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\begin{document}

\title{To Treat or Not to Treat? Facing Spontaneous Remission of a Neonatal
Malignant Mesenchymal Spindle-Cell Neoplasia}



\author[1]{Francesco Venturelli}%
\author[2]{Micol Babini}%
\author[2]{Francesco Toni}%
\author[2]{Mino Zucchelli}%
\author[3]{Marcello Stella}%
\author[4]{Alberto Righi}%
\author[5]{Fraia Melchionda}%
\author[5]{Andrea Pession}%
\affil[1]{University of Ferrara}%
\affil[2]{IRCCS Istituto Delle Scienze Neurologiche di Bologna}%
\affil[3]{AUSL della Romagna}%
\affil[4]{IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy}%
\affil[5]{IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico S Orsola-Malpighi}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
We report a case of malignant mesenchymal spindle-cell neoplasia of the
skull, diagnosed in a female newborn at 13 days of age by biopsy and
subtotal resection. Considering the good clinical condition, the age,
tumor histology and the risks associated with surgery and chemotherapy,
we proposed a ``wait and see'' approach with a close radiologic
monitoring of the tumor lesion. Surprisingly the tumor showed
spontaneous regression both at MRI and ultrasound evaluations. To date,
after 12 months of observation, MRI showed sustained remission: the
infant recovered from surgery and maintains good clinical condition
while follow-up is ongoing.%
\end{abstract}%



\sloppy


\textbf{TITLE} :

To Treat or Not to Treat? Facing Spontaneous Remission of a Neonatal
Malignant Mesenchymal Spindle-Cell Neoplasia.

\textbf{AUTHORS \& AFFILIATIONS:}

FrancescoVenturelli\textsuperscript{1}, Micol Babini\textsuperscript{2},
Francesco Toni\textsuperscript{3}, Mino Zucchelli\textsuperscript{2},
Marcello Stella\textsuperscript{4}, Alberto Righi\textsuperscript{5},
Fraia Melchionda\textsuperscript{6*}, Andrea Pession\textsuperscript{6}.

\textsuperscript{1} Pediatric Unit - Department of Medical Sciences,
University of Ferrara\textsuperscript{2} IRCCS Istituto delle Scienze
Neurologiche di Bologna, Pediatric Neurosurgery, Bologna,
Italia\textsuperscript{3}IRCCS Istituto delle Scienza Neurologiche di
Bologna, UOC di Neuroradiologia, Bologna, Italia\textsuperscript{4} U.O.
Pediatria e Terapia Intensiva Neonatale-Pediatrica, AUSL ROMAGNA
Cesena\textsuperscript{5} Department of Pathology, IRCCS Istituto
Ortopedico Rizzoli, Bologna, Italy\textsuperscript{6}Pediatric Unit -
IRCCS Azienda Ospedaliero-Universitaria di Bologna S.Orsola

\textbf{*CORRESPONDING AUTHOR:} Fraia Melchionda

Address: IRCCS Azienda Ospedaliero-Universitaria di BolognaS.Orsola Via
Massarenti 11, BLDG 13, Bologna 40138 Italy

Phone:+390512144688

Fax: +390512144675

E-Mail: fraia.melchionda@aosp.bo.it

\textbf{WORD COUNT:}

Abstract:100 words

Main Text: 995 words

\textbf{NUMBER OF FIGURES} : 2

\textbf{RUNNING TITLE:} Neonatal Spindle-Cell Neoplasia

\textbf{KEYWORDS:} Neonatal, oncology, mesenchymal neoplasia, skull,
spontaneous remission.

\textbf{Author Contributions:} Conceptualization, F.M. and A.P.; data
curation, F.V., F.M., F.T.; writing-original draft preparation, F.V. and
M.B.; writing-review and editing, A.P., F.M., M.Z.; supervision, A.P.,
M.S., A.R. All authors have read and agreed to the published version of
the manuscript

