Management of neonatal proptosis: A systematic review

Accepted Manuscript Management of Neonatal Proptosis: A Systematic Review Benjamin P. Erickson, MD David T. Tse, MD

PII:

S0039-6257(13)00269-5

DOI:

10.1016/j.survophthal.2013.11.002

Reference:

SOP 6492

To appear in:

Survey of Ophthalmology

Received Date: 12 August 2013 Revised Date:

4 November 2013

Accepted Date: 12 November 2013

Please cite this article as: Erickson BP, Tse DT, Management of Neonatal Proptosis: A Systematic Review, Survey of Ophthalmology (2013), doi: 10.1016/j.survophthal.2013.11.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Management of Neonatal Proptosis: A Systematic Review Benjamin P. Erickson MD1, David T. Tse MD1

Bascom Palmer Eye Institute, Miami, Florida, United States

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Correspondence:

David T. Tse MD [email protected] 900 NW 17th Street Miami, FL 33136

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Abstract. Gross proptosis presenting at birth is an uncommon manifestation of a variety of lesions that can compromise vision and result in disfigurement or even loss of life. Notably, many disease entities have different presentations and prognoses in neonates compared to older children. A structured mental framework is essential to an efficient and coordinated response. We present three challenging cases of neonatal proptosis and discuss the clinical presentation and biological behavior of the lesions that are most often implicated.

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Key words. neonatal proptosis, fetal ultrasound, globe sparing surgery, orbital tumor

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I. Introduction

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Gross proptosis at birth, a source of profound anxiety for both families and clinicians, is an uncommon but well documented presentation for a variety of lesions that can result in vision loss, disfigurement and even death. Despite the relative rarity, all obstetricians, neonatologists, pediatricians, ophthalmologists and orbital surgeons must be prepared to evaluate and manage neonatal proptosis expeditiously. An organized and evidence based approach is paramount.

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While the differential for neonatal proptosis does overlap with that for proptosis in infancy and early childhood, there are also important differences in terms of relative incidence, presentation, treatment considerations, and tumor biology.

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With advances in fetal ultrasound and magnetic resonance imaging (MRI), many ocular and orbital conditions can be detected reliably as early as the first trimester.52 Ideally, this permits a proactive approach in which the obstetrician obtains prenatal consultations with a pediatric ophthalmologist, orbital surgeon, and oncologist. The goal of this multidisciplinary team should be to implement a coordinated plan of care at the time of delivery, thereby maximizing the chances of preserving life, normal anatomy and vision. Occasionally, however, prenatal visits are missed or significant orbital lesions are not identified on fetal ultrasound, and massive proptosis at delivery comes as a surprise and creates much consternation among medical staff.

A. Case 1

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II. Case Presentations

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We present three challenging cases of gross neonatal proptosis, a review of the literature, and a discussion of the clinical presentation and biological behavior of each lesion. A hierarchical approach is suggested as a starting point for evaluation and management by obstetricians, neonatologists, pediatric ophthalmologists, and orbital surgeons. A mnemonic is offered to ensure an orderly sequence of clinical examination and intervention immediately following delivery.

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A two-day-old Caucasian male was born with massive proptosis of the right eye. An abnormality was first observed on fetal ultrasound at 20 weeks. Maternal hypertension did not require medical intervention. The neonate was delivered vaginally at 38 weeks to a 33-year-old gravida 1, para 0. APGAR scores were 8 and 9, and the birth weight was 3.13 kg. Neonatal heart rate, respiratory rate and blood pressure were all high normal or slightly elevated. An orbital MRI obtained on day 1 revealed a right-sided retrobulbar mass, measuring 5.6 x 4.6 x 4.4 cm and containing T2 voids consistent with vascular channels. The irregular post-contrast enhancement pattern was considered ‘almost pathognomonic for cavernous hemangioma' by the interpreting radiologist (Figure 1).

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On initial evaluation, his right eye was grossly proptotic with injection and foci of subconjunctival hemorrhage (Figure 2). The ipsilateral eyelids were diffusely stretched and retracted. The cornea was hazy and the anterior chamber shallow with prominent iris vessels. The orbital mass resisted retropulsion and could not be transilluminated. There was an absent direct pupillary response to light with a brisk consensual reaction. The left eye and periocular structures were within normal limits.

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There were several firm, bluish subcutaneous nodules on the trunk, extremities and tongue. B-scan ultrasound disclosed a highly reflective, irregular mass with low to medium sound attenuation, occupying nearly the entire orbit. These characteristics were considered most consistent with teratoma, but a diagnosis of neuroblastoma was also entertained given the presence of tachycardia and skin nodules. Abdominal ultrasound revealed a 1.4 x 1.1 cm lesion of the right adrenal gland. Biopsy of a superficial lesion was consistent with metastatic neuroblastoma and this diagnosis was subsequently confirmed with bone marrow aspiration.

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The mass was excised on day 3 to minimize corneal exposure-related morbidity and to decrease the risk of necrosis and infection during chemotherapy. Access was achieved via lateral canthotomy and conjunctival peritomy (Figure 3). The mass was dissected free from the superior, medial and inferior rectus muscles but the optic nerve and lateral rectus were grossly infiltrated and had to be sacrificed. The globe itself was successfully preserved.

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Microscopic analysis revealed undifferentiated, round basophilic cells in a matrix of vascularized connective tissue. The partially encapsulated mass was 90% necrotic with scattered calcification and 6 mitotic figures per 10 high-powered fields. Immunostains was positive for neuron specific enolase (NSE) and S-100 but negative for glial fibrillary acidic protein (GFAP), neurofilaments, leukocyte common antigen, chromagranin and desmin. Genetic analysis disclosed diploid DNA and intermediate Myc-N proto-oncogene expression.

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He underwent 4 cycles of cyclophosphamide and VP-16 chemotherapy with apparent resolution of his adrenal mass and skin lesions. During the 5th cycle, however, repeat MRI revealed hydrocephalus secondary to multiple new brain metastases. The infant deteriorated rapidly despite shunting and aggressive chemotherapy and died at 8 months of age. B. Case 2

Routine transabdominal ultrasound at 23 weeks disclosed a large cystic mass of the left orbit in the fetus of a 24-year-old gravida 1, para 0. Subsequent transvaginal ultrasound revealed a 3.3 x 3.9 x 3.0 cm lesion (Figure 4). Follow-up examinations at 26, 30, 34, and 38 weeks gestation demonstrated interval fetal development without lesion enlargement. A girl was delivered at 39 weeks via Cesarean section with APGAR scores of 9 and 9, and birth weight of 4.0 kg.

