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© 2003 American Society for Clinical Oncology Neuroblastoma Mass Screening in Late Infancy: Insights Into the Biology of Neuroblastic Tumors
From the Department of Pediatrics, University of Graz, Graz; Children’s Cancer Research Institute; St. Anna Children’s Hospital, Vienna, Austria. Address reprint requests to Reinhold Kerbl, MD, University Children’s Hospital, Auenbruggerplatz 30, A-8036 Graz, Austria; e-mail: reinhold.kerbl{at}uni-graz.at.
Purpose: Neuroblastoma screening in early infancy has detected predominantly "favorable" tumors. We postponed screening to an age between 7 and 12 months to test whether this shift of screening age might influence the detection rate of genetically/clinically unfavorable tumors. Patients and Methods: In a 10-year period, 313,860 infants were screened by analysis of urine catecholamines. When a neuroblastoma was diagnosed, at least two different areas from every tumor were analyzed for genetic features (MYCN amplification, 1p status, ploidy). Furthermore, neuroblastoma incidence and mortality of the screened group and the cohort of 572,483 children not participating in the screening program were compared. Results: Forty-six neuroblastomas were detected by mass screening. In 17 tumors (37%) at least one of the biologic features was "unfavorable." In 10 of 17 patients, one or more of these alterations were only focally present (tumor heterogeneity). In the screened cohort, neuroblastoma incidence was significantly higher when compared with unscreened children (18.2 v 11.2/100,000 births), while there was a trend towards lower incidence of stage 4 over 1 year (2.2 v 3.8). Mortality was not significantly different (0.96 v 1.57). Conclusion: In contrast to other neuroblastoma screening programs, more than one-third of patients were found with unfavorable genetic markers in our study. The high proportion of focal alterations suggests that biologically young neuroblastomas may consist of genetically favorable and unfavorable parts/areas/clones. We conclude that at least one-third of neuroblastomas detected by screening in late infancy are anticipated cases. This, however, does not result in significantly reduced mortality.
ENCOURAGING RESULTS of the Japanese neuroblastoma screening program describing excellent survival rates for neuroblastomas detected by urinary mass screening1–3 prompted us to introduce a similar program for Austria in 1991. 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.4–7 It was emphasized that neuroblastoma screening doubled the incidence of this tumor without reducing mortality.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.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.6 As a consequence, it was decided by the investigators that the Austrian project postpone the age of screening to between 7 and 12 months.11 Furthermore, in order to eventually detect focal alterations (heterogeneity) of tumors, an extensive work-up of tumor material according to recent guidelines12 was performed whenever possible. After a 10-year experience, the results were analyzed with special regard to genetic hallmarks of the tumors detected by urinary mass screening. Furthermore, neuroblastoma incidence and mortality of screened and unscreened children were compared.
Sample Collection Dried urine samples on filter paper were collected from infants aged 7 to 12 months. Between January 1991 and July 1997, distribution of filter strips was done on a voluntary basis in collaboration with general pediatricians and practitioners.11 Since July 1997, the filter strips had been available to all parents via the generally distributed health booklet for newborns. Parents received written information describing intention and performance of the screening program. Furthermore, a phone number was provided to parents in case of additional questions. Sending of the filter paper by parents was considered as agreement to have the test done. This procedure was approved by the Supreme Council of the Austrian Ministry of Health and repeatedly evaluated by the same institution. Finally, because of the results of the Quebec and German studies,13,14 it was decided in 2002 to discontinue the screening program.
