Multidisciplinary management of congenital giant head and neck masses: Our experience and review of the literature

Accepted Manuscript Multidisciplinary Management of Congenital Giant Head and Neck Masses: our Experience and Review of The Literature

Michele Gaffuri, Sara Torretta, Elisabetta Iofrida, Giovanna Cantarella, Irene Maria Borzani, Fabrizio Ciralli, Edoardo Calderini, Ernesto Leva, Enrico Iurlaro, Fabio Mosca, Lorenzo Pignataro PII: DOI: Reference:

S0022-3468(18)30659-6 doi:10.1016/j.jpedsurg.2018.09.018 YJPSU 58889

To appear in:

Journal of Pediatric Surgery

Received date: Revised date: Accepted date:

16 February 2018 23 September 2018 25 September 2018

Please cite this article as: Michele Gaffuri, Sara Torretta, Elisabetta Iofrida, Giovanna Cantarella, Irene Maria Borzani, Fabrizio Ciralli, Edoardo Calderini, Ernesto Leva, Enrico Iurlaro, Fabio Mosca, Lorenzo Pignataro , Multidisciplinary Management of Congenital Giant Head and Neck Masses: our Experience and Review of The Literature. Yjpsu (2018), doi:10.1016/j.jpedsurg.2018.09.018

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ACCEPTED MANUSCRIPT Title: MULTIDISCIPLINARY MANAGEMENT OF CONGENITAL GIANT HEAD AND NECK MASSES: OUR EXPERIENCE AND REVIEW OF THE LITERATURE Michele Gaffuri1, Sara Torretta1, Elisabetta Iofrida1, Giovanna Cantarella1, Irene Maria Borzani2, Fabrizio Ciralli3, Edoardo Calderini4, Ernesto Leva5, Enrico Iurlaro6, Fabio Mosca3, Lorenzo Pignataro1

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Affiliations:

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1. Department of Otolaryngology and Head and Neck Surgery, Fondazione IRCCS Cà Granda

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Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy

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2. Radiology Unit Pediatric Division, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

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3. Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di

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Milano, Milan, Italy

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4. Pediatric Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

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5. Department of Pediatric Surgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

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6. Department of Obstetrics and Gynecology 'L. Mangiagalli', Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. Corresponding Author: Michele Gaffuri, MD, Department of Otolaryngology and Head and Neck Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Italy. Tel.: +39 0255032563; Fax: + 39 0250320248; e-mail: [email protected] Declaration of interest: None.

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ABSTRACT Background: Large fetal head and neck (HN) masses can be life-threatening at birth and postnatally due to airway obstruction. The two most frequent congenital masses that may obstruct the airway are lymphatic malformation (LM) and teratoma. The aim of this paper was to evaluate the results of our experience in the management of giant congenital HN masses and to conduct a literature review. Methods: The study involved a consecutive series of 13 newborns (7 females) affected by giant HN masses. Prenatal diagnosis was achieved by means of ultrasound (US) and fetal magnetic resonance imaging (MRI). Delivery was performed by means of EXIT procedure in case of radiological evidence of airway obstruction. In the post-natal period all feasible therapeutical options (surgery, sclerotherapy, medical therapy) were discussed and adopted by a multidisciplinary team. Twelve patients underwent surgery and one received Rapamycin for one month, with consequent surgical resection due to increasing size of the mass. Results: The histopathological diagnosis was LM in 11 cases and teratoma in 2 cases. Airway obstruction was solved in 11 cases; 2 LM patients required a tracheotomy because of persistent airway obstruction. Major complications were flap necrosis (one patient) and facial nerve palsy (2 cases). Recurrence occurred in 5 patients. Conclusions: The management of congenital HN masses is always challenging and necessarily requires an interdisciplinary approach. Current therapeutic options include surgery, sclerotherapy, medical therapy or a combination of them. When they are large enough to obstruct the airway, a patient-centred approach should guide timing and modality of treatment.

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Key words: head and neck; EXIT; prenatal diagnosis; lymphatic malformation; teratoma; airway. Level of evidence: IV Abbreviations 3D: three-dimensional; αFP: alpha fetoprotein; CE: contrast-enhanced; CT: computed tomography; EXIT: ex utero intrapartum treatment; GA: gestational age; HASTE: single shot half-Fourier TSE HD: high-definition; HN: head and neck; LM: lymphatic malformation; MRI: magnetic resonance imaging; NICU: Neonatal Intensive Care Unit; TrueFISP: true fast imaging with steady state precession; WB: whole body; US: ultrasonography; VEGF: vascular endothelial growth factor; VIBE; volumetric interpolated breath-hold examination.