\textbf{LIST OF ABBREVIATIONS:}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{MRI} & \textbf{Magnetic Resonance Imaging}\tabularnewline
\midrule
\endhead
\textbf{CT} & \textbf{Computer Tomography}\tabularnewline
\textbf{PCR} & \textbf{Polymerase Chain Reaction}\tabularnewline
\textbf{FISH} & \textbf{Fluorescent In Situ
Hybridization}\tabularnewline
\textbf{FNCLCC} & \selectlanguage{ngerman}\textbf{FédérationNationaledes Centres de LutteContre
Le Cancer}\tabularnewline
\textbf{PNET} & \textbf{Primary Neuroectodermal Tumors}\tabularnewline
\textbf{SIOP} & \textbf{Society of Pediatric Oncology}\tabularnewline
\textbf{RMS} & \textbf{Rhabdomyosarcoma}\tabularnewline
\bottomrule
\end{longtable}

\textbf{ABSTRACT:~}

We report a case of malignant mesenchymal spindle-cell neoplasia of the
skull, diagnosed in a female newborn at 13 days of age by biopsy and
subtotal resection.

Considering the good clinical condition, the age, tumor histology and
the risks associated with surgery and chemotherapy, we proposed a ``wait
and see'' approach with a close radiologic monitoring of the tumor
lesion. Surprisingly the tumor showed spontaneous regression both MRI
and ultrasound evaluations.

To date, after 12 months of observation, MRI showed sustained remission:
the infant recovered from surgery and maintains good clinical condition
while follow-up is ongoing.

\textbf{MAIN TEXT:}

Case Description -

A full term female neonate born by vaginal delivery after regular
gestation showed a rapidly growing retroauricolar swelling after 5 days
of life, requiring hospitalization at 9 days of life. The newborn was
febrile with elevated phlogosis indexes, thus intravenous empiric
antibiotic therapy was started. The MRI and CT scan showed an expansive
lesion of the right petrous bone of unknown origin (Fig. 1). The images
were compared to those obtained from the fetal MRI performed during
gestation due to periventricular white matter increased echogenicity,
showing no in utero malformation.

At 13 days of life, a biopsy with subtotal resection of the lesion was
performed due to volume increase of the neoplasm, especially with
disruption of temporal bone and with cervical-lateral extension limiting
head and neck mobility. The surgeon described an ``encapsulated lesion
that reveals siero-hematic content''. Intraoperative pathology showed
spindle-cell malignant neoplasia.

Initial molecular analysis (PCR and FISH) resulted negative for
ETV6-NTRK3 translocation and \emph{USP6} gene rearrangements ruling out
the suspect of infantile fibrosarcoma and cranial fasciitis respectively
{[}1; 2{]}. Moreover tumor tissue was analyzed by next generation
sequencing to further identify strong fusions and oncogenetic isoforms
of the following genes: \emph{ALK CAMTA1, CCNB3, CIC, EPC1, EWSR1,
FOXO1, FUS, GLI1, HMGA2, JAZF1, MEAF6, MKL2, NCOA2, NTRK3, PDGFB, PLAG1,
ROS1, SS18, STAT6, TAF15, TCF12, TFE3, TFG, USP6, YWHAE} . The final
histologic diagnosis was ``malignant mesenchymal spindle-cell neoplasia,
grade 2 (according to FNCLCC classification {[}3;4{]})''

A multidisciplinary evaluation was carried out: looking at lack of
indication to proceed with chemotherapy regimens in this histology, the
strong therapy-related toxicity reported in the newborn and the
potentially mutilating radical surgery, we proposed a ``wait and see''
approach with a rigorous radiologic follow-up consisting of ultrasound
every 2 weeks and monthly MRI.

The evaluation at 2 months of life showed a significant volumetric
reduction (Figs. 2A and 2B). The lesion appeared confined in the right
petrous bone without any vascular involvement.

Since the first MRI showed spontaneous regression and considering the
good clinical conditions of the patient, we decided to further continue
the radiologic follow-up without other interventions.

MRI at 4 and 7 months of life confirmed the continuous spontaneous
regression of the lesion (Figs. 2C and 2F).

Next MRI is scheduled in two months; to date, the patient maintains good
clinical conditions and automatic acoustic evaluation shows no signs of
hearing damage so far.

Discussion -

Rapidly growing neonatal masses represent a great therapeutic challenge
for the physician: since they remain a rare occurrence, data about
treatments and protocols are scarce. Treatment decisions in the
infantile population must be evaluated carefully, especially in the
first months of life, since surgery sequelae, radiotherapy and
chemotherapy toxicity pose great concerns {[}5-6{]}.