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Ophthalmic examination on day 1 showed a profoundly proptotic left globe enveloped by a large, transilluminating cystic lesion. No pulsations or bruit were detected. The ipsilateral eyelids were retracted, and there was a central corneal ulcer. The left pupil reacted sluggishly to light with a brisk relative afferent pupillary defect (RAPD). The right eye and periocular structures were within normal limits. Orbital ultrasound, CT, and MRI confirmed the isolated, cystic nature of the mass and revealed a stretched and atrophic left optic nerve (Figure 5).

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Complete cyst excision was performed 6 days after birth via a transconjunctival orbitotomy approach. A cleavage plane was identified in the cyst, which was dissected free from adjacent structures and removed in toto without rupture. A lateral tarsorrhaphy was required to correct postoperative lid malposition. The globe was preserved in order to maintain orbital volume and minimize hypoplasia of the bony orbit.

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Gross examination of the specimen revealed a fluid-filled sac measuring 3.3 x 4.0 x 3.0 cm. Microscopic examination disclosed an encapsulated cyst lined with stratified squamous and cuboidal epithelium that contained proteinaceous fluid without evidence of bone, cartilage, hair, or glandular elements. All components appeared histologically benign, confirming the diagnosis of a simple epithelial cyst.

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The left eye retained excellent motility, but developed large angle esotropia. Electrophysiological testing failed to elicit visual evoked potentials, suggesting the absence of useful sight. At 15 months of age, the patient was fitted with a painted scleral shell and achieved an excellent cosmetic outcome (Figure 6). Fifteen years later, she has good facial symmetry and functions well in social settings. C. Case 3

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Routine transabdominal ultrasound in a 30-year-old gravida 5, para 4 appeared unremarkable at 16 weeks. Repeat testing at 34 weeks, however, revealed a heterogenous 3.1 x 3.0 cm mass involving the right orbit. Serial ultrasounds were obtained at two-week intervals to document lesion growth. Planned caesarean section was performed at 40 weeks because of concern for tumor rupture during passage through the birth canal. Initial examination was notable for profound proptosis of the right globe with exposure keratopathy, chemosis and superotemporal erosion accompanied by focal protrusion of the underlying mass (Figure 7). CT and MRI demonstrated a 5.0 x 3.4 x 3.8 cm partially encapsulated, heterogeneous, intraconal mass displacing the globe and stretching the optic nerve. On day 7, the patient underwent surgical debulking of the lesion. While every effort was made to spare the globe, intraoperative evidence of gross tumor infiltration into the globe necessitated a lid-sparing orbital exenteration.

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Microscopic evaluation disclosed a spindle cell tumor, and the diagnosis of congenital infantile fibrosarcoma was made after cytogenetic analysis revealed the characteristic t(12;15) translocation. The apical margin of the exenteration specimen was positive, and the neonate received adjuvant chemotherapy with vincristine, actinomycin, and cyclophosphamide.

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After successful tumor eradication was confirmed, a cantilevered orbital tissue expander was placed to prevent the development of hemifacial deformity. Conventional static implants or dermis fat grafts could not be entertained because of absence of orbital tissues and blood supply. She is currently alive and well without evidence of recurrence or significant orbital volume disparity.

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III. Discussion A. Background

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Tumors are diagnosed prenatally in 7.2 fetuses per 100,000 live births.48,58 Neoplasms involving the orbit are even more rare, and there is no reliable estimate of incidence. Non-neoplastic causes of gross neonatal proptosis are also relatively uncommon.

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Despite the rarity of this presentation, however, it causes significant distress and anxiety for both families and clinicians. Given recent advances in neonatal imaging, we believe that a proactive strategy is possible in the vast majority of cases. The concept of ‘prenatal ophthalmic consultation’ is evolving in conjunction with these technical improvements.43,49

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With expanded medical and surgical capabilities, there has also been a shift towards a globe-sparing paradigm. Several disease entities that can present as orbital lesions are capable of rapid growth in the perinatal period. Vision loss and deformity may therefore be minimized by prompt diagnosis and intervention. Assembly of a multispecialty team prior to birth facilitates decisions regarding postnatal intervention and permits consideration of early delivery for neonates of appropriate gestational age and maturity. B. Neonatal Imaging 1. Ultrasound

A skilled fetal ultrasonographer can detect many abnormalities of the eye and orbit from an early gestational age. By 11 to 12 weeks, the eyes and periocular tissues are visible as distinct structures. Autosomal dominant cataracts have been identified in fetuses as early as 14 weeks.53 Prenatal diagnosis of retinoblastoma, persistent hyperplastic primary vitreous, high myopia, strabismus, microphthalmia, anophthalmia, hypertelorism and orbital masses is possible.7,37,43,63,68

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A number of recent studies have established the anticipated ocular and orbital dimensions in each stage of development. There is a strong linear correlation between gestational age and orbital diameter, circumference and surface area; therefore deviations from expected measurements may provide important diagnostic clues.14,25,35,75

2. Magnetic Resonance Imaging (MRI)

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Three-dimensional ultrasound (3DUS) can now demonstrate planes of section unavailable with two-dimensional studies, making detection of orbital tumors and mass lesions easier and more reliable.39,51 3DUS also permits spatial reconstruction of the fetal face with simultaneous visualization of all features.40 This reconstructed view permits those unfamiliar with fetal ultrasound to recognize orbital defects such as gross proptosis. Even with unfavorable head positioning, 3DUS can provide a variety of diagnostic clues related to the morphology of the orbit and eyelids.83

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C. Evaluation of the Neonate

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Fetal MRI is developing as a useful adjunct to ultrasound. While there are currently no reports of MRI findings for orbital mass lesions, the anticipated lens, orbit, and intraocular dimensions have between characterized between 17 and 39 weeks of gestation.58,66 Even without contrast, which is not recommended for fetal studies, MRI has been demonstrated to offer improved soft tissue contrast in other anatomic locations. An added benefit is that the image quality is not degraded by oligohydramnios as with fetal ultrasound.13

1. The obstetrician and neonatologist

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The task of initial evaluation and stabilization typically falls to the obstetrician and/or neonatologist. We suggest structuring this assessment using the acronym SPARE, which stands for Systemic features, Presence/Absence of a formed eye, Retrobulbar hemorrhage, and Exposure of the ocular surface.

