Neuroblastoma: SAQ

This child has the classic presentation of a metastatic neuroblastoma with the MYCN amplification, and the task is to outline the diagnostic pathway, the risk stratification and the risk-adapted management, contrasting the high-risk disease with the opsoclonus-myoclonus-ataxia syndrome and the spontaneous regression of stage MS. [1][2]

Question 1 (10 marks)

Outline the diagnostic pathway and the risk stratification for this two-year-old girl with the abdominal mass, the periorbital ecchymosis and the elevated urinary catecholamines. [1]

A full-mark answer covers the catecholamine confirmation, the imaging and the staging, the biopsy with the molecular analysis, and the risk group assignment. [2]

Catecholamine confirmation (2 marks). The measurement of the vanillylmandelic acid and the homovanillic acid in a random urine sample, corrected for the creatinine, confirms the diagnosis in over ninety percent of neuroblastomas. The catecholamine secretion reflects the sympathetic lineage of the tumour, which arises from the primordial neural crest cells that form the adrenal medulla and the sympathetic chain. The modern mass spectrometry methods measure the full panel of the catecholamine metabolites with the high sensitivity and the specificity. [1]

Imaging and staging (3 marks). The contrast-enhanced magnetic resonance imaging defines the primary tumour, its extension across the midline and the image-defined risk factors. The iodine-123 metaiodobenzylguanidine scan is the functional imaging that maps the disease extent, because the metaiodobenzylguanidine is taken up by the catecholamine-producing cells, and it is positive in over ninety percent of neuroblastomas. The bone marrow aspirate and trephine biopsy, performed bilaterally, confirm the marrow involvement. The International Neuroblastoma Risk Group staging assigns the L2 stage for the locoregional tumour with the image-defined risk factors, the M stage for the distant metastatic disease, and the MS stage for the metastatic disease confined to the skin, liver and marrow in the infant under eighteen months. [2]

Biopsy and molecular analysis (3 marks). The percutaneous core biopsy or the surgical biopsy of the primary tumour is sent for the histology, the immunohistochemistry and the molecular analysis. The fluorescence in situ hybridisation shows the MYCN amplification with more than ten copies of the gene per cell, which is the single most powerful adverse prognostic marker. The DNA ploidy by the flow cytometry, and the segmental chromosome abnormalities by the comparative genomic hybridisation, complete the molecular profile. [5][12]

Risk group assignment (2 marks). The International Neuroblastoma Risk Group classification integrates the stage, the age, the histology, the MYCN status, the ploidy and the segmental aberrations into the risk group. This child, over eighteen months with the metastatic disease and the MYCN amplification, is assigned to the high-risk group, which carries a five-year survival below fifty percent despite the most intensive treatment in the paediatric oncology. [12][1]

Question 2 (10 marks)

Discuss the risk-adapted definitive management of the high-risk neuroblastoma, and contrast it with the opsoclonus-myoclonus-ataxia syndrome and the spontaneous regression of stage MS. [1]

A full-mark answer reproduces the five phases of the high-risk treatment, the management of the paraneoplastic syndrome, and the observation of stage MS. [12]

High-risk treatment (4 marks). The treatment runs through the five phases. The induction chemotherapy uses the combination of the cisplatin, the etoposide, the cyclophosphamide, the vincristine and the doxorubicin over approximately four months. The surgical resection of the primary tumour is performed after the induction, aiming for the gross total resection. The myeloablative consolidation with the autologous stem cell rescue, followed by the external beam radiotherapy to the primary site, delivers the tumoricidal dose. The anti-GD2 immunotherapy with the dinutuximab beta, in combination with the interleukin-2 and the isotretinoin, targets the minimal residual disease, and the SIOPEN trial of Ladenstein demonstrated the event-free survival benefit. The five-year survival remains below fifty percent, and the treatment carries the significant toxicity of the hearing loss, the cardiotoxicity and the second malignancy. [1]

Opsoclonus-myoclonus-ataxia syndrome (3 marks). The child with the opsoclonus, the myoclonus and the ataxia has neuroblastoma until proven otherwise, because the syndrome is the paraneoplastic signature driven by the autoimmune response against the neural tissue. The opsoclonus is the chaotic multidirectional eye movement that is not the rhythmic nystagmus. The neuroblastoma associated with the syndrome is typically the low-stage, favourable-biology tumour, and the tumour itself carries an excellent prognosis. The devastating contrast with the high-risk disease is the neurological outcome, because the autoimmune injury persists and causes the cognitive, behavioural and motor sequelae despite the tumour cure. The management of the neurological syndrome uses the immunomodulation with the corticosteroids, the intravenous immunoglobulin and the rituximab. [6][9]

Stage MS and spontaneous regression (3 marks). The infant under eighteen months with the metastatic disease confined to the skin, the liver and the marrow carries the unique biology that may undergo the spontaneous maturation or the regression. The asymptomatic infant is managed with the observation and the supportive care, because the disease regresses without the treatment in the majority. The symptomatic infant with the respiratory compromise from the massive hepatomegaly receives the low-dose cyclophosphamide or the hepatic radiotherapy, and the five-year survival is above ninety percent. The contrast with the high-risk disease is stark, because the same disease, separated by the age and the biology, carries a survival above ninety percent versus below fifty percent. [11][1]