Analysis of Urine Catecholamines
Clinical Investigation
Staging and Analysis of Tumor Material Biologic features were determined from different sections of all tumors in accordance with recent protocols.12,20,21 Double fluorescence in situ hybridization (FISH) analyses were carried out on touch preparations and on cytospin slides from resected tumors or biopsies. To evaluate the integrity of the short arm of chromosome 1, the number of centromere signals pUC1–77 (D1Z1) and subtelomere signals of chromosome 1 demonstrated with the variable number of tandem repeats probe p1–79 (D1Z2) specific for the subtelomeric region of 1p (1p36.33) was evaluated in at least 500 nuclei.20,22 The same procedure was performed to evaluate the copy number of the MYCN oncogene. The labeled DNA probe specific for the MYCN gene was used in combination with the centromere 2 specific probe D2Z (Oncor, Q-Biogene, Heidelberg, Germany). Ploidy of tumor cells was determined by flow cytometry according to standard conditions using a FACStar flow cytometer (Becton Dickinson, San Jose, CA). Different genomic features of different tumor pieces were interpreted as focal alterations, representing tumor heterogeneity. Criteria for this classification were published previously.12 For example, focal MYCN amplification was defined by the occurrence of at least 50 MYCN amplified cells surrounded by nonamplified tumor cells.
Treatment In recent years, therapy stratification was based not only on the clinical stage (INSS), but also on findings of molecular biologic investigations. In particular, postoperative chemotherapy was scheduled for all tumors with MYCN amplification whenever residual tumor was left. In contrast, according to LNESG criteria, a postoperative wait-and-see strategy was applied for MYCN nonamplified neuroblastomas even when small tumor residuals were left. This behavior was also extended to some stage 3 patients (residual tumor and/or contralateral positive lymph nodes) with exclusively favorable biologic markers.
Neuroblastoma Registry
Neuroblastoma Incidence, Mortality, and Stage 4 Patients Older Than 1 Year Number of births was taken from the national report of Statistik Austria (Statistisches Jahrbuch Oesterreichs 2003, Oesterreichische Staatsdruckerei, Vienna, 2003). Children living outside Austria during their first year of life were excluded from calculations. There remains small uncertainty for children leaving Austria; however, as emigration rate during the study period was low, these patients may be neglected without major influence on statistical results. For primary calculation of incidence, patients diagnosed by screening, as well as so-called false-negative cases (clinically presenting neuroblastoma after negative screening result), were counted in the screening cohort. For the unscreened cohort, only tumors diagnosed after the median screening age of 257 days (8.5 months) were counted. In a second step, 55 neuroblastoma cases observed in unscreened infants under the age of 257 days were proportionately assigned to the screened (the screening participation rate was 35.4%) and the unscreened cohort (64.6%). This was done in order to demonstrate the incidence of neuroblastoma in early infancy and to allow calculation of the total incidence including early infant cases.
For calculation of mortality, all children younger than 257 days at the time of diagnosis were again excluded, unless neuroblastoma was diagnosed by screening before that age. Data were presented as counts and proportions; incidence and mortality were expressed per 100,000 births with 95% CIs. Significances were calculated by means of
Ascertainment of False-Negative Patients
Between January 1991 and December 2000, neuroblastoma screening was performed in 313,860 infants aged 7 to 12 months, whereas 572,483 infants were not enrolled into screening (participation rate, 35.4%). As a result of elevated levels of urine catecholamines, 68 patients were admitted to the local children’s hospital for further clinical investigations. Among them, 46 patients were diagnosed with neuroblastoma at a median age of 9.8 months and treated according to the above-mentioned treatment protocols. According to INSS criteria, 16 of 46 patients were classified as stage 1, three as stage 2A, eight as stage 2B, 14 as stage 3, four as stage 4, and one as stage 4s. Histological analysis according to the Shimada or INPC system revealed favorable histology in 25/36 (69%) and unfavorable histology in 11 of 36 patients (31%). In 10 cases, histologic Shimada or INPC classification was not done due to insufficient material or lack of biopsy of the primary tumor (in disseminated disease). Analysis of genetic features was performed on availability of sufficient tumor material. In one patient with unresectable retroperitoneal neuroblastoma, sufficient material could not be obtained by biopsy. In all other cases, tumor samples could be evaluated at least for MYCN status. In three patients with disseminated disease (stage 4 or 4s), genetic analyses were done on bone marrow aspirates.