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Systemic features. At the time of delivery, the first priority is to ensure overall stability of the neonate and to provide an appropriate level of support. Neuroblastoma with metastases to the orbit can elaborate vasoactive substances resulting in tachycardia and rarely hemodynamic instability. Monitoring and documentation of these systemic parameters is particularly important when early surgical intervention is planned.3 Presence/Absence of a formed eye. The next step is to establish the presence and condition of the involved eye. With anophthalmia, cystic protrusion may simulate gross proptosis, but careful examination will fail to disclose recognizable ocular structures. In microphthalmia with cyst, the cornea and iris/uveal tissue are usually present, but may be hard to identify. A fully formed globe is generally seen in conjunction with other causes of neonatal proptosis, though it may be compressed, distorted, or infiltrated by tumor. If a formed globe is identified, visual potential must be presumed, and immediate steps

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should be taken to protect the ocular surface from desiccation. Coordinated imaging assessment and surgical intervention aimed at reducing optic nerve compromise may prove necessary.

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Retrobulbar hemorrhage. It is then essential to rule out a compartment syndrome caused by retrobulbar hemorrhage, which may result in gross proptosis and simulate a mass lesion. Bleeding may be iatrogenic (e.g. from forceps or vacuum delivery), related to traumatic passage through the birth canal, or from suction generated by disimpaction of the neonatal head from the maternal pelvis.62 Perhaps for medico-legal reasons, few cases are documented in the literature and none report long-term visual outcomes.18 As in other age groups, however, this condition is potentially blinding and emergent decompression should be undertaken when appropriate. Clinical clues include significant proptosis absent on third trimester ultrasound, evidence of periorbital trauma, and conjunctival congestion or frank subconjunctival hemorrhage. An urgent ophthalmology consultation should evaluate for signs of optic nerve compression and ischemia. These include presence of an afferent pupillary defect, arterial pulsations, and/or impaired retinal perfusion.

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2. The ophthalmologist

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Exposure. The next priority is to prevent corneal decompensation, which can lead to permanent scarring, superinfection, and even globe perforation. In many cases of gross proptosis, the eyelids cannot close adequately, resulting in evaporative loss and ocular surface desiccation. While in the womb, placental fluid bathes the cornea, providing lubrication and nutrition. Following birth, however, severe conjunctival and corneal exposure develop rapidly, and it is therefore essential that the primary team act promptly. We suggest coating the entire exposed ocular surface, both cornea and conjunctiva, with bland ointment and then covering it with plastic wrap (e.g. Saran wrap). This layer does not have to be sterile and will not abrade the corneal epithelium. A moisture chamber is impractical to construct and maintain, and does not achieve the broad ocular surface lubrication required.

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After this initial assessment, responsibility for further evaluation typically falls to a general ophthalmologist who may not have immediate access to an orbital specialist and must be prepared to manage all aspects of care leading up to surgical intervention. A careful pupillary exam provides important clues regarding visual potential of the involved eye. Diminished light reactivity and presence of a RAPD suggest optic nerve compression. In certain circumstances, prompt excision or debulking of the impinging mass may partially reverse this. Optic nerve swelling caused by axoplasmic stasis occasionally may be visualized on a dilated exam. Pallor and atrophy of the nerve are not anticipated for at least 6 weeks; their presence at birth therefore implies a longstanding in utero insult and a poor visual prognosis. Ancillary techniques for determining visual potential exist, but are not uniformly reliable. Visual evoked potentials are cortical responses elicited by a flashing light or pattern

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visual stimulus. They provide clues as to integrity of the visual pathways, but results are challenging to interpret when the brain is immature.12,34

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Lesion characteristics can often help refine the differential diagnosis. Transillumination helps to determine whether a mass is sold or cystic. Engorgement with crying suggests a venous malformation or encephalocele. A bruit indicates an abnormal arterial-venous connection. Pulsatility suggests arterial flow or encephalocele, and these usually can be distinguished based on pulsation frequency. Resistance to retropulsion can also provide clues as to the density of an orbital lesion.

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A thorough examination of the body surface is essential. In Case 1, the presence of cutaneous lesions, coupled with diaphoresis, flushing and tachycardia, suggested metastatic neuroblastoma as an alternative diagnosis. Malignant rhabdoid tumors and alveolar rhabdomyosarcoma also may present with subcutaneous nodules.20,27

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B-scan ultrasound, an excellent initial modality for evaluating neonatal proptosis, is quick, doesn’t require sedation, and readily permits distinction among solid, cystic and vascular lesions. Color Doppler modes enable quantitative evaluation of intralesional flow as well as detection of feeding and draining channels. This is helpful not only for diagnostic purposes but also for surgical planning. Ultrasound can help characterize the relationship between the globe, anterior optic nerve and lesion. Attenuation of sound waves, however, limits evaluation of the deeper tissues and orbital apex. MRI permits more accurate distinction between the mass and normal orbital structures and is also critical to determining whether the lesion is confined to the orbit or extends to involve the brain and adjacent sinuses. CT scans provide the best characterization of bony orbital anatomy and may be helpful in distinguishing cystic lesions and heterotopic brain tissue from orbital encephalocele.

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Ancillary lab tests can occasionally provide useful diagnostic clues. High 24-hour homovanillic acid (HMA) and vanilmandelic acid (VMA) levels or an elevated serum norepinephrine may help to support the diagnosis of neuroblastoma. 3. The orbital surgeon

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It is important to how medically stable the neonate is prior to surgery. Particularly with longer procedures, the risk of blood loss and hypothermia must be weighed against the anticipated benefits of early intervention. When vision or the integrity of the globe is threatened by a large or rapidly growing mass, as in our cases, surgery should be undertaken with an appropriately prepared anesthesia staff. In other situations, as with the correction of encephalocele, surgeons may choose to defer intervention for several months to permit maturation. With orbital malignancy, another important consideration is how best to coordinate surgery and adjuvant therapy. When integrity of the globe is not acutely threatened, it may be appropriate to attempt chemoreduction prior to surgical intervention. This increases the likelihood of negative margins and may reduce the need for an aggressive

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and potentially disfiguring resection. As with Case 1, however, it is often preferable to debulk or resect a large lesion in advance of chemotherapy in order to reduce the risk of complications from necrosis and infection.

