Note: Separate PDQ summaries on Neuroblastoma Treatment and Levels of Evidence for Cancer Screening and Prevention Studies are also available.
Screening, usually at age 6 months, for urine vanillylmandelic acid and homovanillic acid, which are metabolites of the hormones norepinephrine and dopamine.
Based on solid evidence, screening for neuroblastoma does not lead to decreased mortality.Description of the Evidence
Based on solid evidence, screening infants for neuroblastoma leads to an increase in incidence of early-stage neuroblastoma. There is no concurrent decrease in incidence in screened children of advanced-stage disease, which typically does poorly, or of incidence in children older than 1 year. The cases identified by screening almost exclusively have biologically favorable properties.
Based on solid evidence, screening infants for neuroblastoma results in overdiagnosis (diagnosis of some neuroblastomas detectable by mass screening that would not have been clinically diagnosed later). This leads to unnecessary diagnostic and therapeutic procedures with consequent physical and psychological morbidity, including death from treatment complications.Description of the Evidence
About 7% of all malignancies in children younger than 15 years are neuroblastomas. About one quarter of cancers in the first year of life are neuroblastomas, making this the most frequent histological type of infant cancer.   The incidence rate of the disease in children younger than 1 year is about 35 per million but declines rapidly with age to about 1 per million between ages 10 and 14 years.  Males appear to be affected slightly more commonly than females, with about five cases occurring in boys to every four occurring in girls.
The risk factors for and causes of neuroblastoma have not been established, and therefore it is not possible to provide information or advice for the primary prevention of this disease. It is generally thought that many neuroblastomas are present and detectable at birth, thereby allowing for detection of tumors by a single, once-in-a-lifetime screening test, such as those used for neonatal screening for noncancerous conditions (e.g., phenylketonuria). Screening is performed through biochemical tests for metabolites of norepinephrine and dopamine (i.e., vanillylmandelic acid [VMA], and homovanillic acid [HVA]). Seventy-five percent to 90% of cases of neuroblastoma excrete these substances into the urine, which can be measured in urine specimens.  There is no known optimal age for screening, but the most commonly discussed and studied age for a one-time screen has been 6 months. Screening at 12 months has also been evaluated in a population-based study in Germany.  Approximately 65% of cases are present before 6 months.  Furthermore, the clinical significance of screen-detected neuroblastomas is in question since stage I and II localized tumors less than 5 cm have been observed to regress without treatment in an observational study. 
Testing of liquid urine samples or of samples collected on filter paper for VMA and HVA is possible.  The first attempts to conduct mass screening through urinary testing occurred in Japan in the early 1970s.  The VMA and HVA levels are usually measured by gas chromatography, thin layer chromatography, and/or high performance liquid chromatography.
There are no standard cutoff levels between positive and negative VMA and HVA tests. One recommendation is to use a VMA cut-off level of 25 μg/mg creatinine and an HVA cut-off level of 32 μg/mg creatinine. Alternatively, individual laboratories use a level of two standard deviations above that laboratory’s age-specific mean to identify specimens for reanalysis. On reanalysis, a level of three standard deviations above the mean is used to determine the need for diagnostic evaluation. 
The sensitivity of the screening procedure used in different studies ranges from 40% to 80%.     False-positives can be caused by dietary agents such as bananas and vanilla  but are rare with quantitative assays such as gas chromatography (specificity approximates 99.9%).   Because of the low prevalence of the disease, even in the Quebec Neuroblastoma Screening Project in which the specificity of the test was extremely high, the positive-predictive value was only 52%,  i.e., for every two children identified by screening as being likely to have neuroblastoma, only one was actually affected. In the German Neuroblastoma Screening Project, the positive-predictive value has been reported as only 8.4%.  False-positive cases are generally followed for prolonged periods with serial noninvasive testing before a definitive diagnosis excluding cancer can be offered to the parents. 
Evidence of screening effect derives from descriptive studies of local and national programs in Japan, uncontrolled pilot experiences at a number of sites in Europe and the United States, and population-based studies in Canada and Germany.       
An increase in survival rates among screen-detected cases would be expected if screening was detecting neuroblastoma at an earlier and more curable stage. While improved survival rates after initiation of screening have been reported,   these observations should be viewed cautiously because improvements could be caused by lead-time bias, length bias, and identification of cases through screening that would have spontaneously regressed.
Screening results in an increased incidence of early-stage disease. The cases detected by screening almost exclusively have biologically favorable properties (unamplified N-myc oncogene, near triploidy, and favorable histology), and this type of favorable neuroblastoma has a high survival rate, whether detected by screening or detected clinically.            There is evidence that some tumors regress spontaneously in the absence of treatment.    
