In this study, we have demonstrated that overall outcome for patients with neuroblastoma and stage 4S pattern is superior to that for patients with stage 4 pattern, and outcome for older patients is in general worse than that for younger patients (with exception of patients < 19 days of age). Age and metastatic pattern are highly significant prognostic factors.21,27
However, age serves as a surrogate for evolving tumor biology in growing children, so it is not surprising that tumor biology is shown here to be more important than metastatic pattern or age. In patients younger than 18 months old with metastases, MYCN
gene amplification, 11q aberration, MKI, 1p aberration, histology, and metastatic pattern can be used to classify patients into subgroups that are statistically significantly different in terms of outcome. The reason that toddlers age 12 to 18 months have similar EFS regardless of metastatic pattern seems to be because of similar frequencies of unfavorable biologic features for stage 4 and 4S pattern in the toddler age group.
INSS stage 4S has been established as having superior outcome compared with historical results with INSS stage 4 disease in infants younger than 12 months of age.3,4
gene amplification has been shown to be an extremely important prognostic factor in infants with metastatic neuroblastoma in multiple cooperative studies, for infants with both stage 4S3,9
and stage 4 disease.28–30
Infants with either stage 4 or 4s neuroblastoma and MYCN
gene amplification have a 2-year EFS of less than 30% despite intensive therapy,28,30
whereas those without MYCN
amplification may have a 2-year survival of greater than 90% with minimal or no chemotherapy.29,31
Because of the rarity of MYCN
amplification in infants with 4S neuroblastoma (0% to 10%), it has been difficult to show without the help of a large series such as the INRG database that MYCN
status is prognostic independent of age and other factors. The favorable outcome for patients with stage 4 pattern without MYCN
amplification was also extended to toddlers age 12 to 18 months. Two cooperative group analyses showed that this subgroup had a significantly superior survival to older patients with stage 4 disease as well as to those of the same age with MYCN
These findings prompted the revised INRG age limit for 4S metastatic pattern now designated Ms.17
In addition to MYCN
, the other independently prognostic factors were 11q, MKI, ploidy, and LDH, despite the fact that a number of patients lacked information on these biologic variables. Within particular subsets in the survival tree, metastatic pattern, histology, and 1p were also significant. Attiyeh et al32
reported 11q and 1p aberrations as independent unfavorable risk factors in a study of 915 patients, regardless of clinical risk classification. This study included nine of 50 patients with stage 4S and 11q aberration, although this small group was not analyzed separately. Spitz et al33
compared 11q aberration in localized and 4S disease and found metastatic relapse rates to be 30% when 11q aberration was present and 3% with normal 11q status. Although a relatively low proportion of patients in our INRG series had assessment of 11q aberration (181 of 1,675 patients age < 18 months with metastases), the effect of 11q was so strong that even in this small sample, we found significance in multivariable analysis. Patients younger than 12 months or 12 to 18 months of age with MYCN
amplified or 11q LOH tumors would not be considered low-risk patients and would warrant more intensive therapy despite the 4S pattern. Excluding such patients, there were only 18 patients who were age 12 to 18 months with MYCN
not amplified and normal 11q tumors, with 5-year EFS and OS of 87.4 ± 10.3% and 100.0%, respectively.
Previous analyses of 4S disease have found unfavorable histology to be associated with decreased survival.4,9
Diploid tumors have also been associated with poorer outcomes, but the prognostic benefits of hyperdiploid tumors seem to be limited to infants and toddlers age 12 to 18 months without MYCN
Elevated serum LDH may indicate increased tumor burden and has been identified as an independent poor prognostic factor.3,9
In our evaluation of infants with stage 4S disease, we found that risk of an event was high for patients of very young age, that the age subgroup with the best outcome was approximately 19 to 38 days, and that risk of an event increased gradually after age 38 days. Although the definition of young age varies by study, multiple groups have reported that infants younger than 2 to 3 months old have poorer OS than older infants.3,4,9
Massive hepatomegaly in these infants can lead to respiratory, renal, and gastrointestinal impairment as well as coagulation abnormalities.3
In the analysis by Nickerson et al4
of 80 infants with 4S disease, five of the six recorded deaths occurred in infants younger than 2 months of age who had rapidly progressive abdominal disease. A literature review of 119 4S cases found that in 33 deaths, 11 of 12 deaths resulting from hepatomegaly occurred in infants diagnosed in the first 4 weeks of life.13
These young infants with liver enlargement often are treated early and are at greater risk of death, thus explaining the observation in our INRG study that initial treatment is an unfavorable prognostic factor, as noted by others.3
Although this analysis used the largest cohort of patients with 4S metastatic pattern younger than 18 months of age, missing data and the rarity of some of the biologic tumor features resulted in some limitations. For example, some of the contributing groups at certain times allowed patients with so-called 4S disease younger than 12 months with tumors that crossed the midline as well as bone marrow involvement of more than 10%, characteristics that would have excluded patients from 4S categorization by the INSS definition; less than 10% bone marrow involvement was not required for any patient in the 12- to 18-month-old group with 4S pattern, because these patients were not defined as INSS 4S. It is unknown whether the size and stage of primary tumor are important in assigning 4S designation, but our study has shown that the pattern of metastases is less critical for risk group definitions than biologic variables. The most recent European infant protocols have used the metastatic pattern excluding macroscopic bone metastases but ignoring the primary tumor size as criteria for minimizing therapy in infants with metastatic neuroblastoma.29
Finally, a variety of different treatment regimens were used, and thus, we were unable to adjust for treatment effect on EFS and OS. Acquisition of more complete data on biologic tumor features will be critical for future clinical trials to provide improved assignment of treatment intensity and greater insight into the role of biologic and clinical tumor features on patient survival.
In conclusion, although the INSS stage 4S metastatic pattern has a more favorable outcome than stage 4 pattern in the age group of 0 to 18 months, biologic categorization of risk, particularly by MYCN, MKI, 11q, 1p, and histology, is more critical than metastatic pattern to assign risk-adapted therapy. In addition, infants in the very young age group (ie, age younger than 19 days) may require different management.