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With cystic lesions, it is debatable whether aspiration should be attempted prior to a definitive surgical resection. In most circumstances, aspiration should be viewed as a temporizing measure. Despite the inevitable re-accumulation of fluid, aspiration may protect against exposure related complications. There are also some reports of functional cures resulting from multiple aspirations in conjunction with partial cyst wall excision.1,72

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4. Considerations for follow up

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Historically, cases of gross proptosis were treated with exenteration, but this decision should be based on medical necessity and not surgical expedience. The massive loss of orbital volume resulting from acquired anophthalmia presents a formidable challenge, as sustained bone stimulation is necessary to prevent the development of hemifacial deformity.

Management of gross proptosis does not end with lesion resection: Corneal protection remains an ongoing concern. In the aftermath of surgery, the eyelids are often overstretched and hypotonic. Limited ocular motility and a poor protective Bell phenomenon may compound this. It is therefore necessary to continue aggressive lubrication and to maintain a low threshold for performing additional lid procedures.

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Presence of an eye or adequately sized substitute is critical to development of the midface and orbits. In cases that require enucleation, volume may be replaced with an orbital implant or dermis fat graft if residual malignancy or infection is not suspected. Implants may also be required in cases of microphthalmia following cyst excision, as the globe itself is too small to stimulate bony growth. If a mass has resulted in significant expansion of the bony orbit, it may be possible to place a definitive implant of sufficient volume. Otherwise it is necessary to use staged implants of increasing volume, or an orbital tissue expander that permits progressive volume expansion with injections of saline.77

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In Case 3, neither standard orbital implants nor dermis fat grafts are appropriate following exenteration as the result of lack of orbital tissues and absence of blood supply. In such situations, a cantilevered tissue expander anchored to the lateral orbital rim best replaces the volume deficit in order to stimulate bone growth. Amblyopia must also be treated aggressively if visual potential remains following a globe-sparing procedure. Secondary motility disorders and strabismus are also common. D. Etiology of neonatal proptosis Differentials for proptosis at birth are often extrapolated from that pertaining to infants and children. While overlap does exist, there are salient differences to consider in terms

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of incidence, presentation, treatment and prognosis. We discuss the causes of gross neonatal proptosis, organized by etiology and frequency of presentation. Lesions are categorized as malignant neoplastic, benign neoplastic, cystic, vascular or miscellaneous (Table 1).

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1. Malignant neoplastic a. Neuroblastoma

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Neuroblastomas are primitive neuroendocrine tumors arising from the adrenal glands or sympathetic chain. Secondary orbital involvement occurs in 10 to 40% of patients and gross proptosis may be the presenting feature.52 Infrequently, the orbit itself may be the primary site.86 Most neuroblastomas diagnosed prenatally or at birth carry a favorable prognosis, even in the presence of metastatic spread. Indeed, nearly 60% of neonates have metastases at the time of diagnosis.45 Skin lesions known as ‘blueberry muffin spots’ suggest a disseminated presentation.2 If treated expeditiously, neonatal neuroblastoma has a greater than 90% long-term survival.2 Nevertheless, clinical behavior is highly variable; a subset of tumors are highly aggressive and may prove resistant to therapy.2

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Typically, fetal neuroblastoma is discovered on third trimester ultrasound, but tumors have been detected as early as gestational week 19.2,45 On postnatal ultrasound, tumor is heterogeneously echogenic and may contain anechoic foci representing hemorrhage or necrosis.45 Intralesional calcification is common, appearing on 80 to 90% of CT scans.45 Often there is bony destruction, particularly of the lateral wall.52 Screening CT of the chest, abdomen, and pelvis as well as bone marrow aspiration are standard for all newly diagnosed cases.45 Neuroblastoma is typically hypo- to isointense on T1- weighted images and hyperintense on T2-weighted images. The compact nature and high nuclearto-cytoplasm ratio of neuroblastoma cells limits the motion of protons, markedly increasing signal on diffusion-weighted images.79 Primary tumors and metastases may also be evaluated with scintigraphy, making use of the catecholamine analog metaiodobenzylguanidine (MIBG) labeled with iodine-123.

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The catecholamine metabolites HMA and VMA are elevated in more than 80% of neonatal neuroblastoma and may cause maternal hypertension.45,82 Levels can be quantified with a 24-hour maternal urine sample or with fetal urine obtained via amniocentesis.82 VMA is considered the more primitive metabolite, and a VMA-to-HVA ratio is sometimes used to predict tumor differentiation.82 Neuroblasts, undifferentiated, malignant sympathetic cells, are small, round and contain scant cytoplasm. Tumors may be histologically graded based on the presence of necrosis, mitosis, and karyorrhexis.45 Cytogenetic studies also provide important clues as to likely tumor behavior. Deletion of chromosome 1p or gain of 17q may be linked to aggressive behavior, while hyperdiploid DNA and increased levels of CD44 are thought to be protective.45 Unlike in children, however, neonates with amplification of the Myc-N proto-oncogene on chromosome 2p do not appear to have a worse prognosis.6,26

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Cycles of multi-agent chemotherapy are typically delivered. Radiotherapy is reserved for life- or organ-threatening tumor not responding to chemotherapy or surgery. b. Fibrosarcoma

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Congenital infantile fibrosarcoma (CIFS) is a mesenchymal tumor that typically affects the extremities, but orbital involvement may result in gross neonatal proptosis.31,76 Forty percent of cases are diagnosed in utero or at birth.75,83 Overall, it is the most common soft-tissue sarcoma in neonates and infants, and is relatively indolent compared to other spindle cell tumors in this age group.20,31,70 Prognosis for CIFS is much more favorable than for fibrosarcoma manifesting in children and adults; the 5-year survival rate is 84%.17

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Careful monitoring is imperative when tumors suspicious for CIFS are detected on prenatal ultrasound, as fetal exsanguination has been reported from intrauterine rupture.16,73 On postnatal imaging, tumors are often poorly circumscribed with a tendency to infiltrate surrounding tissues and encase neurovascular structures. There may be bowing, cortical thickening of adjacent bone, and osseous destruction.73 Biopsy with cytogenetic analysis may be required to distinguish these tumors from benign hemangiomas and other spindle cell malignancies.20 The t(12;15) translocation linking the ETV6 gene on chromosome 12p13 and the NTRK3 gene on 15q25 is unique to CIFS.31,76

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c. Rhabdomyosarcoma

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Surgery may be curative, though adjuvant or post-resection chemotherapy with vincristine and actinomycin may permit less aggressive excisions.20,74 Local rates of recurrence range from 30% to 50%, but this does not appear to negatively impact prognosis.31,74

