Childhood cancers: neuroblastoma

Characteristics and diagnosis of neuroblastoma

In most cases, the cause of neuroblastoma is not known. Predisposition syndromes have, however, been described: neurofibromatosis type 1, Hirschsprung’s disease, and congenital central hypoventilation syndrome. Very occasionally, neuroblastoma has been observed in association with Beckwith-Wiedemann syndrome or DiGeorge syndrome.

Neuroblastoma develops from the sympathetic nervous system, mainly in the abdomen and sometimes along the spine or in the adrenal glands. Other locations, although more rare, can be the thorax, the neck or the pelvis.

Treatment depends on four main criteria:

• the age of the child at diagnosis, the degree of extension,
• the possibility of surgery on the primitive tumor,
• the amplification of the N-myc gene. 

Indeed, among the genetic alterations described in neuroblastoma, a major prognosis factor was identified in the 1980s: the presence of multiple copies of the N-myc oncogene in a tumor cell. These are associated with a high risk of developing metastases. The analysis of this gene is not part of the diagnostic arsenal. This analysis allows neuroblastoma to be classified into various stages from 1 to 4 and 4s. Stages 1, 2 and 3 correspond to the localized forms, while stage 4 corresponds to the metastatic forms. Stage 4s is characterized by the presence of liver and skin metastases, which are generally significant, sometimes in the bone marrow, but never in the bone. This rather specific form of tumor regresses in a large majority of cases, either spontaneously or following non-aggressive chemotherapy.

Choosing the right treatment for a given tumor

For tumors that are operable at the outset, surgery alone can often be sufficient; for tumors that are not operable at the outset, pre-surgical chemotherapy is needed. In metastatic forms and/or if there is amplification of the N-Myc oncogene, consolidation via intensive chemotherapy with stem cell transplant is most frequently the treatment of choice. Local radiotherapy is reserved for forms with a poor prognosis.

In 2005, the analysis of 905 children suffering from localized neuroblastoma, treated surgically in 10 European countries between January 1995 and October 1999, gave rise to recommendations. This analysis, the first on such a scale, is now used as a basis for the emergence of a more homogeneous surgery to treat children suffering from localized neuroblastoma, and to thus reduce the after-effects of surgical treatments carried out too early on the young patients concerned.

Heading toward personalized treatments

At the same time, developments in genetic techniques offer the option of better deciphering anomalies in development of the neuroblastoma. Thus, the alteration of the Alk gene is a determining event in the development of some neuroblastomas. Given these characteristics, it is the perfect candidate for developing a targeted therapy. Moreover, clinical studies are currently underway to assess the effectiveness of a targeted therapy on this alteration in children suffering from neuroblastoma.

Furthermore, a European protocol currently in progress, known as LINES, aims to adapt the intensity of chemotherapy treatments according to the genome profile. 

At the same time, research is being conducted to better understand relapses among young children and to find leads on how to treat them. One of the other areas studied by the pediatric oncology team, led by pediatrician Gudrun Schleiermacher, is the establishment of a precise diagnosis based on a simple blood test. Analysis of the circulating tumor DNA seems to be a substitute for establishing the neuroblastoma’s genomic profile in cases where access to the tumor itself is impossible or to monitor the tumor’s development.