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\begin{document}

\title{An Unusual Case of Late Recurrence of MS Neuroblastoma in a Young Adult}



\author[1]{Alexis Boulter}%
\author[1]{Tanya Watt}%
\affil[1]{The University of Texas Southwestern Medical Center}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
This case describes an unusual presentation of a young adult with very
late recurrence of stage MS neuroblastoma over 20 years after initial
diagnosis. Tumor histology at relapse demonstrated ganglioneuromatous
foci within her undifferentiated tumor. In combination with evidence of
altered catecholamine metabolism, it proposes a case for
dedifferentiation of unresected ganglioneuromatous lesions as the
etiology of her recurrence of disease. An additional, compelling
component of the case is the overall positive treatment response of the
patient with relapsed neuroblastoma despite the poor prognostic factors
of late relapse and adult age.%
\end{abstract}%



\sloppy


-- An Unusual Case of Late Recurrence of MS Neuroblastoma in a Young
Adult

-- Children's Medical Center Dallas,\textsuperscript{1} University of
Texas Southwestern Medical Center\textsuperscript{2}

-- Alexis Chen Boulter\textsuperscript{1,2} and Tanya
Watt\textsuperscript{1,2}

-- Corresponding Author: Dr. Tanya Watt, Address: 1935 Medical District
Dr Dallas, TX 75235, Phone: 214-456-6363, Fax: 214-456-3593, Email:
Tanya.watt@utsouthwestern.edu

-- Word Count

Abstract: 91 words

Main Text: 1196 words

-- No Tables, Figures, Supporting Information files

-- Running Title: Late Recurrence of MS Neuroblastoma in a Young Adult

-- Keywords: Stage MS Neuroblastoma, Young Adult, Late recurrence,
Neuroblastoma

-- Abbreviation key:\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
INRGSS & International Neuroblastoma Risk Group Staging
System\tabularnewline
\midrule
\endhead
INSS & International Neuroblastoma Staging System\tabularnewline
VMA & Vanillylmandelic acid\tabularnewline
HMA & Homovanillic acid\tabularnewline
\textsuperscript{123}I-MIBG &
\textsuperscript{123}I-meta-iodobenzylguanidine\tabularnewline
VZV & Varicella zoster virus\tabularnewline
\bottomrule
\end{longtable}

-- No previously published papers

\emph{Abstract}

This case describes an unusual presentation of a young adult with very
late recurrence of stage MS neuroblastoma over 20 years after initial
diagnosis. Tumor histology at relapse demonstrated ganglioneuromatous
foci within her undifferentiated tumor. In combination with evidence of
altered catecholamine metabolism, it proposes a case for
dedifferentiation of unresected ganglioneuromatous lesions as the
etiology of her recurrence of disease. An additional, compelling
component of the case is the overall positive treatment response of the
patient with relapsed neuroblastoma despite the poor prognostic factors
of late relapse and adult age.

\emph{Introduction}

Neuroblastomas are neuroendocrine tumors which arise from neural crest
cells in the developing sympathetic nervous
system.\textsuperscript{1}Neuroblastoma is the most common extracranial
solid tumor in pediatric populations and the most common malignancy in
infancy.\textsuperscript{2} The patient described was staged IV-S by the
INSS definition and MS by the INRGSS definition. Stage MS is a distinct
pattern of disease in infants less than 18 months of age and
characterized by metastatic spread to the liver, skin, and limited bone
marrow involvement.\textsuperscript{3} Stage MS generally infers a good
prognosis with survival approximated at 70-90\% depending on clinical
and genetic favorability and frequently with the outcome of spontaneous
regression.\textsuperscript{4, 5} Late recurrence of neuroblastoma,
defined as recurrence greater than five years after diagnosis, is rare
occurring in 3.1\% of all cases and is associated with poor survival
outcomes.\textsuperscript{6,7} This case was compelling due to the
unusual presentation of a very late recurrence of neuroblastoma in a
young adult patient with history of stage MS disease and the overall
favorable treatment response of her relapsed disease.

