng/mL, P < 0.01). Using benign effusions as control and the upper limits of its mean levels for HA (10.5 μg/mL) as the positive boundary value, HA levels exceeded the boundary line in 17 out of 20 malignant effusions and 2 out of 10 benign effusions. Meanwhile, sCD44v6 exceeded the boundary line (27 ng/mL) in 18 out of 20 malignant effusions and 3 out of 10 benign effusions. The calculated sensitivity and specificity of this assay to the diagnosis of malignant effusions were 85 and 80% for HA and 90 and 70% for CD44v6, respectively. We conclude that the HA and sCD44v6 levels in body fluids correlate with the cytology diagnosis and could be used as an ancillary study in cytology to differentiate nonmalignant from malignant effusions. Diagn. Cytopathol. 2007;35:105-110.