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Though a relatively common childhood malignancy, rhabdomyosarcoma (RMS) of the orbit is exceedingly rare at birth.33 Accounting for all sites of origin, the Intergroup Rhabdomyosarcoma Study (IRS) found that only 0.4% of cases present in neonates.44 Unfortunately, prognosis tends to be worse in neonates than older children, and multiple metastases may already be present at the time of delivery.29,32,33 The IRS group reported a 3-year overall survival of only 49% among those with RMS presenting at birth.44 Biopsy with histology, immunostaining and molecular studies is essential to establishing a diagnosis. Further workup should include a chest CT, bone scan and marrow aspirate. The embryonal subtype predominates in the newborn period, but orbital involvement with alveolar RMS occurs.29 The alveolar subtype, characterized by the t(2;13)(q35;q14) and t(1;13)(p36;q14) translocations, has a worse outcome. It is associated with the early development of brain metastases, and disseminated skin nodules are present in more than 50% of affected neonates.20,29,65

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Immaturity of the neonatal organs makes dosing chemotherapy extremely challenging. Myelosuppression and toxicity are common and there is a narrow therapeutic window.20 The current European protocol recommends treating children less than 1 month of age with vincristine and actinomycin D only.20 Those receiving actinomycin D, however, should be carefully monitored for hepatotoxicity, as they are at a higher risk compared to older children.20 Supplemental radiotherapy may be required, but is delayed when possible because of the deleterious impact on development. To date, there is no record in the literature of long-term survivors of orbital rhabdomyosarcoma presenting at birth.29 d. Malignant rhabdoid tumor

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Malignant rhabdoid tumors (MRT) are a group of neoplasms histologically similar to but biologically distinct from rhabdomyosarcoma.27 Orbital involvement may result in gross proptosis and has been detected on prenatal ultrasound.38 Tumor is sometimes confined to a single locus, but a disseminated soft tissue presentation with subcutaneous nodules is more common.27 Mutations of the tumor suppressor gene hSNF5/INI on chromosome 22q11.2 have been implicated in pathogenesis.20

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Microscopically, rhabdoid rumors are characterized by sheets of medium-large round or oval cells admixed with fibrovascular septae.38 They contain abundant eosinophilic cytoplasm with multiple inclusions and prominent nucleoli.27,38 Large areas of necrosis are often present and multiple mitoses and apoptotic figures may be seen.27,38 Unlike rhabdomyosarcoma, however, cross-striations are not characteristic.27 Immunostaining is generally positive for vimentin with variable reactivity to cytokeratin and epithelial membrane antigen (EMA).

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The respective roles of surgery and systemic chemotherapy remain in debate. Recurrence-free survival may occur with excision of congenital MRT confined to the orbit.73,81 One neonate was exenterated with tumor free margins only to die with liver and brain metastasis.38 The prognosis for disseminated disease is poor regardless of management, though a multidrug regiment containing doxorubicin and vincristine is currently the treatment of choice.20,27,81 Adjunctive Gamma Knife radiosurgery may be used for unresectable tumors.81 e. Miscellaneous

Hemangiopericytomas are mesenchymal tumors derived from the vascular pericytes of Zimmerman.74 Rarely, they may involve the orbit and produce proptosis in neonates.55 The congenital/infantile form usually presents in those younger than 2 months of age and has an excellent prognosis.67 Doppler ultrasound demonstrates intralesional flow, and intense post-contrast enhancement is typical on CT and MRI.55 Extreme caution must be exercised during biopsy of these vascular tumors. There is potential for life threatening bleeding that responds only to ligation of the external carotid artery.55,67 Neoadjuvant chemotherapy is generally effective in rendering larger tumors surgically resectable. Maturation to capillary hemangioma may occur after incomplete excision.67

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Mesenchymal chondrosarcoma is another rare causes of neonatal proptois.78 2. Benign Neoplastic

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a. Teratoma

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Teratomas, encapsulated choristomas with cystic and solid components, arise from pluripotent embryonic stem cells and contain contributions from all three germ cell layers. Seventy to 80% of tumors arise in the sacrococcygeal region, but the head and neck are also commonly involved.80 Teratomas are among the most commonly reported causes of gross neonatal proptosis.60,71 For unknown reasons, orbital teratomas occur with twice the frequency in females.4,42 There are only three cases of malignant transformation from an orbital teratoma.23,48

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Imaging typically discloses a heterogeneous mass with foci of calcification and areas of fat density/intensity.24,41 Rapid growth is common and expansion of the bony orbital may result in significant deformity.24,48 As Case 1 illustrates, however, no clinical or imaging findings are pathognomonic for teratoma. The ipsilateral globe is usually completely formed but may rarely be small and shrunken.59 Teratomas may also extend into paranasal sinuses or through the superior orbital fissure to involve the cavernous sinus.41

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Common ectoderm-derived components include epithelium-lined cysts, hair follicles, sweat glands, and neural elements. Even formed teeth may be found.64 The mesoderm contributes muscle, bone, cartilage, and fat, while the endoderm produces cysts lined by gastrointestinal and respiratory-type epithelium. It is these cystic spaces lined by glandular epithelium that are responsible for the rapid growth potential of teratomas.24 Exceptionaly, whole or partial fetuses develop within the orbit.50

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Complete surgical excision is critical because presence of residual tumor typically leads to recurrence.42 With large tumors, some authors advocate aspirating fluid from the larger cystic spaces to facilitate resection.71 Roughly one third of reported cases have been treated with globe sparing surgery, but preservation of useful vision is unfortunately extremely rare as prolonged stretching of the optic nerve usually renders it nonfunctional.42 b. Congenital myofibroma Congenital myofibroma, a rare, locally invasive tumor of myofibroblasts, typically arises in the head and neck, although visceral organs may also be involved and may be either solitary or multifocal.84 In contrast to solitary lesions, which have an excellent prognosis, multifocal myofibroma involving the viscera is associated with a 75% mortality.54 There is a propensity for orbital involvement.54 In cases with gross proptosis, compressive optic neuropathy may be severe.84 Congenital myofibroma is characterized by rapid growth in the perinatal period and may destroy bone, as well as invade adjacent

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sinuses.