ACCEPTED MANUSCRIPT 1. INTRODUCTION Large fetal head and neck (HN) masses can be life-threatening at birth and post-natally because of the risk of airway obstruction [1]. The two most frequent masses that may obstruct the airway are lymphatic malformations and teratomas [2,3]. Lymphatic malformations (LMs), which are cystic masses that can violate tissue planes, and

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compress or encase the airway, are due to the abnormal development of embryonic lymphatic

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vessels or jugular lymph sacs that fail to form connections with the venous system [4]. It is

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estimated that they occur in 1/1,775 live births, and are more frequent in the HN (45-52%) [5]. They are classified as macrocystic (>2 cm), microcystic (<2 cm), or mixed [6]. Congenital teratomas are

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less frequent (incidence 1/40,000), may be cystic or solid and contain calcifications, and are predominantly cervical (2-9% of all congenital teratomas) [7,8]. The masses can cause extrinsic

birth and leading to a high mortality rate.

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compression and significant anatomical distortion, thus making it impossible to ensure an airway at

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Prenatal diagnosis has greatly improved patient outcomes [9,10] as the use of high-definition (HD)

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ultrasonography (US) at the beginning of the second trimester and subsequent foetal magnetic resonance imaging (MRI) can signal the need to control a precarious airway at the time of delivery

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[11]. In such cases, ex utero intrapartum treatment (EXIT) involving a multidisciplinary team of otolaryngologists, neonatologists, paediatric surgeons, anaesthesiologists and maternal healthcare

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specialists can allow the airway to be secured at birth by means of direct laryngoscopy, rigid bronchoscopy or tracheotomy while the foetus is still receiving placental support [12]. Once the airway has been secured and the neonate’s clinical condition is stable, post-natal treatment is required as most HN malformations persist throughout life and grow proportionally with the patient. Post-natal whole-body (WB) MRI can reveal the involvement of surrounding sites and structures, and help in formulating a differential diagnosis [13]. The treatment of choice for cervical teratomas is surgical resection because of the possible presence of malignant foci [14] but, in the

ACCEPTED MANUSCRIPT case of LMs, treatment decisions are more complex as they depend on the patient’s symptoms, the clinical presentation, size and location of the cyst, and possible functional complications [15]. The aim of this paper is to describe the multidisciplinary management of neonates with congenital

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HN masses treated at Milan’s Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico.

ACCEPTED MANUSCRIPT 2. PATIENTS AND METHODS The study involved 13 neonates (seven female) with pre- or perinatally detected giant HN masses who were treated at Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico in Milan, Italy, between January 2009 and September 2017. The data collected from their clinical records included their demographic characteristics, the time of

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diagnosis, the tumour site, the presence of airway obstruction, pre- and post-natal imaging findings,

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therapeutic management and outcomes, histopathology, complications, the duration of follow-up,

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recurrences and secondary treatments. The exclusion criterion was the appearance of an HN mass more than three months after birth. Two patients affected by a neck mass, in both cases located

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in the nuchal region and become evident respectively at four and six months, were excluded from our series.

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2.1 Prenatal management

HD US (Voluson E8 RAB 4-8 transducer, GE Medical Systems, Milwaukee, WI) was used for the

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prenatal examinations. In the case of evidence of an HN mass, an ultra-fast foetal MRI (Fig. 1a)

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scan was recorded by the 34th week of gestation using a WB 1.5 Tesla superconducting unit with actively shielded imaging gradients (MAGNETOM Avanto 1.5T: Siemens Medical Solutions,

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Malvern, PA) and a six-channel, phased array body and spine coil. Each examination consisted of coronal, axial and sagittal T2-weighted (T2w) images obtained using a single shot half-Fourier TSE

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(HASTE) sequence and coronal, axial and sagittal T1-weighted (T1w) images (VIBE- volumetric interpolated breath-hold examination). In addition, we applied a three-dimensional (3D) T2weighted balanced steady state sequence (TrueFISP) in the sagittal plane to study the airways and the findings were used to plan elective EXIT for the patients with suspected airway deviation/obstruction/compression (Fig.1b) and/or the involvement of the oral floor and/or tongue base. 2.2 Delivery

ACCEPTED MANUSCRIPT The EXIT procedure [1] was performed under deep maternal general anaesthesia, and consisted of a wide low transverse laparotomy at least 6 cm from the placental edge revealed by sterile intraoperative US. After hysterotomy, the fetal head, upper torso and one arm were exteriorised, whereas the rest of the body remained within the uterine cavity in order to maintain uterine volume and foetal temperature.

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Once the head had been exposed, the cervical mass was assessed in order to determine the

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appropriate means of securing the airway: the operative sequence was: a) direct laryngoscopy with

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intubation (Fig.1c); b) rigid bronchoscopy with intubation; and c) surgical tracheotomy. Once the airway had been secured, the umbilical cord was clamped and the baby delivered. After delivery,

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the patients were transferred to our Neonatal Intensive Care Unit (NICU). 2.3 Post-natal management

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Once the neonates’ clinical condition had stabilised (Fig.2a), a post-natal assessment was made within the first week of life using contrast-enhanced (CE) WB MRI (MAGNETOM Avanto 1.5T,

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Siemens Medical Solutions). The scans included: coronal T2w SPACE 3D sequence to reconstruct

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the cervical mass (Fig.2b), axial STIR sequence and T2w sequences in the three orthogonal planes to determine the presence of adipose tissue and the volume of the mass, which was calculated by

