Background: Thymus and Activation Related Chemokine (TARC), also known as CCL17, is a chemokine that is highly secreted by tumor cells in classic Hodgkin lymphoma (HL). TARC levels are dramatically increased in serum samples of newly diagnosed HL patients (1).
Aim: To evaluate if and how long serum TARC levels are increased prior to a clinical diagnosis of HL.
Methods: We measured serum samples from the Department of Defense (DoD) Serum Repository that were collected over several years prior to the diagnosis of HL in the active-duty U.S. military population. Incident HL cases were diagnosed between 1990 and 1999 and included for analysis when a pre-diagnostic serum sample was available (n=101). The median age at diagnosis was 26 years and 10% were female. Pathology review revealed a normal distribution of subtypes and tumor cell EBV status was positive in 23% of cases. For each case, two matched controls were selected from the DoD Serum Repository based on age, sex, race and ethnicity, number of serum samples and sample collection date. The serum samples of these cases and controls were previously analyzed for IL-6, IL-10, soluble CD30 and total IgE (2). TARC levels were measured by a Luminex assay. Differences in log-transformed TARC levels between cases and matched controls were evaluated using mixed model analyses.
Results: TARC levels were measured in 211 samples from 101 patients, collected up to 9.8 years before diagnosis, and in 422 samples from matched controls. TARC levels were significantly higher in patients compared to controls (median 921 pg/ml (max. 1.6x105) vs. median 422 pg/ml (max. 3.5x102)), respectively (p=1.2x10-47 in the mixed model analysis). This effect was strongest in nodular sclerosis (NS) and EBV-negative cases, but also present in non-NS and EBV-positive cases. The longest time interval between an increased TARC level and diagnosis was 6.2 years for an individual who developed NS HL, with a logarithmic increase of TARC over time.
Conclusions: Increased serum TARC levels often precede diagnosis of classic HL by several years. This implies a long pre-diagnostic phase in which secretion of TARC and the resulting attraction of CD4+ T cells is an important mechanism in pathogenesis. In the clinical setting, serum TARC is being used as a therapy response marker(3) and its indication may be extended to diagnostic and even pre-diagnostic screening.
Arjan Diepstra, Ilja M. Nolte, Anke van den Berg, Lynn I. Levin, Otoniel Martínez-Maza