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MRI findings are varied, but myofibroma typically demonstrates low to intermediate signal on T1-weighted and high signal on T2-weighted images. Peripheral post-contrast enhancement may occur.5 Given the implications for prognosis, it is vital to evaluate for the presence of multifocal disease with a full physical exam as well as imaging studies of the chest, abdomen, and pelvis.54

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Microscopic examination discloses foci of myofibroblastic spindle cells in a staghorn pattern that resembles hemangiopericytoma.5 Two distinct populations are seen; plump spindle cells and small round blue cells.54 Apoptosis and rare mitotic figures may be present.5,54,84 Immunostaining is generally positive for vimentin and smooth muscle actin (SMA).54

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Fortunately, recurrence is rare following an adequate surgical resection. Tumors are generally encapsulated and easily dissect free of adjacent structures.84 Spontaneously resolution may occur in other parts of the body, but prompt surgical resection is recommended when critical structures are involved.54 c. Miscellaneous

Lipoblastoma, a rare benign tumor that arises from embryonic white fat, is a rare cause of neonatal proptois.69

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3. Cystic Lesions a. Microphthalmia with cyst

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Microphthalmia with cyst is a subtype of coloboma and the most common congenital eye malformation, with an incidence of 1.8 per 10,000 live births.9,15 Microphthalmia with cyst and other colobomata develop as a result of failure of the fetal fissure to close between the 5th and 7th gestational weeks.15 Approximately one quarter of cases are bilateral.9 Sixty-seven percent of bilateral and 29% of unilateral cases are accompanied by other congenital malformations, including congenital heart defects, central nervous system abnormalities, cleft lip and/or palate, pulmonary hypoplasia, and renal agenesis.9 Visual potential of the microphthalmic globe is typically poor. The microphthalmic eye may be difficult to visualize. In some cases, a large cyst may displace the malformed globe so posteriorly that it is invisible to external inspection.15 Accordingly, definitive differentiation between microphthalmia with cyst and congenital cystic eye may require histology. Microscopically, the cyst is composed of two layers; an inner layer with primitive neuroretinal tissue and an outer connective tissue layer continuous with the sclera of the microphthalmic globe.71 Aspiration may be a temporizing measure for large and symptomatic cysts, but total excision is recommended because the mass will recur.15

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b. Congenital cystic eye

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Congenital cystic eye (anophthalmia with cyst) is a benign lesion resulting from partial or complete failure of the primary optic vesicle to invaginate. This prevents neuroectodermal elements from developing into formed ocular structures.10,71 It is usually unilateral and is occasionally seen in conjunction with contralateral microphthalmos with cyst.30 When bilateral, it is often associated with other congenital abnormalities, including cleft lip and/or palate, basal encephalocele, agenesis of the corpus callosum, microcephaly, and tetralogy of Fallot.10 Ultrasound reveals a large cystic cavity without any discernable ocular structures. Glial components within the cyst may produce fluid, resulting in progressive enlargement.10

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Histologically, the cystic eye consists of dense fibrovascular connective tissue resembling sclera admixed with smooth muscle.10 It may be lined with immature retinal tissue, which stains positively for S-100 and GFAP.10,30 Melanin containing cells resembling primitive retinal pigment epithelium are occasionally visualized. An astrocytic structure akin to the optic nerve may extend from the posterior aspect of the cyst.71 c. Encephalocele

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Anterior encephaloceles occur in 1 of 35,000 live births.46 For unclear reasons, there is a significantly higher incidence in South-East Asia. The frontoethmoid subtype is most common and isolated orbital encephaloceles account for only 8% of cases.47 While present at birth, growth is generally slow, and profound proptosis is unusual. The orbital mass may be pulsatile, enlarge with coughing, or reduce under direct pressure, but these features are not consistently present.8,61 Rarely, encephaloceles are associated with neurofibromatosis 1 and sphenoid hypoplasia.46 Additional developmental defects may include hypertelorism, cleft lip and/or palate, spina bifida, agenesis of the corpus callosum, and microphthalmos or optic nerve defects.8

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Computerized tomography is the study of choice as it permits the easiest characterization of bony defects and aids in operative planning. Surgery is rarely indicated in neonates without CSF leakage. Earlier intervention generally leads to better cosmetic and functional outcomes, but most specialists advocate delaying surgery until 8 to 10 months of age, when infants are more developed and better able to tolerate blood loss and hypothermia.47 Surgery for orbital encephaloceles generally entails dural repair followed by reconstruction of the sphenoid wing using autologous rib or methylmethacrylate implants.46 d. Ectopic brain tissue Choristomatous rests of brain tissue within the orbit may result in neonatal proptosis, with or without a fully formed eye.28 These benign lesions are usually slow growing and rarely cause profound deformity or exposure. Leading theories of etiology include herniation through a bony defect with subsequent closure, resulting in orbital sequestration, and presence of embryonic rests within the orbit capable of developing into

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a variety of neural tissues.8 With CSF producing lesions, a demonstrable connection to the brain must be carefully ruled out with preoperative imaging.57 Surgical excision is occasionally indicated for compressive sequelae and cosmesis. e. Other cysts

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Simple conjunctival cysts have been detected by prenatal ultrasound as early as 23 weeks and may cause profound neonatal proptosis with stretching of the optic nerve and exposure-related phenomena.72,85 Imaging reveals a discrete cyst with no evidence of ocular, nerve sheath, or intracranial connections. When diagnosis is uncertain, aspiration of cyst fluid can be used to rule out a nerve sheath meningocele; beta-2 transferrin is a marker found exclusively in the cerebrospinal fluid.72 Microscopic examination discloses a simple cyst lined by a non-keratinized, stratified squamous to cuboidal epithelium, lacking dermal appendages.72,85 Ideal management consists of complete excision, but when this is not safe or practical, partial cyst excision with fluid drainage can yield favorable results.1,72 Deep orbital dermoid cysts generally manifest in adolescence or adulthood, but may rarely result in neonatal proptosis. As with the more common superficial form, deep endophytic dermoids arise from epidermal cells entrapped during embryonic development.11,19

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Other rare cysts implicated in neonatal proptosis include congenital glial cysts of the optic nerve and glioependymal cysts arising intracranially and extending secondarily into the orbit.36,37,56 These consist of glial/connective tissue lined by a single layer of ciliated cuboidal or columnar epithelium and stain positively for GFAP and S-100.56

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Thrombosed orbital varices rarely cause profound neonatal proptosis. In the absence of complete thrombosis, varices often increase dramatically in size with straining and crying. CT and ultrasound may disclose phleboliths while Doppler studies are useful for characterizing flow. Surgery is indicted for optic nerve compression or severe exposure.21 Cavernous carotid aneurysm or other arterial lesions may also cause neonatal proptosis in unusual circumstances.22 On MRI, T2 flow voids may be seen contiguous to the internal carotid artery, and post-contrast enhancement is strong. Doppler ultrasound reveals pulsatile arterial flow. When indicated, treatment entails coiling. IV. Conclusions

