Metastatic, secondary, and lacrimal gland tumors

Biology and genetics

Clinical and biological heterogeneity are the hallmarks of neuroblastoma. Biological factors and a better understanding of the molecular development of neural crest cells, have allowed categorization of neuroblastic tumors. Up to 1%–2% of cases are familial and the majority of these are associated with a germline mutation in either ALK (Anaplastic Lymphoma Kinase) or PHOX2B (Paired-Like Homeobox 2B) genes. Interestingly, among the ~99% of sporadic neuroblastoma cases, recent genome-wide association studies have identified common polymorphisms that contribute to neuroblastoma predisposition, and segregate into disease-phenotype subsets.

Somatically acquired alterations of each tumor have important prognostic significance; amplification of MYCN (N-myc) proto-oncogene occurs in approximately 20% of primary tumors and is independently associated with reduced survival. Conversely, infants without MYCN gene amplification and disseminated neuroblastoma have an excellent outcome with reduced treatment.

Hyperdiploidy of tumor cell DNA content confers an improved prognosis. Conversely, segmental chromosomal alterations are associated with more aggressive disease. The most frequent somatically acquired copy number abnormality is allelic gain of distal chromosome 17q, identified in over 50% of primary tumors. An unbalanced gain is associated with more aggressive disease and decreased survival. The International Neuroblastoma Risk Group Stratification schema incorporates both biologic staging and demographic criteria to determine clinical risk group. This risk stratification is critical in ensuring children with favourable disease biology avoid potentially unnecessary therapy. In contrast, children with high-risk neuroblastoma are often resistant to multimodality treatment and despite recent advances and intensification of therapy approach have a 5-year survival rate of less than 50% .

Clinical presentation

Most cases occur under 3 years of age, 90% are diagnosed by age 5, with fewer cases occurring up to the late teens. Older children with high-risk neuroblastoma have a more indolent course but ultimately poor long-term prognoses. The adrenals are the primary site in 51% of cases, but it can arise in the cervical sympathetic chain, mediastinum, or pelvis. Neuroblastoma is also more common in patients with neurofibromatosis type 1 (NF1).

The clinical features vary according to the site of origin, tendency for multiple metastases, any hormone secretion, or paraneoplastic syndrome. Pain, fever, and weight loss are common; cerebellar encephalopathy (ataxia, myoclonic jerks, opsoclonus of unknown cause), diarrhea (from tumor vasoactive peptide production), Horner syndrome (sympathetic chain involvement), and hypertension with flushing episodes (catecholamine production) are classic signs of neuroblastoma.

The diagnosis is often not made until the patient has widespread metastases ; 40% have metastases at presentation, increasing to 55% in patients over the age of 1 year. In infants with stage MS or localized (L1) disease, tumors and their metastases undergo spontaneous regression, a feature occurring 100 times more commonly than for any other human cancer. This underlies the cautious treatment approach outlined below.

Ninety percent of patients have abnormally high levels of vanillylmandelic and homovanillic acid (VMA and HVA) in their urine due to catecholamine secretion. The urinary VMA concentration can be useful for diagnosis and to monitor treatment.