NEUROBLASTOMA

Neuroblastoma is the commonest extracranial solid tumor in children, accounting for ~8-10% of all childhood cancers, it is also the commonest tumor in infancy.

Epidemiology: Neuroblastoma is predominantly a tumor of early childhood with peak incidence at 2 years and ~90% cases are diagnosed by 5 years.

Family history is present in 1-2% cases, linked to mutations PHOX2B and ALK genes. MYCN ampli­fication, which encodes N-myc proto-oncogene proteins, is present in ~15-20% cases, associated with more aggressive disease.

Important associated abnormalities include Neuro­fibromatosis, Hirschsprung's disease and Beckwith- Wiedemann syndrome. Some parents also have history of occupational chemical exposure.

Pathology: Neuroblastoma originates from primitive neural crest cells, which normally develop into sympa­thetic ganglia and adrenal medulla. Primary tumors usually develop in abdomen (65%) from adrenals or retroperitoneal ganglion, though ~30% arise from cervical, thoracic or pelvic ganglia.

Subsequent course of primary tumors is highly vari­able, including—(a) spontaneous regression, (b) differ­entiation into benign ganglioneuroma, or (c) aggressive disease with distant metastasis, more common in older cases.

Common sites of metastasis include bone marrow, lymph nodes, liver and skin. Lung and brain metastasis is rare.

Histologically, it is an encapsulated, small round-cell tumor with three distinct types of prognostic signifi­cance: well-differentiated ganglioneuroma, ganglio- neuroblastoma and undifferentiated neuroblastoma.

Clinical presentation depends on the site and extent of tumor and includes:

a. Asymptomatic local mass, accidentally palpable in abdomen or visible on chest X-rays.

b. Invasion or compression of surrounding structures with abdominal pain and ascites in abdominal tumors, difficulty in defecation/micturation in pelvic tumors; dyspnea, dysphagia or Horner syndrome in cervicothoracic tumors, and paraplegia or urinary retention in lower spinal tumors.

c. Secondary metastasis with bone pains, pancytopenia, lymphadenopathy, hepatomegaly and bluish skin nodules.

d. Signs of paraneoplastic syndromes due to secretion of various substances by tumor, e.g. hypertension (catecholamines), diarrhea (vasoactive intestinal peptides), etc.

Opsoclonus-myoclonus is a rare paraneoplastic syndrome in neuroblastoma due to auto-antibody production against neural tissue, which presents as ataxia, myoclonus and chaotic eye movements (Dancing eye-Dancing feet syndrome).

Diagnosis depends on—(a) tissue biopsy for histo­pathology, cytogenetic studies and molecular markers, along with, (b) imaging studies, e.g. CT/MRI to identify extent of primary tumor and metastasis. Urinary catecholamine excretion, e.g. vanillylmandelic acid (VMA) or homovanillic acid (HVA) may be elevated.

Further evaluation is necessary to detect metastasis with—(i) MIBG (meta-iodo-benzyl guanidine) scan to detect silent metastasis, (ii) bone marrow aspirate for neuroblasts, and (iii) PET scan, (iv) molecular studies for N-Myc amplification.

International neuroblastoma staging system (INSS) is commonly used to stage the disease for treatment purpose and asses the outcome (Table 20.11).

Management depends on site of tumor for operational feasibility and stage of disease (Table 20.11).

TABLE 20.11: INSS staging system of neuroblastoma with treatment and survival

Stage Extent of disease

Treatment survival 5-yr

*beyond 1 year age, better (75%) in infants

B/L: Bilateral; LN: Lymphnode

S: Surgery; CT: Chemotherapy; RT: Radiotherapy

Surgical removal is usually curative in localized disease and indicated for all cases (except stage IV/IV-S tumors very near to vital organs) to confirm histopathology and prevent compressive symptoms.

Chemotherapy is indicated in all cases except stage I disease, using four drugs — cyclophosphamide, cis­platin, etoposide and vincristine. In advance disease, high-dose chemotherapy followed by bone marrow transplant or use of monoclonal (anti GD-2) antibodies against neuroblastoma cell-surface proteins is under trial.

Radiotherapy is indicated in advanced disease as well as surgically inaccessible tumors or metastasis, e.g. spinal cord compression.

Stage IV-S may regress spontaneously or with low- dose cyclophosphamide/radiotherapy.

Prognosis depends on age (better in infants), staging, histology, and cytogenetic markers (poorer in tumors with chr-1p deletion or amplication of mycn proto­oncogene). Relapses are common in cases with high-risk neuroblastoma.

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