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 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: 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 < 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”.