Neonatal tumors encompass a heterogeneous group of diseases, ranging
from benign lesions (such as lymphatic malformations) to malignant
neoplasms (such as soft tissue sarcomas). More than 75\% of soft tissue
tumors diagnosed in the first year of life show a benign pathology, 10\%
are borderline lesions, and only 15\% show malignant characteristics
{[}7{]}. Malignant soft tissue sarcomas of the infancy are rare diseases
with an estimated incidence of 1.6/100.000 children \textless{} 1 year
of age {[}8{]}.

Although it might be difficult to obtain a precise characterization of
these tumors, it is important to identify soft tissue primary
neuroectodermal tumors (PNETs), as the prognosis of this particular
subset of non-Rhabdomyosarcoma (RMS) neoplasm is poor and may require
aggressive treatment {[}9{]}.

Previous reports from the Society of Pediatric Oncology (SIOP) Malignant
Mesenchymal Tumor Committee suggest that RMS is the most frequent
histology, with undifferentiated spindle-cell sarcomas representing a
small group of non-RMS histologic type {[}6{]}. The term
``undifferentiated sarcomas'' highlights the lack of specific
immunohistochemical and molecular features, and it has been used
extensively to identify a wide range of tumors with variable biology and
clinical behavior {[}10; 11{]}. Alaggio et al. suggested that
undifferentiated sarcomas might developed as a result of an arrested
maturation of the mesenchymal fibroblastic stem cell in its maturative
path towards fibroblast-myofibroblast-pericyte {[}11{]} but specific
molecular diagnostic markers are lacking and therapeutic approaches
might vary.

A recent case series highlights the favourable clinical course of
congenital undifferentiated sarcomas treated with surgery, chemotherapy
or a combination of the two, with four patients out of five alive
without recurrence after 1-11 years of follow-up {[}9{]}, but lacked
information about molecular analysis. However, spontaneous remission of
undifferentiated spindle-cell sarcomas is reported in past case series
{[}6{]} but since the number of patients is limited, choosing the
wait-and-see approach over the treatment could be a very difficult
decision. In our case molecular cytogenetic analysis and NGS studies
were particularly helpful to rule out most of the more aggressive tumor
histologies, making possible a wait and see approach.

Age at diagnosis has been considered as a potential favourable
prognostic factor for STS: past reports from the German Soft Tissue
Sarcoma Study Group showed that whilst children diagnosed with RMS in
the first year of life have a poor prognosis, other histologies show a
more favorable behavior in infants than in older children, with an
overall survival reported as high as 100\% for congenital fibrosarcoma
{[}12{]}. However, for non-RMS mesenchymal tumors, Orbach et al.
reported no statistically significant differences of the overall
prognosis between infants and older children {[}6{]}.

Another factor investigated in the literature that might correlate with
the outcome is primary anatomic site of the infantile undifferentiated
sarcomas: in their series, Alaggio et al. suggested that truncal
location correlates with aggressive clinical behaviour, whilst the
subset with fibrosarcoma-like characteristics that showed a favourable
outcome developed on the extremities {[}11{]}, with the only patient
diagnosed with undifferentiated sarcoma with less than one year at
diagnosis emerging from the extremities.

After almost one year of follow-up, our patient still maintains clinical
remission: even without a biological mechanism explaining the tumor
regression, we think it is important to share our experience with this
rare congenital neoplasm which confirms the need to keep in mind the
principle of ``primum non nocere''.

\textbf{CONFLICT OF INTEREST STATEMENT:}

The authors declare no conflict of interest.

\textbf{ACKNOWLEDGEMENTS:} We sincerely thank Gianni Bisogno, Hematology
and Oncology Division, Department of Women's and Children's Health,
University of Padova, Italy for clinical case discussion

\textbf{FUNDING:} This research received no external funding.

\textbf{REFERENCES:~}

1 - Paulson VA, Stojanov IA, Wasman JK, Restrepo T, Cano S, Plunkitt J,
Duraisamy S, Harris MH, Chute DJ, Al-Ibraheemi A, Church AJ. Recurrent
and novel USP6 fusions in cranial fasciitis identified by targeted RNA
sequencing. Mod Pathol. 2020 May;33(5):775-780. doi:
10.1038/s41379-019-0422-6. Epub 2019 Dec 11. PMID: 31827231.

2 - Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PH. Molecular
detection of the ETV6-NTRK3 gene fusion differentiates congenital
fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol.
2000 Jul;24(7):937-46.