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measuring the greatest dimensions on the transverse (T), anterior-posterior (AP), and longitudinal (L) axes and using the ellipsoid volume formula 25 V= (T×AP×L)/2; and axial T1w VIBE sequence

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before and after intravenous contrast medium administration to determine if the malformation was lymphatic, venous or mixed and to reconstruct the cervical vessel tree (Fig.2c). On the basis of the baby’s clinical condition and the size, location and anatomical extension, cyst size, and differential diagnosis of the mass, the feasible therapeutic options (surgery, sclerotherapy, medical therapy, or watchful waiting) were described to the parents at a post-natal counselling session in order to explain the aims, limitations and possible complications of each. Surgery (complete mass excision using a cervical approach whenever possible, or debulking if the mass occupied different planes and radical resection was infeasible) was considered for teratomas

ACCEPTED MANUSCRIPT or LMs responsible for airway obstruction with no chance of endotracheal (ET) removal, or if the mass was rapidly growing. Sclerotherapy was considered in case of isolated, non-enlarging macrocystic LMs; i.e US-guided percutaneous cysts aspiration by means of a 16–25 gauge needle and the subsequent injection of a pro-inflammatory substance (i.e.: OK-432/Picibanil). Subsequently this treatment requires the

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injection of an approximate equal volume of OK-432 (10 mg/mL of saline, maximum 20 mL) [15].

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Medical therapy was considered for stable, non-growing LMs not involving the deep structures in

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spontaneously breathing patients: i.e. the twice daily oral administration of Rapamycin 0.8 mg/m 2 (target serum levels 10-15 ng/mL), an mTOR inhibitor whose anti-angiogenic activity impairs

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vascular endothelial growth factor (VEGF) function [16]. Patients are clinically re-assessed one month after treatment, with WB-MRI being considered in selected cases. If this documents that

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there has been no change in the volume and/or effects of the mass, the patients undergo surgery. After discharge, the patients were clinically re-examined one week, one month and six months later,

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and then every year in order to check the course of wound healing and the absence of a recurrence.

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In the case of teratomas, the patients were monitored every six months using alpha fetoprotein (αFP): levels of >10 ng/L were considered as justifying the suspicion of recurrent or metastatic

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performed.

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disease. In a recurrence was suspected, in both cases an imaging assessment by means of MRI was

In the case of any clinical or radiological evidence of a recurrence, individualised secondary adjunctive surgery/medical therapy was planned.

ACCEPTED MANUSCRIPT 3. RESULTS Table 1 shows the data concerning diagnosis, management and delivery of the 13 patients. 3.1 Prenatal management Eight of the 13 pregnancies (62%) were followed at our hospital, four patients (31%) were transferred to us soon after birth; and one pregnancy (7%) was not followed at all. All but this last

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foetus were assessed by means of serial US. The prenatal diagnosis of seven of the eight cases

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followed at our hospital was made at a median gestational age (GA) of 23 weeks (range 20–29); the

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diagnosis was made at birth or within a few hours of delivery in the remaining cases. All of the patients had a normal karyotype. One case was a twin gestation, and the foetus with the cervical

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mass presented with Prader-Willi syndrome.

Seven of the US-positive patients underwent mid-gestation ultrafast foetal MRI at a median GA of

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32 weeks (range 24-34): five studies showed macrocystic lesions and two mixed macro- and microcystic lesions. Six lesions were located on the left side and one on the right. Airway

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obstruction (tracheal narrowing and deviation) was visible in five cases; no intraluminal

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involvement was detected. Three foetuses developed polyhydramnios. 3.2 Delivery

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Eight patients were delivered by caesarean section at a median GA of 36 weeks (range 34–39). Five patients underwent elective EXIT at a median gestational age of 36 weeks (range 35-37): three

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late preterm (GA 35 weeks) due to polyhydramnios, one of whom had bilateral pleural effusion requiring bilateral chest tube placement, and two at term (GA 37 weeks). In all cases, the airway was successfully accessed by direct laryngoscopy. No maternal or neonatal deaths occurred, and maternal blood loss was 500-800 mL in all cases. Five patients were delivered vaginally at a median GA of 38 weeks (range 37-39). Two developed respiratory distress soon after birth, underwent subsequent ET intubation, and were transferred to our NICU. 3.3 Post-natal management

ACCEPTED MANUSCRIPT Table 2 shows the clinical presentations and post-natal diagnostic assessments. Seven patients showed airway obstruction with no chance of ET removal, and six rapidly increasing mass volume due to intralesional haemorrhaging. Post-natal, CE WB-MRI revealed a median mass volume of 186 mL (range 82-327). The MRI findings of multi-loculated cystic suggested a LM in 11 cases and a teratoma in two cases.

