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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