Some authors have argued that the Japanese experience shows that the number of children older than 1 year, who are diagnosed with neuroblastoma, may have decreased since the inception of screening  and that overall mortality has declined during this period.   A true reduction in neuroblastoma mortality may reflect improvements in treatment efficacy as much as a benefit of treating earlier-stage disease. Mortality has decreased in other countries where screening does not occur.  In another study of regional comparisons, disease rates were compared between Osaka, Japan, where screenings were initiated in 1985, and Great Britain, where screening was not done.  There was little change during this time in the cumulative mortality rates in either region; 52 versus 57.5 per million between 1970 and 1979 versus 1991 and 1994 in Osaka, compared with 78.6 versus 70.1 in the corresponding periods in Great Britain. In any case, the majority of cases detected by screening at 6 months appear to have biologically favorable prognoses independent of stage.      Furthermore, despite the shift in stage distribution of cases detected by screening compared with those that are routinely detected, the evidence of reduction in the incidence of advanced-stage cancers in the Japanese experience has been disputed;    in the Quebec Project, as noted below, no such reduction is observed. 
A study of mortality trends before and after the national mass screening program in Japan for neuroblastoma analyzed age-specific mortality rates from 1980 through 2006. Screening began in the mid-1980s and was halted in 2003. Mortality rates were either stable through the entire period for age groups 5 years to 9 years and 10 years to 14 years, or were declining before the initiation of screening and continued to do so through 2006 for age groups younger than 1 year and 1 year to 4 years. Because the most recent year of death analyzed was 2006, any increase in age-specific mortality associated with the cessation of mass screening in 2003 would have been expected to occur among children younger than 1 year or 1 year to 4 years. No such increase was observed. This is the first postscreening analysis to provide evidence that screening had no impact on mortality rates and that stopping screening had no adverse effect. 
A study compared neuroblastoma incidence and mortality rates in Japan in three cohorts: children born before screening between 1980 and 1983, and those born during screening between 1986 and 1989, and between 1990 and 1998.  Cumulative incidence was higher in the screened cohorts (21.56–29.80 cases per 100,000 births) compared with the prescreening cohort (11.56 cases). Cumulative mortality was lower in the screened cohorts compared with the prescreening cohort (2.83–3.90 vs. 5.38 deaths per 100,000 births). The impact of changes in treatment on these rates is unclear.
Before and after the cessation of the Japanese mass screening program in 2003, another study of neuroblastoma incidence and mortality was conducted in five prefectures (incidence) and nationwide (mortality). This study extended follow-up after cessation of screening several years beyond that reported in previous publications.  The incidence rate for infants younger than 1 year, the screened age-group, dropped markedly after the cessation of screening, while the rate for older children remained similar. The mortality rate in each age group was very similar over the entire time period studied (1993–2014). In addition, children were divided into two birth cohorts, those born before the cessation of screening (2003 or earlier) and those born 2004 or later. Cumulative incidence up to 5 years was lower after the cessation of screening, but there was no substantial change in mortality. Results of the mass screening program in Japan are consistent with no effect on neuroblastoma mortality and document that the program caused substantial overdiagnosis with no counterbalancing benefit. 
The Quebec Neuroblastoma Screening Project compared neuroblastoma incidence and mortality in a 5-year birth cohort (n = 476,603) from Quebec (where urinary screening was offered at 3 weeks and 6 months [overall compliance, 92%]) with various North American birth cohorts in which no screening took place. In this study, the incidence of early-stage disease in children younger than 1 year, in the screened population, more than doubled that expected; while in the control population, it approximated that expected (standardized incidence ratio, 3.03; 95% confidence interval [CI], 2.30–3.86) in Quebec versus 0.82 in Minnesota (95% CI, 0.41–1.38) and Ontario (95% CI, 0.53–1.17).  The incidence of advanced-stage disease (stage III and stage IV) in older children in Quebec showed a statistically nonsignificant increase over that which would have been expected (standard incidence ratio, 1.52; 95% CI, 0.95–2.23).  After approximately 8 years of follow-up (range 6–11 years) the neuroblastoma death rate in the screened population was not significantly different from rates in unscreened populations (standardized mortality ratio, 1.11 [95% CI, 0.64–1.92] for the Quebec cohort compared with Ontario children).  Similar findings were observed in the German neuroblastoma study.  Although final mortality rates are expected in 2008, an interim analysis shows that the death rate from neuroblastoma is similar in screened and control populations (1.6 vs. 1.9 deaths per 100,000 children). A study in Austria yielded a similar conclusion, though screening was performed at age 7 to 12 months. In the screening cohort, neuroblastoma incidence was statistically significantly higher than in children who were not screened (18.2 vs. 11.2 per 100,000 births), while mortality was not statistically significantly different (0.96 vs. 1.57 per 100,000 births). 
There is no evidence from controlled studies or randomized trials of decreases in mortality associated with screening.
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Added text about another study of neuroblastoma incidence and mortality which extended follow-up after cessation of the Japanese mass screening program in 2003 beyond that which was reported in previous publications; results of the mass screening program in Japan are consistent with no effect on neuroblastoma mortality and document that the program caused substantial overdiagnosis with no counterbalancing benefit (cited Shinagawa et al. as reference 33).
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PDQ® Screening and Prevention Editorial Board. PDQ Neuroblastoma Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389460]
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