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The LMs were classified as macrocystic (diameter >2 cm and <5 cysts) in eight cases, and mixed in

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four (multiple cysts of any size with solid elements containing microscopic channels). Table 3 shows the treatments and outcomes. Twelve patients underwent surgical resection within 15 days of

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birth, and one received rapamycin 0.8 mg/m2 twice daily for one month (target serum level 10-15

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ng/mL) but, as post-treatment CE WB-MRI showed that mass volume had increased, the patient subsequently underwent surgical resection. The histopathological diagnosis confirmed the pre-

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treatment MRI findings of seven macrocystic (Fig.3a, 3b. 3c) and four mixed LMs, and two mature teratomas (Fig.4a, 4b, 4c). During the median 45-month follow-up (range 1-120 months), 4 of the

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11 patients with LM experienced a recurrence (three cases of epiglottic and aryepiglottic fold cysts

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partially obstructing the airway, excised by means of CO2 laser direct laryngoscopy, which led to complete recovery; and one microcystic recurrence in the neck, treated with Rapamicyn – treatment

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still ongoing), as did one teratoma patient. All of the other patients are still disease free.

ACCEPTED MANUSCRIPT 4. DISCUSSION In line with previously published epidemiological data [10], most of our patients with large HN masses causing airway obstruction had cervical LMs (85%), and two (15%) had mature teratomas. Their median post-natal volume was 186 mL (range 82-327 mL), thus suggesting their description as “giant” masses, according to other cases previously reported in literature [17, 18].

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The management of such masses should begin with an early prenatal diagnosis, which was made by

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means of US during seven of the eight pregnancies followed at our hospital at a median GA of 23

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weeks (range 20-29). Prenatal US can identify foetuses at risk by visualising a cervical mass, but its full extent may not be clear because of the difficulty of directly visualising the larynx and trachea

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[19] although signs such as polyhydramnios, decreased swallowing and tongue protrusion may indirectly suggest airway obstruction [20]. However, fetal MRI can characterise congenital lesions

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with unprecedented detail [21] by precisely determining the extent of the mass toward the oral floor, tongue base or mediastinum and, very importantly, the presence of deep cervical extensions

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potentially obstructing the airway at birth. Moreover, the advent of faster MRI scanning techniques

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has significantly decreased movement artefacts, and T2w sequences provide excellent contrast resolution of the foetal airway as the trachea is filled with high-signal fluid [22].

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Our seven fetal MRI examinations revealed tracheal narrowing and deviation in five cases, and no intraluminal pathology. Of the other six cases, one whose pregnancy was followed at our hospital

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had a mature teratoma with retropharyngeal and retro-laryngeal development that appeared in the right sub-mandibular region a few hours after birth and caused respiratory distress; four followed at other hospitals were diagnosed as having rapidly growing masses at birth, and were subsequently transferred to our NICU; the sixth was not followed at all during pregnancy. Eight patients (62%) were delivered by caesarean section, and six (48%) were delivered vaginally. Prenatal imaging was critical in determining that the benefits of EXIT were not outweighed by potential maternal risks or possible long-term consequences: five elective procedures were performed and allowed successful, laryngoscope-guided, ET access to the neonatal airway. A

ACCEPTED MANUSCRIPT relatively high proportion (23%) of patients developed polyhydramnios secondary to upper digestive tract obstruction and impaired swallowing of amniotic fluid [1], all of whom were delivered at a GA of 35 weeks. Two cases did not undergo EXIT: the first was part of a twin gestation, delivered by means of a standard caesarean section, and successfully intubated; the second had a LM on the right posterior-lateral side of the neck not compressing the airway.

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There were no EXIT-related complications or neonatal deaths. Laje et al. [1] reported a 23%

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mortality rate in a series of 17 teratoma-related EXIT procedures after placental detachment due to

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severe pulmonary hypoplasia, and Macarthur [23] has noted that the EXIT-related mortality increases to >36% when cervical congenital malformations are associated with chromosomal

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abnormalities. All of our EXIT procedures involved patients with LMs and no neonatal death occurred. There were also no neonatal deaths among the patients who did not undergo EXIT,

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although two required urgent ET intubation because of respiratory distress; this result is very different from the experience of Neidich et al. [24], who reported a mortality rate of approximately

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80%.

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Like other soft tissue masses, congenital HN malformations are best evaluated postnatally by means of MRI [21] as their high fluid content clearly distinguishes them from normal anatomical structures

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in T2-weighted sequences. All of our radiological diagnoses were histologically confirmed, thus supporting the view that radiology can avoid the risks of infection and misdiagnosis associated with

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surgical biopsies [22]. Furthermore, the use of a 3D MRI reconstruction algorithm allowed a preoperative assessment of the relationships between the mass and the underlying nervous and vascular structures [25], thus making it possible to avoid potentially fatal complications during surgery. Twelve (92%) of our patients underwent surgery as their primary treatment. While surgery is the only therapeutic option in the case of congenital teratoma [26] considering the 10% risk of malignant foci or degeneration [14] and 80-100% mortality rate among cases not treated surgically, there is currently insufficient published evidence to create treatment decision-

