Neuroblastoma

Classification according to ICCC : IV.a (Neuroblastoma and ganglioneuroblastoma)

Definition

Neuroblastoma is a typical embryonic tumour, which arises most frequently from adrenal glands or from paravertebral ganglia along the length of the sympathetic trunk (most commonly in the abdominal region, less frequently in the thoracic, pelvic and cervical regions). It metastasises into lymph nodes, bone marrow, bones, liver and skin, rarely into lungs and CNS. Apart from metastasing, neuroblastoma can grow through intervertebral canals into the spinal canal and press on the spinal cord. Neuroblastoma is one of the few tumours which can regress spontaneously. Localised forms have a very good prognosis and require only a minimal treatment. On the other hand, there are very aggressive forms of neuroblastoma, the treatment of which is very difficult, and the chance of cure is significantly lower. Due to its large biological variability, neuroblastoma is sometimes referred to as a mysterious tumour. Apart from the clinical stage, the progosis is influenced by the patient’s age, location of metastases, histopathological type of tumour, and presence of the n-myc oncogene in tumour cells.

Occurrence

Neuroblastoma accounts for about 8% of all childhood cancers; it is the most common extracranial tumour, and the most common tumour in infants and toddlers. The median age at the time of diagnosis is 18 months. The prevalence rate is 1 case per 7,000 live births; this means that about 15 new cases can be expected to be diagnosed in the Czech Republic each year.

Symptoms

Symptoms of neuroblastoma depend on the location of primary tumour or metastases. It can be palpated during an abdominal examination, or even visible as an enlargement of the abdomen, which can be caused either by the tumour itself, or by the liver infiltrated by metastases. Cervical neuroblastomas are visible as an asymmetrical mass, rigid on palpation. Skin metastases in newborn and infants are often visible as dark-blue nodules (similar to blueberries), or palpable as rigid subcutaneous nodules. Bone metastases occur more frequently in toddlers, are rather rare in infants (predilection sites: long bones, flat bones of the skull, bones of the orbit), and often manifest themselves as the so-called post-infectious coxarthroses – patients refuse to walk or to sit up. Rigid structures are visible or palpable on the head and on the long bones. Orbital metastases manifest themselves by the protrusion or deviation of eye bulbs, marked swelling and haematomas of the eyelids (“raccoon eyes”). The first symptoms of a tumour growing into the vertebral canal are neurological: limited mobility of lower limbs, paresis or plegia, urinary retention, or defaecation disorders. Asymptomatic neuroblastoma might be found accidentally at an abdominal ultrasound (newborns, infants) or in the mediastinum during an examination of the lungs.

Diagnosis

It is important to determine the location of the primary tumour (and possible metastases), and to decide whether the tumour is suitable for an initial surgical treatment or chemotherapy – magnetic resonance imaging, possibly CT scan, bone marrow aspiration, neurological examination when intraspinal spreading is suspected. MIBG scan (scintigraphy based on iodine-131-meta-iodobenzylguanidine, MIBG) is usually used to detect dissemination: MIBG is a noradrenaline analogue, and is taken up in all foci of neuroblastoma. Changes in the blood count (mostly anaemia) are only detectable at advanced stages of the disease. Tumour markers are not present in the peripheral blood, not even when the bone marrow is infiltrated. Biochemical parameters might involve higher levels of LDH and ferritin; up to 90% of neuroblastomas produce an excessive amount of catecholamines, and its derivatives (vanillylmandelic acid, homovanillylmandelic acid) are  excreted into the urine. The tumour tissue is examined in order to determine the histopathological type (favourable or unfavourable), presence of the n-myc oncogene, ploidia, and the proof of potential structural or numerical changes in the chromosomes. Paraneoplastic neurological syndrome (opsoclonus myoclonus syndrome / dancing eye syndrome, OMS/DES) is present in about 1 to 2 percent of patients with neuroblastoma. This syndrome often presents the initial manifestation of the disease, and neuroblastoma is diagnosed afterwards. In most cases, OMS/DES develops in patients with localised and biologically favourable neuroblastomas. Unusually, neurological symptoms do not necessarily disappear after neuroblastoma surgery or treatment, and require further treatment; and vice versa, OMS/DES sometimes develops later, after the removal of neuroblastoma.

Classification

Apart from the clinical stage, one must take into consideration the patient’s age, histological type, presence of amplification of the n-myc oncogene, as well as potential structural or numerical changes in the chromosomes of neuroblastoma cells.

Therapy

Neuroblastoma treatment is stratified according to the degree of risk, and is carried out in two specialised centres in the Czech Republic (Department of Paediatric Haematology and Oncology in Prague, Department of Paediatric Oncology in Brno), which are equipped with necessary diagnostic and therapeutic methods. Both facilities cooperate with multinational working groups (SIOPEN in Europe, COG in North America). An active participation in international trials enables both facilities to apply the most recent knowledge in diagnostic and therapeutic procedures.

  • Observation relies on the natural ability of neuroblastoma to regress, and is employed in infants with a localised disease in the adrenal gland, or in patients with prognostically favourable metastases (skin, liver).
     
  • Surgery without subsequent chemotherapy is employed in patients with localised neuroblastomas which do not grow into the surrounding tissues.
     
  • Chemotherapy followed by surgery: primarily inoperable neuroblastomas become smaller after chemotherapy, thus enabling the subsequent surgical procedure.
     
  • Treatment of neuroblastomas propagating to the vertebral canal: urgent chemotherapy might be indicated for patients who show a rapid deterioration of neurological symptoms: this treatment aims to stop neuroblastoma from growing, and to decrease the pressure on neural structures. In well-responding patients, it is possible to avoid the spinal decompression surgery (laminectomy or laminotomy), which immediately improves the neurological impairment, but negatively affects the further development of vertebral column, and stabilisation surgeries are subsequently necessary in most patients.
     
  • Treatment of high-risk neuroblastoma patients usually starts with an intensive induction chemotherapy, followed by surgery of the primary neuroblastoma focus, high-dose chemotherapy with an autologous reinfusion of haematopoietic cells, radiotherapy focused on the area of primary tumour, and biological therapy inducing the differentiation of residual cancer cells. Administration of specific antibodies against GD2, which also support the destruction of residual cancer cells, has been introduced recently.

Treatment outcomes

Localised neuroblastomas can be cured in more than 90% of patients. However, treatment of children with disseminated neuroblastomas still remains a challenge. Despite an intensive chemotherapy and the application of all available and effective treatment modalities, only about 40% of patients can be cured. On top of that, treatment of these neuroblastomas is linked to a 40% risk of developing late effects of this intensive cancer treatment, including the development of secondary cancers.

Role of general paediatrician

The general paediatrician plays a key role in the evaluation of a wide range of neuroblastoma symptoms. If neuroblastoma is suspected, the general paediatrician refers the patient to a specialised centre as early as possible. Warning signs involve a palpable or even visible mass in the abdominal area, skin problems, periorbital haematomas, palpable structures on flat bones of the skull or on long bones, painful or limited movement of limbs, neurological symptoms resulting from a possible pressure on spinal structures – disorders of limb movement, urination and/or defaecation disorders.

In the course of treatment, the general paediatrician follows up the patient, and deals with the social issues of the patient and his/her family. Vaccination of paediatric patients with ALL is performed in vaccination clinics.