Hormonal Activity May Predict Aggressive Behavior in Neuroblastoma

Abstract

Overproduction of catecholamines (dopamine [DA], norepinephrine [NE]) and their metabolites (homovanillic [HVA] and vanillylmandelic [VMA] acids) characterizes neuroblastoma (NB). In previous studies, increased urinary DA/NE, and DA/VMA ratios have been associated with poor prognosis, whereas low DA/NE ratios have been associated with longer disease-free survival. Higher urinary VMA, HVA, and NE levels have been found in association with low MYCN amplification, in contrast to cases with high MYCN amplification in which normal levels have been found. It is then believed that an “immature” catecholamine pattern indicates poor prognosis. We correlated urinary DA, NE, VMA, and HVA levels with age, clinical tumor stage, histological features (favorable [FH]/unfavorable [UH]) and MYCN status of 33 patients with NB. DA/VMA and DA/HVA ratios were also calculated. Wilcoxon rank sum and chi-squared tests were performed to determine statistical significance. Eighty-eight percent (15/17) of stage 3–4 cases had DA levels >2 times the upper limit of normal, but only 8% (1/12) of stage 1–2 cases had DA levels twice the upper limit of normal. In 61% (11/18) of stage 3–4 cases, the VMA level was >10 times the upper limit of normal, in contrast to stage 1–2 cases, in which only one patient (1/15) had a VMA level >10 times the upper limit of normal. Similar findings were obtained with urinary HVA and NE. Patients older than 12 months of age at diagnosis also had higher urinary levels of DA, VMA, HVA, and NE than those of patients younger than 12 months of age at diagnosis. Eighty-two percent (14/17) of stage 3–4 cases had DA/VMA ratios <0.78, with the other 18% (3/17) showing ratios between 1.4 and 8.82 (all stage 4 and >12 months of age). In contrast, all stage 1–2 cases (12) had ratios <1.4. All (12/12) non–MYCN-amplified cases had DA/VMA ratios <1.4 (0.06–0.84), while one MYCN-amplified case (1/3) had a ratio of 8.82; the other two MYCN-amplified cases had DA/VMA ratios of 0.09–0.11. Twenty-nine percent (2/7) of cases with UH had a DA/VMA ratio >1.4, but in all FH cases (14/14) the DA/VMA ratio was <1.4 (0.08–0.084). Similar to previous studies, we found that aggressive NB is associated with higher urinary levels of DA, VMA, HVA, and NE. We also confirmed the previous observation that there appears to be a subset of NB in which a possible blockade in DA metabolism is associated with poor prognostic features (>12 months, stage 4, UH, and MYCN amplification). A seemingly novel observation in our study is that all high DA/HVA and DA/VMA ratios were obtained in stage 4 tumors, suggesting an association between the inability to metabolize DA and the acquisition of metastatic potential. On the basis of our results, we would like to emphasize the importance of determining not only DA, HVA, and VMA urinary levels, to support the diagnosis of NB, but also DA/HVA and DA/VMA ratios as a rapid initial assessment of prognosis in these patients.