The survivin:Fas ratio is predictive of recurrent disease in neuroblastoma.
OBJECTIVE
Several clinical and biologic features of neuroblastoma (NB) are used to predict the risk of recurrent disease. The balance between antiapoptotic and proapoptotic factors within a tumor may affect its ability to survive. Survivin is an antiapoptotic factor expressed in highly proliferative NB, whereas Fas is a proapoptotic factor that portends a favorable prognosis. The authors determined whether the ratio of survivin to Fas (S:F ratio) is predictive of recurrent disease in patients with NB. The authors previously have shown the S:F ratio is predictive of recurrent disease in pediatric renal tumors.


METHODS
The authors quantified the levels of 9 different apoptotic mRNA species using Rnase Protection assay (RPA, Riboquant, PharMingen, San Diego, CA). Twenty-eight primary tumor specimens were evaluated from patients with ganglioneuroma (n = 3), ganglioneuroblastoma (n = 2), and neuroblastoma (n = 23) from tumors of all clinical stages obtained at the time of diagnosis. mRNA levels were calculated as a percentage of L32 for each specimen assayed, and positive expression was assumed to be greater than 10% of L32.


RESULTS
Survivin was expressed in 90% of tumors that went on to recur and only in 27.7% of those that were cured. The S:F ratio was significantly greater in tumors that went on to recur (n = 10) compared with those from patients that were cured (n = 18) (median S:F ratio, 3.3 v 0.75; P =.0002, Wilcoxon rank-sum test). A cutoff ratio of 2.3 was highly predictive of tumor recurrence irrespective of clinical stage of disease (area under ROC curve = 0.906). Sensitivity was 80% (CI, 44.4% to 97.5%), specificity was 94.4% (CI, 72.7% to 99.9%), positive predictive value was 88.9% (CI, 51.8% to 99.7%), and negative predictive value was 89.5% (66.9% to 98.7%). Twenty-five of 28 (89.3%) tumor ratios were correct in predicting outcome.


CONCLUSIONS
The survivin:Fas ratio in primary tumors may be used to predict the risk for recurrent disease in patients with NB. The S:F ratio appears to be a more sensitive predictor of recurrent disease than survivin expression alone. Determining this ratio may not only be helpful in guiding follow-up of patients with NB, but also may aid in stratifying patients for more aggressive therapeutic strategies.
Sandler
Anthony
A
Department of Surgery, Department of Pediatrics, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
Scott
David
D
Azuhata
Takeo
T
Takamizawa
Shigeru
S
O'Dorisio
Sue
S
D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D009367:Neoplasm Staging; D009380:Neoplasms, Nerve Tissue / Q000737:chemistry / Q000473:pathology; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D000077022:Survivin; D019014:fas Receptor / Q000032:analysis*
C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D019014:fas Receptor