ACCEPTED MANUSCRIPT making algorithms for LMs [13]. Historically surgery has been the standard therapeutic choice for LMs, but the risk of functional (damage of blood vessels and nerves) and aesthetic damage, together with high rates of recurrence secondary to incomplete excision, led to the development of alternative approaches. In particular, recent evidence has shown that LMs respond very well to percutaneous sclerotherapy: Cahill et al. [27] and Burrows et al. [28] have

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respectively reported 76% (11/17 patients), and 83% cases of reduction (41/60 patients). In general

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macrocystic lesions are more responsive to any sclerotherapy agent than microcystic or mixed

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lesions, with reported response rates between 88-100% using agents such as doxycycline, OK432, and bleomycin [27]. This technique is precise, minimally invasive and safe, with lower

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recurrence and morbidity rates than surgery [28,29]; it can also be used in combination with surgical excision in case of failure of the primary treatment [30,31]. In our series, seven out of

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11 LM patients (64%) had macrocystic lesions and four (36%) had mixed lesions, and could have theoretically been treated by means of sclerotherapy; however, all the masses were large and

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deep with areas that were inaccessible to intralesional injection of sclerosing agents. This

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condition, together with the impossibility of ET removal due to airway obstruction and rapid mass growth, led us to choose surgery, a decision that was always made by a multidisciplinary

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team of otolaryngologists, paediatric surgeons, neonatologists, radiologists and anaesthesiologists. The parents undergo pre-surgical counselling in order to inform them about functional risks

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(damage to veins, arteries or cranial nerves embedded within the mass), the risks of aesthetic deformity or recurrence even after almost total resection, and therapeutic alternatives. Another alternative is medical treatment, and Rapamycin (a serine/threonine kinase regulated by phosphoinositide-3-kinase that acts on mTOR and inhibits VEGF-C) has proved to be effective in treating LMs [16,24,32]. Strychowsky et al. [29] successfully used sirolimus as primary treatment in 17 patients, and suggested that responses may be better in macrocystic than mixed or microcystic LMs, and in younger patients. We used Rapamycin in the primary treatment of one mixed LM that rapidly grew to a stable size without any associated symptoms although, after one month, an MRI

ACCEPTED MANUSCRIPT scan showed further enlargement and so the patient underwent secondary surgery. The main symptoms (airway obstruction and mass enlargement) were solved in all but two patients (15%) who were respectively treated for a mixed cervical and suprahyoid LM. Total resection was not possible in either case because of microcystic infiltration of the oral floor and intrinsic muscles of the tongue and, as ET removal failed, the patients underwent tracheostomy plus gastrostomy. Both

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patients were born after undergoing EXIT and thus accounted for 40% of the five patients

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undergoing this procedure, which is substantially in line with the conclusion of Laje et al. [1] that

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50% of patients surviving EXIT require tracheostomy before one month of age, and that at least half of these require a permanent tracheostomy.

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In one of these two patients, rapid postnatal growth of the mass secondary to intralesional bleeding caused the subcutaneous layer to become very thin, lose its vascular support, and necrotise one

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week after surgery, thus requiring reconstruction by means of a double myocutaneous pectoralis flap to close the tissue defect. This confirms that mixed or microcystic LMs are more difficult to

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treat than macrocystic LMs and burdened with a high rate of morbidity [31,32]. Functional

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complications occurred in three cases (23%): two patients suffered permanent facial nerve palsy after surgery, and one recurrent transient nerve palsy that resolved in one month. Elluru et al. [13]

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have shown that lymphatic malformations can largely displace or completely embed nervous structures, leading to a high risk of surgical damage. Our results are in line with those of Lerat et al.

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[33], who reported two cases of facial nerve palsy and three cases of aesthetic deformity in a series of 23 patients with LMs.

The rate of LM recurrence (46%) is in line with previous findings [27]: Benazzou et al. [34] reported a >50% rate of recurrences of extensive, poorly demarcated and widespread microcystic LMs, and Elluru et al. [13] a 30% rate of persistence in patients with large cervical masses that had undergone gross excision. Brodsky et al. [35] encountered just one recurrence in a series of 14 patients with congenital teratomas over a period of 41 years, thus suggesting that residual disease is rare and that complete

ACCEPTED MANUSCRIPT surgical excision has an excellent prognosis. One of our patients with a mature teratoma experienced a persistence of pathology in the left infratemporal space due to the infiltrative nature of the lesion, and was treated in another centre by means of surgical revision and reconstruction

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with an anterolateral thigh free flap.

ACCEPTED MANUSCRIPT 6. CONCLUSIONS The management of congenital HN masses is always challenging and necessarily requires an interdisciplinary approach. When they are large enough to obstruct the airway, a patient-centred approach should guide timing and modality of treatment. Current therapeutic options include surgery, sclerotherapy, medical therapy or a combination of them. Large controlled trials are

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needed to assess the optimal management of such conditions and the effectiveness and safety of

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alternative therapeutic procedures.

ACKNOWLEDGMENTS: MG, ST and LP conceived the paper. MG and EI performed

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acquisition of the data. MG performed the analysis of the data. MG and ST drafted the manuscript. GC, EC, EL, IB, EI, FC, FM, LP participated in paper coordination and critically revised the

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manuscript for important intellectual contents. All the authors read and approved the final

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manuscript.