Biologic analyses showed MYCN amplification in eight of 45 patients (17%), imbalance or deletion of the short arm of chromosome 1 in eight of 43 patients (19%), and di- or tetraploidy in seven of 35 patients (20%). Of the 46 patients diagnosed through the screening program, 17 (37%) had at least one genetically unfavorable marker (MYCN amplification, 1p deletion/imbalance, di-/tetraploidy). Interestingly, in 10 of 17 patients tumor heterogeneity was proven for at least one of these features (Table 1
All combinations of unfavorable markers were seen. Most remarkable, in one patient with genetically heterogenous thoracic neuroblastoma (and few neuroblastoma cells in bone marrow) the neuroblastoma cells analyzed were complementary concerning MYCN and 1p imbalance status (ie, MYCN amplified cells did not disclose 1p imbalance, MYCN nonamplified cells showed 1p imbalance by FISH). Treatment consisted of surgical resection alone in 27 of 46 patients, chemotherapy alone (after bone marrow aspiration and biopsy) in one patient, and combined operation and chemotherapy in 18 patients. Two of the latter patients were additionally treated by local irradiation of the tumor field. At a median follow-up of 61 months, 44 of 46 patients (96%) diagnosed through the screening program were alive, 38 without evidence of disease, four with small tumor residuals demonstrable by imaging techniques, and one with partial response. One patient with previous stage 2B disease developed disseminated relapse 7 months after incomplete resection of a tetraploid neuroblastoma. Following intensified treatment, the patient is alive 89 months after diagnosis although no complete remission could be achieved (stable disease). Two of 46 patients (4%) died of therapy-related complications.
Between January 1991 and June 2002, 11 false-negative neuroblastoma patients were identified (Table 2
The comparison of the 313,860 screened and 572,483 unscreened children showed a significantly higher incidence in the screened group (18.2 v 11.2 per 100,000 births), which accounts for seven additional cases per 100,000 births in the screened cohort. In contrast, there was a trend towards lower incidence of stage 4 cases in children over one year in the screened group (2.2 v 3.8). Mortality was slightly lower in the screened cohort (0.96 v 1.57), but because of small numbers in both groups, there are wide and overlapping confidence intervals. Further details are shown in Table 3  .
The main goal of any cancer screening is reduction of mortality.24,25 However, besides promising results in the 1980s,3 the huge Japanese screening program with a nationwide screening at 6 months has so far failed to demonstrate this. Whereas screening has doubled the incidence of neuroblastoma, a clearly proven reduction of mortality could not be shown.5,8,26,27 In the North American screening program, double screening was performed at 3 weeks and 6 months. However, mortality was similar in the screened and unscreened cohort.13,28 Both, the failure to reduce mortality and the observation of overdiagnosis29 with an overwhelming frequency of low-stage and so-called favorable cases with almost uniformly benign biologic features among screened patients30 have recently been used as major arguments against neuroblastoma screening in infancy.13,24,31 As a consequence, screening age was postponed in some studies. In the German study, screening was performed around 12 months.32 However, even at that age, mass screening apparently leads to substantial overdiagnosis and seems not to significantly reduce mortality.14 In Austria, neuroblastoma screening was introduced in 1991 with the aim of reducing overdiagnosis and the incidence of false-negative cases, and of detecting more cases with otherwise unfavorable prognosis.11 In contrast to earlier studies, screening was postponed to between the age of 7 to 12 months. Subsequently, this study has shown that neuroblastoma screening in late infancy is indeed able to detect a good proportion of so-called unfavorable cases. Seventeen of 46 patients (37%) had at least one biologic feature that is generally associated with adverse outcome. The proportion of genetically unfavorable tumors is comparable to that reported for clinically diagnosed cases,33–36 and similar to the proportion in the false-negative cases of our study and the Quebec study.30 It remains a matter of speculation as to which extent this relatively high proportion of unfavorable cases in a screened cohort may be attributed to the higher age at screening, to a more extended work-up of tumor material, or both. The extended analysis of tumor material (according to the LNESG guidelines) enabled the detection of biologic heterogeneity and therefore led to new insights into tumor biology. Heterogeneous tumors—consisting of a favorable and an unfavorable