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Circulating Neuroblastoma Cells Detected by Reverse Transcriptase Polymerase Chain Reaction for Tyrosine Hydroxylase mRNA Are an Independent Poor Prognostic Indicator in Stage 4 Neuroblastoma in Children Over 1 Year

From the Candlelighter’s Children’s Cancer Research Laboratory, Imperial Cancer Research Fund Cancer Medicine Research Unit and Department of Paediatric Oncology, St James’s University Hospital, Leeds; Department of Epidemiology and Public Health, University of Leicester, Leicester; Department of Child Health, Royal Victoria Infirmary, Newcastle Upon Tyne; and Department of Paediatric Oncology, The Royal Marsden NHS Trust, Sutton, United Kingdom.

Address reprint requests to SA Burchill, Imperial Cancer Research Fund Cancer Medicine Research Unit, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, United Kingdom; email: s.a.burchill@ leeds.ac.uk.

PURPOSE: In this prospective, multicenter study, the independent prognostic power of neuroblastoma cells detected by reverse transcriptase polymerase chain reaction (RT-PCR) for tyrosine hydroxylase (TH) mRNA was evaluated.

PATIENTS AND METHODS: The clinical significance of disease detected by RT-PCR in peripheral blood from children at diagnosis was compared with established prognostic markers [ie, age, lactate dehydrogenase (LDH), neuron-specific enolase, ferritin, and MYCN gene amplification] by multivariate analysis. The value of disease detection by RT-PCR during treatment and follow-up was also examined.

RESULTS: TH mRNA was detected in peripheral blood from 33 of 49 (67%) children with stage 4 neuroblastoma > 1 year old at diagnosis and was a significant predictive factor for overall survival [hazard ratio (HR) = 2.40, 95% confidence interval (CI) 1.19 to 4.84, P = .014) and event-free survival (HR = 2.09, 95% CI 1.06 to 4.17, P = .034) in a multivariate analysis. Detection of disease in blood from clinically disease-free children was related to increased risk of death (HR 2.54, 95% CI 1.42 to 4.55, P = .0014).

CONCLUSION: TH mRNA in peripheral blood of children with neuroblastoma is a poor prognostic indictor, reflecting the propensity for dissemination via the bloodstream. When combined with a serum LDH > 1500 IU/L, this is the most powerful poor prognostic model at diagnosis for children > 1 year old with stage 4 disease. The detection of TH mRNA in peripheral blood from clinically disease-free children is related to increased risk of relapse and death.

Presented on behalf of the United Kingdom Children’s Cancer Study Group.

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