3 - Costa J, Wesley RA, Glatstein E, Rosenberg SA. The grading of soft
tissue sarcomas. Results of a clinicohistopathologic correlation in a
series of 163 cases. Cancer. 1984 Feb 1;53(3):530-41. doi:
10.1002/1097-0142(19840201)53:3\textless{}530::aid-cncr2820530327\textgreater{}3.0.co;2-d.
PMID: 6692258.

4 - PDQ Pediatric Treatment Editorial Board. Childhood Soft Tissue
Sarcoma Treatment (PDQ\selectlanguage{ngerman}®): Health Professional Version. 2020 Dec 3. In:
PDQ Cancer Information Summaries {[}Internet{]}. Bethesda (MD): National
Cancer Institute (US); 2002-. Available
from:\emph{https://www.ncbi.nlm.nih.gov/books/NBK65923/}

5 - Campbell AN, Chan HS, O'Brien A, et al: Malignant tumours in the
neonate. Arch Dis Child 62:19-23, 1987

6- Soft Tissue Sarcoma or Malignant Mesenchymal Tumors in the First Year
of Life: Experience of the International Society of Pediatric Oncology
(SIOP) Malignant Mesenchymal Tumor Committee, D. Orbachte al, J Clin
Oncol 23:4363-4371.

7 - Cof\selectlanguage{english}fin CM, Dehner LP: Soft tissue tumors in \selectlanguage{english}first year of life: A
report of 190 cases. Pediatr Pathol 10:509-526, 1990

8 - Ferrari A, Orbach D, Sultan I, Casanova M, Bisogno G. Neonatal soft
tissuesarcomas. Semin Fetal Neonatal Med. 2012 Aug;17(4):231-238. doi:
10.1016/j.siny.2012.05.003. Epub 2012 May 25. PMID: 22633289.

9 - Sebire NJ, Ramsay AD, Levitt G, Malone M, Risdon RA. Aberrant
immunohistochemical expression in non-rhabdomyosarcoma soft tissue
sarcomas of infancy: retrospective review of clinical material. Pediatr
Dev Pathol. 2002 Nov-Dec;5(6):579-86. doi: 10.1007/s10024-002-0022-0.
Epub 2002 Oct 10. PMID: 12370769.

10 - Somers GR, Gupta AA, Doria AS, Ho M, Pereira C, Shago M, Thorner
PS, Zielenska M. Pediatric undifferentiated sarcoma of the soft tissues:
a clinicopathologic study. PediatrDevPathol. 2006 Mar-Apr;9(2):132-42.
doi: 10.2350/08-05-0098.1. Epub 2006 Jun 16. PMID: 16822084.

11 - Alaggio R, Bisogno G, Rosato A, Ninfo V, Coffin CM.
Undifferentiated sarcoma: does it exist? A clinicopathologic study of 7
pediatric cases and review of literature. Hum Pathol. 2009
Nov;40(11):1600-10. doi: 10.1016/j.humpath.2009.04.013. Epub 2009 Aug 3.
PMID: 19647855.

12 - Koscielniak E, Harms D, Schmidt D, et al: Soft tissue sarcomas in
infants younger than 1 year of age: A report of the German Soft Tissue
Sarcoma Study Group (CWS-81). Med Pediatr Oncol 17:105-110, 1989

\textbf{LEGENDS~}

Figure 1: CT scan images on axial (A) and coronal (B) planes. Partially
cystic, expansive lesion infiltrates and erodes the petrous bone,
extending with its more solid component, above the mastoid region,
inferiorly along the upper portion of the latero-cervical region (A and
B). The lesion extends intracranially, budging within the adjacent
portion of middle and posterior fossa. (C) Axial 3D T2 weighted-imaging
better highlights the inhomogeneous cystic content and the infiltration
of the posterior part of the bony labyrinth. (D) CT scan axial imaging
showing the removal of the mastoid part of the lesion, with air within
the surgical cavity (arrowhead).

Figure 2. Serial MR axial fat-saturated images T2 images at the
mid-level of the bony labyrinth (upper row) and slightly inferiorly
(lower row), performed 1 (A, B), 4 (C, D) and 7 (E, F) months after
surgery. The images clearly shows the significant volumetric reduction~
of the lesion (arrowheads) with ossification of the petrous bone and the
inner ear bony structure (dotted line in A and C).\selectlanguage{english}
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