Addressing neonatal proptosis may challenging and frightening for families and clinicians alike. A prompt, orderly and evidence-based approach, however, optimizes outcomes. Advances in fetal imaging have improved the likelihood of prenatal diagnosis, allowing for early assembly of multidisciplinary teams equipped to implement the best

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strategy for preservation of life, normal appearance and vision. While the differential for proptosis in neonates overlaps with those for infants and children, there are important differences with respect to incidence, biological behavior, and prognosis. V. Methods for Literature Search

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Case reports were identified via Medline using the search strings and keywords ‘neonatal proptosis,’ ‘neonatal orbit mass,’ and ‘fetal orbit mass.’ We included reports only if they contributed new information about the characteristics, diagnosis or treatment of the relevant disease processes. Each reference was reviewed for possible publications missed in the initial search.

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VI. Disclosures

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The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. References

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1. Alsuhaibani AH, Al-Hussein H, Al-Katan H, et al. Management of congenital unilateral proptosis from an orbital epithelial cyst by cyst aspiration. J AAPOS. 2006 Dec;10(6):589-91. 2. Avni FE, Massez A, Cassart M. Tumours of the fetal body: a review. Pediatr Radiol. 2009 Nov;39(11):1147-57. 3. Bailey AG, Mounce G. Vasoactive mediastinal mass in an infant. J Clin Anesth. 2009 Aug;21(5):366-8. 4. Bilgiç S, Dayanir V, Kiratli H, et al. Congenital orbital teratoma: a clinicopathologic case report. Ophthal Plast Reconstr Surg. 1997 Jun;13(2):1426. 5. Bloom RI, Schwarcz RM, Zhang C, et al. A case of congenital myofibroma of the orbit presenting at birth. Orbit. 2013 Feb;32(1):33-5. 6. Bordow SB, Norris MD, Haber PS, et al. Prognostic significance of MYCN oncogene expression in childhood neuroblastoma. J Clin Oncol. 1998 Oct;16(10):3286-94. 7. Bronshtein M, Zimmer E, Gershoni-Baruch R, et al. First- and second-trimester diagnosis of fetal ocular defects and associated anomalies: report of eight cases. Obstet Gynecol. 1991 Mar;77(3):443-9. 8. Call NB, Baylis HI. Cerebellar heterotopia in the orbit. Arch Ophthalmol. 1980 Apr;98(4):717-9. 9. Chaudhry IA, Arat YO, Shamsi FA, et al. Congenital microphthalmos with orbital cysts: distinct diagnostic features and management. Ophthal Plast Reconstr Surg. 2004 Nov;20(6):452-7. 10. Chaudhry IA, Shamsi FA, Elzaridi E, et al. Congenital cystic eye with intracranial anomalies: a clinicopathologic study. Int Ophthalmol. 2007 Aug;27(4):223-33. 11. Chaudhry IA. Management of deep orbital dermoid cysts. Middle East Afr J Ophthalmol. 2008 Jan;15(1):43-5.

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12. Chayasirisobhon S, Gurbani S, Chai EE, et al. Evaluation of maturation and function of visual pathways in neonates: role of flash visual-evoked potentials revisited. Clin EEG Neurosci. 2012 Jan;43(1):18-22. 13. Coakley FV, Glenn OA, Qayyum A, et al. Fetal MRI: a developing technique for the developing patient. AJR Am J Roentgenol. 2004 Jan;182(1):243-52. 14. Dilmen G, Köktener A, Turhan NO, Tez S. Growth of the fetal lens and orbit. Int J Gynaecol Obstet. 2002 Mar;76(3):267-71. 15. Doglietto F, Massimi L, Dickmann A, et al. Microphthalmia and colobomatous cyst of the orbit. Acta Neurochir (Wien). 2006 Oct;148(10):1123-5. 16. Dumont C, Monforte M, Flandrin A, et al. Prenatal management of congenital infantile fibrosarcoma: unexpected outcome. Ultrasound Obstet Gynecol. 2011 Jun;37(6):733-5. 17. Ertürk C, Yarmpapuç R, Altay MA, et al. A giant congenital fibrosarcoma of the leg. J Pediatr Orthop B. 2010 Jul;19(4):348-52. 18. Ezzadin EM, Liu D, Al-Rashed W, et al. Bilateral orbital hemorrhage in a newborn. Am J Ophthalmol. 2000 Apr;129(4):531-3. 19. Fasina O, Ogun OG. Giant deep orbital dermoid cyst presenting early in infancy in a Nigerian child: a case report and review of the literature. J Med Case Rep. 2012 Sep 25;6(1):320. 20. Ferrari A, Orbach D, Sultan I, et al. Neonatal soft tissue sarcomas. Semin Fetal Neonatal Med. 2012 Aug;17(4):231-8. 21. Foroozan R, Shields CL, Shields JA, et al. Congenital orbital varices causing extreme neonatal proptosis. Am J Ophthalmol. 2000 May;129(5):693-4. 22. Gallia GL, Moore C, Jordan L, et al. Neonatal cavernous carotid artery aneurysm: case report. J Neurosurg. 2005 Apr;102(3 Suppl):332-7. 23. Garden JW, McManis JC. Congenital orbital-intracranial teratoma with subsequent malignancy: case report. Br J Ophthalmol. 1986 Feb;70(2):111-3. 24. Gnanaraj L, Skibell BC, Coret-Simon J, et al. Massive congenital orbital teratoma. Ophthal Plast Reconstr Surg. 2005 Nov;21(6):445-7. 25. Goldstein I, Tamir A, Zimmer EZ, et al. Growth of the fetal orbit and lens in normal pregnancies. Ultrasound Obstet Gynecol. 1998 Sep;12(3):175-9. 26. Goto S, Umehara S, Gerbing RB, et al. Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer. 2001 Nov 15;92(10):2699-708. 27. Gottlieb C, Nijhawan N, Chorneyko K, et al. Congenital orbital and disseminated extrarenal malignant rhabdoid tumor. Ophthal Plast Reconstr Surg. 2005 Jan;21(1):76-9. 28. Grover AK, Chaudhuri Z, Popli J. Clinical anophthalmia with orbital heterotopic brain tissue. Ophthalmic Surg Lasers Imaging. 2007 Mar-Apr;38(2):148-50. 29. Grundy R, Anderson J, Gaze M, et al. Congenital alveolar rhabdomyosarcoma: clinical and molecular distinction from alveolar rhabdomyosarcoma in older children. Cancer. 2001 Feb 1;91(3):606-12. 30. Guthoff R, Klein R, Lieb WE. Congenital cystic eye. Graefes Arch Clin Exp Ophthalmol. 2004 Mar;242(3):268-71. 31. Hamidah A, Reena M, Halim AR, et al. Successful treatment of very large

