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 infant cancer.[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.[3] Males appear to be affected slightly more commonly than females, with about five cases occurring in boys to every four occurring in girls.

Screening Method and Sensitivity

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.[4] 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.[5] Approximately 65% of cases are present before 6 months.[6] 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.[7]

Testing of liquid urine samples or of samples collected on filter paper for VMA and HVA is possible.[8] The first attempts to conduct mass screening through urinary testing occurred in Japan in the early 1970s.[9] 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 of 25 µg/mg creatinine and an HVA cut-off 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.[10]

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 [14] 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%,[11] 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%.[5] 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.[16]

References:

1. Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75 (8): 2186-95, 1995.
2. Gao RN, Levy IG, Woods WG, et al.: Incidence and mortality of neuroblastoma in Canada compared with other childhood cancers. Cancer Causes Control 8 (5): 745-54, 1997.
3. Stiller CA, Parkin DM: International variations in the incidence of neuroblastoma. Int J Cancer 52 (4): 538-43, 1992.
4. Williams CM, Greer M: Homovanillic acid and vanilmandelic acid in diagnosis of neuroblastoma. JAMA 183 (10): 836-840, 1963.
5. Schilling FH, Spix C, Berthold F, et al.: Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany. Cancer Lett 197 (1-2): 19-28, 2003.
6. Parker L, Craft AW: Neuroblastoma screening: more questions than answers? Eur J Cancer 27 (6): 682-3, 1991.
7. Yamamoto K, Hanada R, Kikuchi A, et al.: Spontaneous regression of localized neuroblastoma detected by mass screening. J Clin Oncol 16 (4): 1265-9, 1998.
8. Tuchman M, Auray-Blais C, Ramnaraine ML, et al.: Determination of urinary homovanillic and vanillylmandelic acids from dried filter paper samples: assessment of potential methods for neuroblastoma screening. Clin Biochem 20 (3): 173-7, 1987.
9. Sawada T: Past and future of neuroblastoma screening in Japan. Am J Pediatr Hematol Oncol 14 (4): 320-6, 1992.
10. Chamberlain J: Screening for neuroblastoma: a review of the evidence. J Med Screen 1 (3): 169-75, 1994.
11. Woods WG, Tuchman M, Robison LL, et al.: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348 (9043): 1682-7, 1996 Dec 21-28.
12. Nishi M, Miyake H, Takeda T, et al.: Mass screening for neuroblastoma and estimation of costs. Acta Paediatr Scand 80 (8-9): 812-7, 1991 Aug-Sep.
13. Chamberlain J: Neuroblastoma. In: Chamberlain J, Moss S, eds.: Evaluation of Cancer Screening. London: Springer, 1996, pp 145-149.
14. Woods WG, Tuchman M: Neuroblastoma: the case for screening infants in North America. Pediatrics 79 (6): 869-73, 1987.
15. Scriver CR, Gregory D, Bernstein M, et al.: Feasibility of chemical screening of urine for neuroblastoma case finding in infancy in Quebec. CMAJ 136 (9): 952-6, 1987.
16. Bernstein ML, Woods WG: Screening for neuroblastoma. In: Miller AB, ed.: Advances in Cancer Screening. Boston, Mass: Kluwer Academic Publishers, 1996, pp 149-163.