component—have been rarely observed among clinically diagnosed cases36 even if the tumor work-up was similar as in our screened patients. In a series of 514 clinically diagnosed neuroblastomas, only eight cases (1.6%) displayed focal MYCN amplification (I.M.A. & P.F.A., unpublished results) while the proportion of focal MYCN amplification was significantly higher in our screened group (seven of 46; 15.2%). It may be speculated that in heterogeneous neuroblastomas, the malignant clone(s) may possess the potential of uncontrolled proliferation, finally resulting in overgrowing of these cells as shown in one case by Lorenzana et al37 and recently by Noguera et al38 for a patient with stage 4s disease. It remains a matter of speculation why focal MYCN amplification has been rarely found in clinically detected tumors. Possibly, this finding is limited to a specific age group. In neuroblastoma, an age of around 12 months may be crucial for the further course of the tumor being subject to either regression/maturation or progression. This might explain the accumulation of heterogeneous patients in our screened cohort. Further investigations of (incidentally diagnosed) asymptomatic neuroblastomas are needed to confirm this speculation. For our study it can, however, not be fully excluded that some oncologists may have handled screened neuroblastomas in a special and more sophisticated way when sending tumor samples for molecular biologic analyses. In our study, besides the relatively high proportion of tumors with unfavorable genetic markers, there was nevertheless significant overdiagnosis of neuroblastomas in the screened cohort. Most likely, some of the neuroblastomas detected by screening would have regressed or matured spontaneously. Furthermore, several false-negative cases were observed. Apparently, in the latter cases, tumor burden was either not existent or not large enough at the time of screening to be detected by biochemical screening (all but one were catecholamine-positive at clinical diagnosis). A median interval of 23 months between (negative) screening and clinical diagnosis, however, suggests that the preventive measure of biochemical screening covers a certain period, similar to screening for breast, cervical, or prostate cancer. For this reason, repeated screening was suggested by several investigators, and some have gained limited experience in pilot studies.39,40 However, even repeated screening does not fully avoid false-negative cases, and from the economic point of view, repeated neuroblastoma screening seems not to be justified. Another important aspect concerns the treatment of neuroblastomas detected by screening. Recently, some centers have adopted a wait-and-see strategy for these patients, and in fact several cases with spontaneous regression or maturation have been observed.41,42 However, it still remains to be clarified which criteria should be used to decide for or against treatment. To date there is only one generally accepted parameter predicting tumor progression; that is MYCN amplification. Other genetic/biologic factors still await general clinical acceptance.43–45 The absence of MYCN amplification, however, does not necessarily predict a benign course of the disease.46 More knowledge has to be collected until a wait-and-see strategy can be recommended in general.47 Some knowledge can be drawn from stage 4s cases which frequently regress without any therapy.20,48,49 From the screening studies we have learned that the feature of spontaneous tumor disappearance is not limited to stage 4s, but may similarly occur in lower stages41,42 which could be classified as stages 1s, 2s or even 3s. Furthermore, it appears that the mechanisms of regression and maturation are not limited to the first year of life,32,41 although the likelihood for those mechanisms may decrease with increasing age. The decision about (non) treatment and intensity of treatment has to consider currently known prognostic markers and should result in a patient-tailored regimen.23,50–53 This could be a wait-and-see strategy for selected cases, and should be a minimally aggressive therapy in young patients with favorable histologic and biologic features, but in contrast, intensified treatment including high-dose chemotherapy and (repeated) autologous stem cell transplantation as well as consideration of additional noncytotoxic modalities like GD2 antibodies, interleukin-2, and retinoic acid for high-risk patients. Totally resected tumors do not require further treatment even in the case of unfavorable prognostic markers, and Cohn et al54 have demonstrated an excellent outcome for patients with low stages and MYCN amplification. For patients with tumor heterogeneity and incomplete resection/remission, some conflict may arise as to which extent intensified treatment may be justified.55 This