\emph{Results}

A 20-year-old female with history of stage MS neuroblastoma presented
with three weeks of progressive mid-epigastric abdominal pain. Her
medical history was notable for stage MS neuroblastoma diagnosed at 7
weeks of age with clinical findings of abdominal distension and skin
nodules. At initial diagnosis, she had elevated VMA and HVA levels (291
mg/g and 212 mg/g) and \textsuperscript{123}I-MIBG avid disease. She was
staged MS with palpable skin nodules, right adrenal mass, and
\textless{}10\% marrow disease. The patient underwent 90\% resection of
retroperitoneal mass at 20 months with pathology demonstrating favorable
histology, N-MYC nonamplified and DNA index 1.2. She received
isotretinoin for 44 months due to multiple progressions with gradually
increasing size of residual retroperitoneal mass and delayed
catecholamine normalization. Stabilization of mass was achieved, but
catecholamines did not normalize until 175 months after diagnosis. She
had subsequently been followed in survivor clinic until presentation.

Computerized tomography imaging demonstrated an abnormal portacaval
node, a retroperitoneal mass with periportal extension, and a proximal
right femoral lesion. Fine-needle aspirate of the periportal mass
confirmed recurrent neuroblastoma. FISH showed N-MYC nonamplification,
and \textsuperscript{123}I-MIBG scan demonstrated avidity in tumor bed,
portocaval and paraaortic lymph nodes, T8 vertebra, and proximal right
femur. Urine VMA and HMA were 3.3 mg/g and 3.4 mg/g respectively. Bone
marrow biopsy was negative for disease. The patient was diagnosed with
stage M or stage IV neuroblastoma 20.5 years after initial diagnosis, a
very late recurrence.

She was initiated on high-risk neuroblastoma therapy per ANBL0532
protocol. Aggressive biopsy of retroperitoneal mass demonstrated
neuroblastic tumor with histologic evidence of early treatment response
versus ganglioneuromatous stroma with foci of maturing ganglions. She
underwent tandem autologous stem cell transplant and radiation with a
total of 2160 cGy to the vertebral bodies, right femoral head, and right
adrenal gland. Patient tolerated treatment well with reimaging
demonstrating stable \textsuperscript{123}I-MIBG uptake. Due to severe
VZV-esophagitis, TPN initiation was indicated, ultimately delaying
immunotherapy initiation. After stabilization of nutritional status, she
was treated per ANBL0032 with clearance of bone disease on
immunotherapy. End of treatment scans demonstrated no evidence of
metastatic disease and stabilization of retroperitoneal mass with
minimal \textsuperscript{123}I-MIBG positivity.

Patient's clinical course was complicated by severe liver fibrosis
secondary to transfusion-related iron overload. She endured recurrent
episodes of abdominal pain and ascitic fluid accumulation with eventual
peritoneovenous shunt placement. She unfortunately passed due to septic
shock and peritonitis suspected to be due to shunt dysfunction. This was
23 months and 19 days from achieved clinical remission of neuroblastoma
without evidence of disease progression.

\emph{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\%.\textsuperscript{5,
8}Relapse occurs in these patients but almost exclusively within the
first two years of diagnosis.\textsuperscript{8} To our knowledge, there
have been only two previously reported cases of late recurrence of MS
disease. \emph{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.\textsuperscript{9} The second case presented by \emph{Kato et al.}
\textsuperscript{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, \textsuperscript{123}I-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.\textsuperscript{11,12}

Similar to the case presented by \emph{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.\textsuperscript{13} The discrepancy in the
described patient's urinary catecholamine status from initial diagnosis
to relapse suggests a change in predominant catecholamine
metabolism.\emph{In vitro} studies have demonstrated that negative
catecholamine excretion signal less differentiated tumor secondary to
decreased tyrosine hydroxylase expression.\textsuperscript{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.\textsuperscript{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.\textsuperscript{16}The
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.\textsuperscript{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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