Discussion
This case represented an uncommonly late relapse of neuroblastoma, 20.5 years after initial diagnosis. Interestingly, she had a recurrence of stage MS neuroblastoma, a stage which overall portends a good prognosis with event-free survival reported between 85-90%.5, 8Relapse occurs in these patients but almost exclusively within the first two years of diagnosis.8 To our knowledge, there have been only two previously reported cases of late recurrence of MS disease. Cervera et al. described a patient with MS disease whose course complicated by interval development of several skin metastases with ganglioneuromatous histology at 3 and 19 years of age followed by eventual development of a bone metastasis at 23 years of age.9 The second case presented by Kato et al. 10 described a 12-year-old female eleven years after complete remission. This patient had a history of stage MS disease with primary adrenal tumor and diffuse liver metastases who developed recurrent tumor in the liver. As in this case, the patient presented at relapse with normal urinary catecholamines, 123I-MIBG avidity, and N-MYC nonamplified tumor. She underwent chemotherapy and ASCT but experienced local recurrence 11 months after myeloablative therapy and died of progressive disease. Notably ganglioneuromatous lesions were found within the periphery of the patient’s undifferentiated hepatic tumor on autopsy pathology. Literature does report additional cases of IV-S with late recurrence; however, based on their clinical descriptions and revised staging definitions, they would be reclassified as stage IV or M.11,12
Similar to the case presented by Kato et al , our patient’s histopathologic findings demonstrated ganglioneuromatous foci within the undifferentiated mass. A suggested hypothesis for late relapses after apparent clinical remission proposes that neuroblastoma development occurs after malignant conversion via dedifferentiation of unresected ganglioneuromatous lesions.13 The discrepancy in the described patient’s urinary catecholamine status from initial diagnosis to relapse suggests a change in predominant catecholamine metabolism.In vitro studies have demonstrated that negative catecholamine excretion signal less differentiated tumor secondary to decreased tyrosine hydroxylase expression.14 Perhaps, the change in catecholamine metabolism strengthens the dedifferentiation theory over the alternate explanation of late activation of primary disease. Further study of catecholamine metabolism patterns in relapsed patients may provide better insight into the biologic differences in relapsed disease and could improve monitoring mechanisms to increase clinical ability to predict recurrence of disease.
Another intriguing component of the case was the relapse in adulthood at 20 years of age. There is a relative paucity of data regarding neuroblastoma in adolescent and young adult populations largely driven by the skewed age distribution of the disease in infancy and early childhood. Adolescents and young adults make up less than 5% of all neuroblastoma cases.15 Studies of tumors in these older patients demonstrate significantly lower rates of N-MYC amplification and catecholamine elevation and higher rates of ATRX mutations, suggesting alternative cancer biology.16The described patient’s N-MYC nonamplified status and normal catecholamine levels were consistent with the general patterns of neuroblastoma in adolescents and young adults; however, she was negative for ATRX mutations. Further highlighting an intrinsic difference of neuroblastoma in these older populations is the poorer health outcomes in adolescents who have decreased event-free and overall survival for all stages of neuroblastoma as well as a more indolent, protracted course.15-17 This patient did well from an oncologic perspective on high-risk, aggressive therapy with 23 months of event-free-survival until she unfortunately passed prematurely due to complications from comorbid conditions. At the same time, her apparent positive response to therapy may represent the more indolent nature of neuroblastoma in older populations as long-term follow-up was not possible. Further research into tumor biology and characteristics is needed to better elucidate and guide treatment of adolescents and young adults with neuroblastoma
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