holds true especially for the observation of 1p imbalance and focal 1p deletion. The prognostic impact of these alterations remains to be determined, although the proliferative potential of such cells was recently shown by Noguera et al.38 Worldwide, oncologists and biologists are thus far not sure about the correct interpretation of tumor heterogeneity.56 Further experience has to be collected in more patients to answer the question of adequate treatment.57 In unscreened areas, up to 34% of all neuroblastomas are diagnosed by incidence.58 The patient tailored therapy stratification should consequently include all neuroblastoma patients equally if detected clinically, incidentally, or by mass screening. A treatment strategy limited to screening cases appears not to be justified. Mass screening has contributed to the knowledge that neuroblastoma is not a single disease, but represents at least three prognostically different entities.34 The clinicians have to carefully consider this aspect in order to avoid unnecessary treatment and fatal events. In our screened cohort, three therapy-related deaths were observed, while none of the patients died of disease in the true-positive nor the false-negative group. Observations like this may support the argument that screening might do more harm than good.31 All deaths, however, occurred in an early phase of our screening study. Recently, clinicians have learned to use less aggressive therapies in favorable cases,33,50,51 but to administer intensified treatment in unfavorable cases52 and on demand (eg, tumor progression).
As shown in Table 2 The Austrian neuroblastoma screening study has contributed to the understanding of the natural history of neuroblastomas. So far, it has commonly been assumed that MYCN amplification is either an initial event or develops at an early stage of tumor evolution, and MYCN status was considered as stable and invariable. However, the presence of MYCN heterogeneity among screened tumors suggests that widespread MYCN amplification and 1p deletion/imbalance may also be acquired at a later stage of tumor evolution or progression. Interestingly, it appears that also triploid neuroblastomas, which are mostly considered as favorable tumors, may display or acquire MYCN amplification and/or 1p deletion. Neuroblastoma screening at an optimal age may be of benefit for these patients with potentially aggressive disease whose treatment could then be restricted to surgery alone. As a result of population size, even after a 10-year study, the Austrian project is unable to answer the epidemiological question of mortality, and at least another 25 years of screening would be necessary for this.59,60 However, studies from North America, Japan, and Germany have shown that neuroblastoma screening is unlikely to significantly reduce disease-related mortality.8,13,28,29,32 The authors of the German study estimate that only one-third of neuroblastomas detected by screening might be anticipated cases, and only 7% might, in fact, benefit from screening.14 Comparing the German and the Austrian studies, the findings of incidence, overdiagnosis, and mortality are similar in both studies. In our study, however, there was a trend toward an excess of stage 4 cases over the age of 1 year in the unscreened cohort which was not observed in the unscreened area of the German trial. However, the German study reports a similar excess of such cases in children of the screening area who did not participate in screening. One may speculate that this is a consequence of bias through parental awareness. In contrast to the Quebec and German studies, the Austrian screening program had no prospective control population. In our study, participants and nonparticipants were compared, and the inherent selection bias may have some influence on mortality results. In conclusion, the proportion of anticipated cases, together with the incidence of overdiagnosis through mass screening, overtreatment in screened cases, and gradually improving outcome for clinically diagnosed neuroblastoma cases, appears to be too low to justify neuroblastoma mass screening as a general preventive measure. While nationwide screening is still going on in Japan, the German trial was stopped in 2001, and Austria has terminated the screening program in 2003. Apparently, neuroblastoma mass screening has failed to significantly improve the outcome of screened patients, but it has lead to important insights into the biology of neuroblastic tumors in childhood, giving way for new diagnostic and therapeutic approaches.
The authors indicated no potential conflicts of interest.
This study was supported by the Styrian Government, the Styrian Children’s Cancer Fund, and the Children’s Cancer Research Institute, Vienna, Austria.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
2 test. 