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REFERENCES 1. Laje P, Peranteau WH, Hedrick HL, Flake AW, Johnson MP, Moldenhauer JS, Adzick NS. Ex utero intrapartum treatment (EXIT) in the management of cervical lymphatic malformation. J Pediatr Surg. 2015;50(2):311-4. 2. Ryan G, Somme S, Crombleholme TM. Airway compromise in the fetus and neonate: Prenatal assessment and perinatal management. Semin Fetal Neonatal Med. 2016;21(4):230-9. 3. Moldenhauer JS. Ex Utero Intrapartum Therapy. Semin Pediatr Surg. 2013;22(1):44-9. 4. Hochman M, Adams DM, ReevesTD. Current knowledge and management of vascular anomalies, II: malformations. Arch Facial Plast Surg. 2011;13(3):425–433 5. Howarth ES, Draper ES, Budd JL, Konje JC, Clarke M, Kurinczuk JJ. Population based study of the outcome following the prenatal diagnosis of cystic hygroma. Prenatal Diagn 2005;25:286-91. 6. Benazzou S, Boulaadas M, Essakalli L. Giant pediatric cervicofacial lymphatic malformations. J Craniofac Surg. 2013;24(4):1307-9. 7. Forrester MB, Merz RD. Descriptive epidemiology of teratoma in infants, Hawaii, 1986-2001. Paediatr Perinat Epidemiol 2006;20:54-8. 8. G. Tonni, C. De Felice, G. Centini, C. Ginanneschi, Cervical and oral teratoma in the fetus: a systematic review of etiology, pathology, diagnosis, treatment and prognosis. Arch. Gynecol. Obstet. 2010;282(4):355-361. 9. Zieliński R, Respondek-Liberska M. The role of prenatal ultrasound assessment in management of fetal cervicofacial tumors. Arch Med Sci. 2016;12(4):850-5. 10. Tranvinh E, Yeom KW, Iv M. Imaging neck masses in the neonate and young infant. Semin Ultrasound CT MR. 2015;36(2):120-37. 11. Wataganara T, Ebrashy A, Aliyu LD, Moreira de Sa RA, Pooh R, Kurjak A, Sen C, Adra A, Stanojevic M. Fetal magnetic resonance imaging and ultrasound. J Perinat Med. 2016;44(5):53342. 12. O TM, Rickert SM, Diallo AM, Scheuermann-Poley C, Otokiti A, Hong M, Chung HY, Waner M. Lymphatic malformations of the airway. Otolaryngol Head Neck Surg. 2013;149(1):156-60. 13. Elluru RG, Balakrishnan K, Padua HM. Lymphatic malformations: diagnosis and management. Semin Pediatr Surg. 2014;23(4):178-85. 14. Hasiotou M, Vakaki M, Pitsoulakis G, Zarifi M, Sammouti H, Konstadinidou CV, Koudoumnakis E. Congenital cervical teratomas. Int J Pediatr Otorhinolaryngol. 2004;68(9):11339. 15. Tu JH, Do HM, Patel V, Yeom KW, Teng JMC. Sclerotherapy for lymphatic malformations of the head and neck in the pediatric population. J Neurointerv Surg. 2017;9(10):1023-1026. 16. Amodeo I, Cavallaro G, Raffaeli G, Colombo L, Fumagalli M, Cavalli R, Leva E, Mosca F. Abdominal cystic lymphangioma in a term newborn: A case report and update of new treatments. Medicine (Baltimore). 2017;96(8). 17. Gezer HÖ, Oğuzkurt P, Temiz A, Bolat FA, Hiçsönmez A. Huge Neck Masses Causing Respiratory Distress in Neonates: Two Cases of Congenital Cervical Teratoma. Pediatr Neonatol. 2016;57(6):526-530. 18. Liechty KW, Hedrick HL, Hubbard AM, Johnson MP, Wilson RD, Ruchelli ED, Howell LJ, Crombleholme TM, Flake AW, Adzick NS. Severe pulmonary hypoplasia associated with giant cervical teratomas. J Pediatr Surg. 2006;41(1):230-3. 19. Mirsky DM, Shekdar KV, Bilaniuk LT. Fetal MRI: head and neck. Magn Reson Imaging Clin N Am. 2012;20(3):605-18. 20. Zieliński R, Respondek-Liberska M. The role of prenatal ultrasound assessment in management of fetal cervicofacial tumors. Arch Med Sci. 2016;12(4):850-5. 21. Kathary N, Bulas D, Newman KD, Schonberg RL. MRI imaging of fetal neck masses with airway compromise: utility in delivery planning. Pediatr Radiol. 2001;31(10):727-31.

