Are thoracic neuroblastomas really different?

N euroblastoma is the most frequent extra-cranial solid tumour of childhood, derived from neural crest stem cells and is characterised by a widely varying clinical behaviour. The clinical course of neuroblastoma ranges from spontaneous regression of localised and/or disseminated stage 4s tumours to therapy-resistant progressive/recurrent tumour growth in the majority of patients over the age of 1 year at diagnosis with disseminated stage 4 disease [1]. Various clinical factors influence the behaviour of neuroblastoma in patients, younger patients have a more favourable clinical outcome, dissemination to bone does predict more aggressive behaviour and the localisation of the primary tumour has been reported to be associated with clinical course. In this issue of Pediatric Blood & Cancer, Demir et al. report on their single centre experience of the Hacettepe University in Ankara, Turkey with thoracic neuroblastoma. They describe a series of 87 children with neuroblastoma with a thoracic primary diagnosed between 1973 and 2007. The average age at diagnosis was 2.1 years, 17% of tumours were ganglioneuroma, 23% of cases were diagnosed incidentally, 42% were localised tumours and prognosis was favourable with a 10-year survival rate of 71.2%. The current clinical consensus is that thoracic neuroblastoma are indeed a distinct subset of neuroblastoma presenting at earlier age and more localised stages with a more favourable prognosis, although the origin of the clinical differences is largely unknown. Some discussion on the real independent prognostic value of thoracic primary localisation remains, the large series of the Pediatric Oncology group published by Morris et al. [2] on 227 thoracic neuroblastoma cases reports a significantly better survival rate for patients with thoracic neuroblastoma independent of other clinical and biological variables, whereas in the GPOH series published by Haberle et al. [3] on 113 thoracic cases multivariate analysis showed that stage, MYCN-status and serum-LDH, but not thoracic location, are independent prognostic factors. The Demir et al. paper reports a favourable survival, but no multivariate analyses are reported. The biology of thoracic neuroblastoma seems to be somewhat different, although not totally distinct; NMYC amplification occurs significantly less frequent, the DNA-index is more often >1.0 and serum-LDH and ferritin are significantly less often elevated [2,3]. This biological favourable profile explains the better prognosis in part, although also MYCN-amplified tumours with a thoracic primary seems to have a better outcome compared to other primary sites [2]. There are no indications that molecular events involved in tumourigenesis are distinct in thoracic neuroblastoma, although no screen for DNA mutations comparing thoracic and other primary neuroblastoma has been performed. The Demir et al. series has some interesting differences compared to the POG and GPOH series; Turkish patients tend to be diagnosed at an older age, are more likely to have stage 3 disease and present more often with symptoms. These clinical differences could be compatible with the hypothesis that thoracic neuroblastoma have a higher tendency for spontaneous regression at younger age and that a relatively longer delay in diagnosis lead to overrepresentation of nonregressing cases in the Demir et al. series. In the large neuroblastoma screening series reported by Schilling et al. [4] no support for this hypothesis could be found, as the primary site was not presented. The finding that incompletely resected thoracic neuroblastoma only shows local recurrence in 1 out of 13 patients [5] support an important role for spontaneous regression in thoracic neuroblastoma. Finally, the question of treatment choice remains to be resolved. If there is a better overall prognosis explained by a higher tendency for spontaneous regression, then we should consider withholding treatment for thoracic neuroblastoma. At least for thoracic neuroblastoma without other clinical and/or biological unfavourable markers we should consider a wait-and-see policy with careful monitoring of the tumour course. The current NB2004 study of the GPOH neuroblastoma group is using a wait-and-see policy for patients with stage 1 and 4s of any age without MYCN amplification, for patients with stage 2 disease of any age without MYCN amplification and with normal chromosome 1p and for patients with stage 3 disease younger than 2 years of age without MYCN amplification and with normal chromosome 1p. The clinical series of Demir et al. shows us again the usefulness of careful analyses of our clinical series of neuroblastoma to detect subtle differences which might point to biological differences with clinical relevance.