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\begin{document}

\title{Composite Adrenocortical Tumor and Neuroblastoma in an Infant with a
Heterozygous TP53 Germline Mutation}



\author[1]{John Rafael}%
\author[1]{Chibuzo O'Suoji}%
\affil[1]{Texas Tech University Health Sciences Center}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\begin{abstract}
Composite malignancy of both Li Fraumeni syndrome (LFS) associated
adrenocortical tumor (ACT) and neuroblastoma (NB) is extremely rare. We
report a 10-month-old boy with a right sided abdominal mass that, after
multiple resections, noted two separate tumors. The adrenal resection
revealed characteristics notable for an ACT; the para-aortic and pelvic
lymph nodes showed poorly differentiated NB. Additional analysis
revealed a wild-type TP53 expression pattern and negative MYCN
amplification, and germline testing revealed a heterozygous TP53
germline c.818G\textgreater{}A, pArg273His mutation, one only associated
with separate tumors. This composite NB and ACT is thus the first
reported in the literature.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Li Fraumeni syndrome (LFS) is characterized by TP53 mutations and
increases susceptibility to tumors, such as sarcoma, breast cancer,
brain tumors, and adrenocortical tumor (ACT)\textsuperscript{1}.
Neuroblastoma (NB) is the most common malignancy of the adrenal medulla
in infants and is notably associated with the MYCN gene amplification.
Composite malignancy in adrenal glands or other organs is extremely rare
and usually seen in adults; only a weak association between LFS and NB
has been reported.\textsuperscript{2,3} Simultaneous ACT and NB has only
been reported in six other cases, all with varying TP53 mutations.

\textbf{Case Report}

A 10-month-old Hispanic male born at 32 weeks with no significant past
medical history was seen in the ER for evaluation after he and his
father were involved in an all-terrain vehicle accident in which his
father lost his life. CT scan done at the emergency room did not reveal
any internal injury, however an incidental finding of a right-side
adrenal mass concerning for a NB was noted. (Fig. 1). An MIBG scan was
done which was avid in the pelvic and periaortic lymph nodes on the
right side; however, there was no uptake in right adrenal mass.

A biopsy of the mass and lymph nodes was done. Initial histology of the
adrenal mass was indeterminate while initial pathology of the lymph
nodes showed diffuse small blue cells throughout the specimen.
Fluorescence in situ hybridization (FISH) analysis of the right iliac
lymph node showed no evidence of MYCN amplification (Fig. 2). The
specimens were submitted for a second opinion. Results from the second
opinion showed that they were two distinct tumors. Sections of the
adrenal mass revealed a sheet-like pattern of growth with partially
retained thick fibrous capsule. The nuclei displayed pleomorphism and
hyperchromasia with scattered, peculiar nuclei; these findings are
consistent with diagnosis of an ACT. Analysis of the peri-aortic and
pelvic lymph nodes showed a different neoplasm composed of small round
blue cells with uniform nuclei and little cytoplasm.
Immunohistochemistry stained positive for chromogranin, synaptophysin,
PIIOX2B, tyrosine hydroxylase, S100 and CD56 and negative for CD45,
CD20, CD79a, CD3, MyoD, pancytokeratin, desmin, and TdT. Further
analysis revealed a wild-type TP53 expression pattern suggestive of a
poorly differentiated neuroblastoma.

Additional germline testing was performed on the patient which revealed
a heterozygous TP53 germline c.818G\textgreater{}A, pArg273His mutation.
The patient continues to be monitored and one year post diagnosis has
not showed any evidence of disease recurrence as he continues to reach
appropriate developmental milestones.

\textbf{Discussion}

Composite tumors in children are very rare and usually have no
definitive etiology. Many of them have been linked to TP53, a gene that
controls many cell cycle regulation pathways and thus is susceptible to
many germline mutations that have been identified. ACT in particular is
noted as closely related tumor to the TP53 gene
mutation.\textsuperscript{4} Very little evidence links NB to LFS.

Cases of LFS with multiple malignancies are numerous but are rarely
simultaneous.\textsuperscript{5} A handful of cases have reported
homozygous TP53 mutations with associated with ACT and NB, most of which
presented with unique presentations and TP53 gene
variations.\textsuperscript{6--9} One case did report a simultaneous ACT
and NB in an eight-month-old infant, but its germline p53 mutation was
not present in this patient.\textsuperscript{10} The variation in this
case is different from any previously cited in the literature. To
discern understanding links between ACT and NB in the context of TP53,
more cases are warranted.

The patient's particular mutation, c.818G\textgreater{}A, pArg273His, is
one that has only been cited twice, both due to different malignant
etiologies. One case report indicated a child with LFS with two separate
germline mutations, c.818G\textgreater{}A and c.814G\textgreater{}A,
leading to three separate malignancies presenting as early as four
months.\textsuperscript{11--13} Although none of the three malignancies
were either ACT or NB, it is notable that the c.818G\textgreater{}A
mutation is present in both cases. The mutation c.818G\textgreater{}A is
within the DNA binding domain of TP53 and prevents wild-type
transcriptional activity. This can inactivate the second allele,
granting gain-of-function properties that show a more aggressive
phenotype than mutations resulting in loss of TP53
expression.\textsuperscript{14} This may explain the early onset of the
compound tumor in this patient and literature reveals a near decade
earlier mean age of onset of primary cancer in LFS due to TP53 gene
missense mutations compared to TP53 deletions\textsuperscript{15}. The
other article indicated its pathogenicity, among many other mutations,
in cases of adult gastric type mucinous carcinoma.\textsuperscript{16}It
is noteworthy that c.818G\textgreater{}A, pArg273His has now been seen
in tumors in both pediatric and adult patients. Additional links between
the mutation and its various linked pathologies across the lifespan are
warranted but are out of the scope of this paper.

It is speculated that this germline mutation may be a factor in the
pathogenesis of this composite tumor and in composite adrenal
malignancies in general. Family cancer history also plays an important
clue for TP53 gene mutation screening due to LFS's autosomal dominant
inheritance, such analysis maybe indicated for the first-degree
relatives of this patient, and close monitoring is warranted for
subsequent LFS-related tumors in the patient.

We report a composite NB and ACT in an infant associated with a
heterozygous TP53 c.818G\textgreater{}A, pArg273His mutation, the first
of its kind. The mutation is pathogenic and may predispose carriers to
malignancies across the lifespan.

\textbf{Conflict Of Interest}

The authors declare that there is no relevant conflict of interest to
report.

\textbf{Acknowledgments}

We thank Dr. Hiroyuki Shimada and the pathologists at Stanford
Healthcare for their valuable second opinions about the tumors. We also
thank the geneticists at Gene Dx for their insights and NeoGenomics
Laboratories for their FISH analysis.

\textbf{References}

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3. Candanedo-Gonz\selectlanguage{ngerman}ález FA, Alvarado-Cabrero I, Gamboa-Domínguez A, et al.
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13. Zerdoumi Y, Aury\selectlanguage{english}-Landas J, Bonaiti\selectlanguage{english}-Pellie C, et al. Drastic Effect
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15. Bougeard G, Sesboue R, Baert-Desurmont S, et al. Molecular basis of
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doi:10.1136/jmg.2008.057570

16. Jung H, Bae GE, Kim HM, Kim HS. Clinicopathological and Molecular
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\textbf{Figure Legends}

Figure 1. MRI taken after initial CT scan showing the ``incidentaloma'',
indicating a mass later identified as an ACT

Figure 2. FISH analysis of right iliac lymph node showing no evidence of
MYCN amplification in the identified NB\selectlanguage{english}
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