Different genomic and metabolic patterns between mass screening-positive and mass screening-negative later-presenting neuroblastomas

Abstract

The mass screening of neuroblastoma has been undertaken in Japan by measuring urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) in all infants at the age of 6 months. This program may not only improve the prognosis but also provide important insights into the biology and evolution of human neuroblastoma. The authors studied and discuss the clinical significance of the N‐myc oncogene, catecholamine metabolism, and other tumor markers in 43 patients with neuroblastoma who underwent the urinary screening test at 6 months of age. Thirty patients were found by the screening, and 13 were negative at the screening but later had a tumor. In the former group, the tumors were mostly in early stages (Stage I, 12; Stage II, 11; Stage III, seven), no amplification of N‐myc was observed, and all patients are alive without disease. Although two patients whose urine at the screening showed elevated VMA and HVA levels and accidentally were not treated for 13 and 17 months, there was no change in the values of VMA and HVA during that time. However, in the latter group, the tumors were mostly in advanced stages (Stage I, one; Stage III, four; Stage IV, eight), and N‐myc amplification was observed in seven of 13. Only two of these 13 are alive without disease. The age at diagnosis of the screening‐negative group was 23 months compared with 8 months in the patients identified by screening, and the pattern of catecholamine metabolites in the screening‐negative group tended to be dopaminergic with a low VMA–HVA ratio, especially in cases with N‐myc amplification. These data suggest that the screening‐positive patients with neuroblastoma may have favorable characteristics, and the biology of these tumors may be different from that of screening‐negative later‐presenting tumors. They also suggest that there may be at least two distinct subsets of neuroblastoma. For the early detection of the poor prognostic neuroblastomas, the measurement of urinary dopamine with VMA and HVA at later ages, such as 1 to 2 years, should be considered.

Biological aspects of neuroblastoma screening

“…This finding implies that a number of tumors in this age group have the capacity to spontaneously regress or mature, and they would not have been detected clinically. In the Japanese studies, the screening was performed at the age of 6 months and virtually no diploid or MYCN amplified tumors were detected [2,3]. This is consistent with nonscreened populations, in which only a small percentage of tumors with MYCN amplification or diploid/tetraploid DNA content are diagnosed before 12 months of age [4].…”

Perinatal risk factors for neuroblastoma

“…Occurrence is most common in infancy, with declining incidence in early childhood, and rare occurrence after age five or six years. Biologically, neuroblastoma that arises in infancy is generally believed to be a different disease from neuroblastoma occurring among preschoolers [2][3][4]. This belief arises from the fact that neuroblastoma in infancy has different cytogenetic characteristics (hyperdiploidy and lack of MYCN oncogene amplification) and good prognosis, whereas neuroblastoma diagnosed after age 12-18 months has a less favorable prognosis [5][6][7].…”

“…This regression is related to the normal differentiation and apoptosis of neural crest cells during infancy [8]. Attempts to institute screening programs to diagnose neuroblastoma at six months of age in order to prevent later cases have shown that, in fact, neuroblastomas that are diagnosed among preschoolers often do not represent progress from infant neuroblastoma, but are in fact separate clinical entities [2,3,[10][11][12]. Screening programs identifying infant neuroblastoma have failed to reduce mortality from the disease, or even lessen the rates of neuroblastoma in older age groups, although delaying screening to age 12 months improved the results [13][14][15].…”

Neuroblastoma Mass Screening in Late Infancy: Insights Into the Biology of Neuroblastic Tumors

“…However, at that time, first reports appeared which argued that neuroblastoma mass screening performed early in life might predominantly detect cases which would otherwise regress spontaneously. 4,9,10 From these observations it was concluded that neuroblastoma screening at or before an age of 6 months might be of little or no benefit. 8 Additionally, biologic features of neuroblastomas detected by urinary mass screening were almost uniformly favorable, 9 and patients developing neuroblastoma after the first year of life were frequently missed by early screening.…”