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22. Herruela-Suffee C, Warin M, Castier-Amouyel M, Dallery F, Bonnaire B, Constans JM. Wholebody MRI in generalized cystic lymphangiomatosis in the pediatric population: diagnosis, differential diagnoses, and follow-up. Skeletal Radiol. 2016;45(2):177-85. 23. MacArthur CJ. Prenatal diagnosis of fetal cervicofacial anomalies. Curr Opin Otolaryngol Head Neck Surg 2012;20:482–90. 24. Neidich MJ, Prager JD, Clark SL, Elluru RG. Comprehensive airway management of neonatal head and neck teratomas. Otolaryngol Head Neck Surg 2011;144: 257–61. 25. Renjen P, Kovanlikaya A, Narula N, Brill PW. Importance of MRI in the diagnosis of vertebral involvement in generalized cystic lymphangiomatosis Skeletal Radiol. 2014;43(11):1633-8. 26. Alexander VR, Manjaly JG, Pepper CM, Ifeacho SN, Hewitt RJ, Hartley BE. Head and neck teratomas in children--A series of 23 cases at Great Ormond Street Hospital. Int J Pediatr Otorhinolaryngol. 2015;79(12):2008-14. 27. Cahill AM, Nijs E, Ballah D, Rabinowitz D, Thompson L, Rintoul N, Hedrick H, Jacobs I, Low D. Percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations: a single center experience. J Pediatr Surg. 2011;46(11):2083-95. 28. Burrows PE, Mitri RK, Alomari A, Padua HM, Lord DJ, Sylvia MB, Fishman SJ, Mulliken JB. Percutaneous sclerotherapy of lymphatic malformations with doxycycline. Lymphat Res Biol. 2008;6(3-4):209-16. 29. Strychowsky JE, Rahbar R, O'Hare MJ, Irace AL, Padua H, Trenor CC 3rd. Sirolimus as treatment for 19 patients with refractory cervicofacial lymphatic malformation. Laryngoscope. 2017 [Epub ahead of print] 30. Defnet AM, Bagrodia N, Hernandez SL, Gwilliam N, Kandel JJ. Pediatric lymphatic malformations: evolving understanding and therapeutic options. Pediatr Surg Int. 2016;32(5):42533. 31. Bagrodia N, Defnet AM, Kandel JJ. Management of lymphatic malformations in children. Curr Opin Pediatr. 2015;27(3):356-63. 32. Amodeo I, Colnaghi M, Raffaeli G, Cavallaro G, Ciralli F, Gangi S, Leva E, Pignataro L, Borzani I, Pugni L, Mosca F The use of sirolimus in the treatment of giant cystic lymphangioma. Medicine 2017;96:51(e8871) 33. Lerat J, Mounayer C, Scomparin A, Orsel S, Bessede JP, Aubry K. Head and neck lymphatic malformation and treatment: Clinical study of 23 cases. Eur Ann Otorhinolaryngol Head Neck Dis. 2016;133(6):393-396. 34. Benazzou S, Boulaadas M, Essakalli L. Giant pediatric cervicofacial lymphatic malformations. J Craniofac Surg. 2013;24(4):1307-9. 35. Brodsky JR, Irace AL, Didas A, Watters K, Estroff JA, Barnewolt CE, Perez-Atayde A, Rahbar R. Teratoma of the neonatal head and neck: A 41-year experience. Int J Pediatr Otorhinolaryngol. 2017;97:66-71.

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Figure 1. a) Prenatal MRI of a patient obtained at 33 weeks gestation: coronal T2-weighted image demonstrates a large multicystic mass on the right side of the neck (asterisk), compressing the airway. b) The antero-posterior diameter of the compressed trachea (white arrow) can be evaluated on sagittal images c) Ex-utero intrapartum treatment (EXIT) of the fetus by means of direct laryngoscopy. Figure 2. a) A picture and b) coronal T2-weighted MRI image of a seven–days-old neonate affected by a left giant multicystic cervico-facial mass. c) A 3D MRI reconstruction shows the relationship between the mass, airway and vascular structures. d) A picture and e) coronal T2- weighted MRI image and f) a 3D MRI reconstruction of a 10–days-old neonate affected by a bilateral suprahyoid giant multicystic cervico-facial mass. Figure 3. a) Picture of a 10-days-old neonate affected by a mixed left neck lymphatic malformation. b) Surgical removal of the mass; the mass was extremely infiltrating deep spaces of the neck c) The patient eight years after surgery, a scar is visible on the left neck. Figure 4. a) Picture of a 10-days-old female patient affected by a large left cervico-facial multicystic mass. b) Surgical removal of the mass. c) Definitive histopathological diagnosis was mature teratoma.

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TABLES Table 1. Fetuses with congenital head and neck malformations. M: male. F: female. GA: gestational age. EXIT: ex utero intrapartum treatment. Table 2. Clinical presentation and post-natal diagnostic assessment of congenital head and neck masses. Table 3. Treatments and outcomes of neonatal patients with congenital head and neck malformations.

ACCEPTED MANUSCRIPT Table I: Fetuses with congenital head and neck malformations. M: male. F: female. GA: gestational age. EXIT: Ex utero Intrapartum Treatment.

