10 Neuroblastoma	115

•Factors such as alcohol and other drugs during pregnancy (i.e., fetal hydantoin syndrome), parental occupation, and viral infection should be considered

•Familial occurrence as well as sibling and twin disease with different stages of neuroblastoma within the same family is rarely described

•Association with neurofibromatosis, Hirschsprung disease, heterochromia iridis

•Tumor cell chromosomal changes and various karyotypic abnormalities in the majority of patients are detectable (see below)

10.4Molecular Cytogenetics

•The oncogene NMYC is located on chromosome 2p23-24 and amplified in up to 50% of patients with stage 3 or 4 disease

•NMYC amplification and expression of neurotropic receptors (TRK1, -2, -3), neuropeptides (vasoactive intestinal polypeptide, VIP, somatostatin, SS), DNA index, and chromosomal changes (deletion 1p suppressor gene on chromosome 11, deletion 14, etc.) are prognostic factors which are summarized below

•Cell ploidy (DNA): 55% of locoregional neuroblastomas are hyperdiploid with a favorable prognosis, 45% of neuroblastomas are diploid with mostly unfavorable prognosis

Cytogenetic prognostic criteria

Age at diagnosis	NMYC	DNA	TRK1	Stage	Prognosis
					(survival rate)
<12 months	Usually normal	Hyperdiploid	High	1, 2, 4 S	95%
>12 months	Usually normal	Diploid	Low	3, 4	50%
1–5 years	Commonly	Diploid	Low	3, 4	25%
	amplified

•Anaplastic lymphoma kinase ALK may have mutations in the tyrosine kinase domain (TKD) which are observed in families with predisposition of neuroblastoma. Mutated ALK is currently being tested as a target in patients in Phase I/II trials

10.5Pathology

10.5.1 Macroscopic Features

Pale gray, soft tumors with necrosis and calcification; in large tumors the demarcations are unclear; and the tumors are highly invasive.