Neuroblastoma Screening (PDQ®): Screening - Health Professional Information [NCI] - Significance
Incidence and Mortality
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 infantcancer.[1,2] 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 cut-off 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%.[10,11,12,13] 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%).[12,15] 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.
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