Yes

Macrocys tic

Yes

No

-

No

-

No

No

M 2009 Birth

-

No

-

No

F 2013 Birth

-

No

-

No

2

F 2009 Birth

3

4

cesare an

Yes

37

cesare an

No

38

No

vaginal

No

38

No

No

vaginal

No

37

No

No

RI

F 2009

PT

Prenat 25 al

1

GA at Associated Deliver birth EXIT malformations y (week s)

SC

GA at Time Fet diagn Patie Se of al Mass Polyhydram Hydro Year osis nt x diagn MR feature nios ps (week osis I s)

Macrocys tic

No

-

Prader -Willi Syndrome

No

No

No

vaginal

No

37

Yes

No

No

cesare an

Yes

35

No

No

No

vaginal

No

38

Yes

No

No

cesare an

Yes

35

Macrocys tic

No

No

No

cesare an

No

39

Macrocys tic

Yes

No

No

cesare an

Yes

35

Yes Mixed

No

No

No

cesare an

Yes

37

No

No

No

No

vaginal

No

38

7

M 2014

8

M 2014 Birth

9

M 2015

Prenat 20 al

Yes Mixed

10

M 2015

Prenat 26 al

Yes

11

F 2017

Prenat 20 al

Yes

12

F 2017

Prenat 21 al

13

F

2017

Birth

PT E Yes

Macrocys tic

CE -

D

M 2013 Birth

-

NU No

6

Prenat 29 al

No cesare (twins 34 an gestatio n)

No

F 2013

-

MA

Yes

5

AC

Prenat 24 al

No

No

-

-

ACCEPTED MANUSCRIPT Table II: Clinical presentation and post-natal diagnostic assessment of congenital head and neck masses. mL: millilitres. Main Symptoms Site

Volume (mL)

223

Yes

-

MRI

Lymphangioma

Left anterolateral neck, mediastinum

2

Yes

-

MRI

Teratoma

Left infratemporal space, left anterolateral neck

172

3

-

Yes

MRI

Lymphangioma

130

4

-

Yes

MRI

Lymphangioma

5

-

Yes

MRI

6

-

Yes

MRI

7

Yes

-

8

Yes

-

9

Yes

10

-

11

Yes

RI

PT

1

SC

Patien Airway Increasin Post-natal Radiological t Imaging diagnosis Obstructi g on Volume

NU

Left anterolateral neck

194

Lymphangioma

Left anterolateral neck

129

Lymphangioma

Left anterolateral neck

82

PT E

D

MA

Right anterolateral neck

Lymphangioma

Left neck, mediastinum

327

MRI

Lymphangioma

Bilateral suprahyoid neck

166

-

MRI

Lymphangioma

Left anterolateral neck

194

Yes

MRI

Lymphangioma

Right posterior-lateral neck, mediastinum

273

-

MRI

Lymphangioma

Left anterolateral neck, mediastinum

300

AC

CE

MRI

12

-

Yes

MRI

Lymphangioma Left anterolateral neck

115

13

Yes

-

MRI

Teratoma

111

Right neck, retropharynx, retrolarynx

ACCEPTED MANUSCRIPT Table III: Treatment modalities and outcomes of neonatal patients with congenital head and neck giant masses

108

3

Macrocystic surgery Lymphangiom a

96

4

Macrocystic surgery Lymphangiom a

42

5

Macrocystic surgery Lymphangiom a

48

6

Macrocystic surgery Lymphangiom a

7

Mixed surgery Lymphangiom a

Yes (2014)

larynx

CO2 direct laryngoscopy Transoral laser resection (o Transoral laser mcrosurgery)

PT

No

No

infratemporal space

No

-

-

No

No

-

-

No

No

-

-

41

No

No

-

-

31

No

Yes (2015)

larynx

CO2 direct laryngoscopy

36

necrosis of the skin flap, facial nerve palsy, airway obstruction

Yes

tongue, oral floor

Cutaneous transposition flaps and oral surgery (endolaryngeal)

Yes

No

PT E

CE

AC

Yes (2016)

Adjunctive Treatment

RI

2

Mature Teratoma

No

Site of recurrence

SC

surgery

120

NU

Macrocystic surgery Lymphangiom a

MA

1

Therapeut Follow Histopatholog Recurren ic Up Complications y ce approach (months)

D

Patie nt

8

Mixed surgery Lymphangiom a

9

Mixed surgery Lymphangiom a

31

airway obstruction, facial nerve palsy

10

Macrocystic surgery Lymphangiom a

31

No

larynx, tongue, vedi sopra CO2 oral floor direct laryngoscopy

-

-

ACCEPTED MANUSCRIPT

11

medical Mixed therapy - Lymphangiom surgery a

12

Macrocystic surgery Lymphangiom a

13

surgery

Yes

left neck

Sirolimus

2

No

No

-

-

6

No

No

-

-

AC

CE

PT E

D

MA

NU

SC

RI

PT

Mature Teratoma

12

transient recurrent nerve palsy

Figure 1

Figure 2

Figure 3

Figure 4