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congenital infantile fibrosarcoma. Pediatr Int. 2011 Oct;53(5):768-70. 32. Harlow PJ, Kaufman FR, Siegel SE, et al. Orbital rhabdomyosarcoma in a neonate. Med Pediatr Oncol. 1979;7(2):123-6. 33. Himmel S, Siegel H. Congenital embryonal orbital rhabdomyosarcoma in a newborn. Arch Ophthalmol. 1967 May;77(5):662-5. 34. Kato T, Watanabe K. Visual evoked potential in the newborn: does it have predictive value? Semin Fetal Neonatal Med. 2006 Dec;11(6):459-63. 35. Katorza E, Rosner M, Zalel Y, et al. Prenatal ultrasonographic diagnosis of persistent hyperplastic primary vitreous. Ultrasound Obstet Gynecol. 2008 Aug;32(2):226-8. 36. Kim KM, Kang SJ, Kim DS, Chi JG, Kim SM. Congenital intraorbital optic nerve cyst. Case report. J Neurosurg. 1999 Aug;91(2):325-7. 37. Kim MJ, Lee JH, Lee DW, et al. Congenital axial high myopia detected by prenatal ultrasound. J Pediatr Ophthalmol Strabismus. 2009 Jan-Feb;46(1):50-3. 38. Kook KH, Park MS, Yim H, et al. A case of congenital orbital malignant rhabdoid tumor: systemic metastasis following exenteration. Ophthalmologica. 2009;223(4):274-8. 39. Kurjak A, Azumendi G, Andonotopo W, et al. Three- and four-dimensional ultrasonography for the structural and functional evaluation of the fetal face. Am J Obstet Gynecol. 2007 Jan;196(1):16-28. 40. Kurjak A, Azumendi G, Andonotopo W, et al. Three- and four-dimensional ultrasonography for the structural and functional evaluation of the fetal face. Am J Obstet Gynecol. 2007 Jan;196(1):16-28. 41. Lacey NA, McWilliams S, Jan W, et al. Case of the month: congenital unilateral proptosis. Br J Radiol. 2002 Feb;75(890):191-2. 42. Lee GA, Sullivan TJ, Tsikleas GP, et al. Congenital orbital teratoma. Aust N Z J Ophthalmol. 1997 Feb;25(1):63-6. 43. Lehman SS. Antenatal ophthalmology. J AAPOS. 2003 Dec;7(6):428-9. 44. Lobe TE, Wiener ES, Hays DM,et al. Neonatal rhabdomyosarcoma: the IRS experience. J Pediatr Surg. 1994 Aug;29(8):1167-70. 45. Lonergan GJ, Schwab CM, Suarez ES, et al. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: radiologic-pathologic correlation. Radiographics. 2002 Jul-Aug;22(4):911-34. 46. Mahapatra AK. Anterior encephaloceles. Indian J Pediatr. 1997 SepOct;64(5):699-704. 47. Mahapatra AK, Agrawal D. Anterior encephaloceles: a series of 103 cases over 32 years. J Clin Neurosci. 2006 Jun;13(5):536-9. 48. Mahesh L, Krishnakumar S, Subramanian N, et al. Malignant teratoma of the orbit: a clinicopathological study of a case. Orbit. 2003 Dec;22(4):305-9. 49. Mahony R, McParland P. Approaches to the management of antenatally diagnosed congenital tumours. Pediatr Radiol. 2009 Nov;39(11):1173-8. 50. Mehta M, Chandra M, Sen S, et al. Orbital teratoma: a rare cause of congenital proptosis. Clin Experiment Ophthalmol. 2009 Aug;37(6):626-8. 51. Merz E, Abramovicz J, Baba K, et al. 3D imaging of the fetal face recommendations from the International 3D Focus Group. Ultraschall Med. 2012 Apr;33(2):175-82.

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52. Mirzai H, Baser EF, Tansug N, et al. Primary orbital neuroblastoma in a neonate. Indian J Ophthalmol. 2006 Sep;54(3):206-8. 53. Monteagudo A, Timor-Tritsch IE, Friedman AH, et al. Autosomal dominant cataracts of the fetus: early detection by transvaginal ultrasound. Ultrasound Obstet Gynecol. 1996 Aug;8(2):104-8. 54. Mynatt CJ, Feldman KA, Thompson LD. Orbital infantile myofibroma: a case report and clinicopathologic review of 24 cases from the literature. Head Neck Pathol. 2011 Sep;5(3):205-15. 55. O'Driscoll DA, O'Neill M. Progressive proptosis in a neonate. Postgrad Med J. 1998 Sep;74(875):559-61. 56. Obaldo RE, Shao L, Lowe LH. Congenital glioependymal cyst presenting with severe proptosis. AJNR Am J Neuroradiol. 2007 Jun-Jul;28(6):999-1000. 57. Ortube MC, Lazareff J, Vinters HV, et al. Orbital ectopic brain tissue in Aicardi syndrome. J Craniofac Surg. 2010 Sep;21(5):1551-3. 58. Paquette LB, Jackson HA, Tavaré CJ, et al. In utero eye development documented by fetal MR imaging. AJNR Am J Neuroradiol. 2009 Oct;30(9):1787-91. 59. Paragache G, Panda NK, Joshi K. Unilateral progressive proptosis in neonate. Indian J Otolaryngol Head Neck Surg. 2004 Jan;56(1):35-6. 60. Parkes SE, Muir KR, Southern L, et al. Neonatal tumours: a thirty-year population-based study. Med Pediatr Oncol. 1994;22(5):309-17. 61. Pellant A, Chrobok V, Mejzlík J. Anterior orbital meningoencephalocele. Eur Arch Otorhinolaryngol. 2010 Sep;267(9):1475-6. 62. Preece JM, Cornette L, El-Hindy N. Simple management of isolated proptosis at birth. Arch Dis Child Fetal Neonatal Ed. 2005 May;90(3):F234. 63. Ramos GA, Ylagan MV, Romine LE, D'Agostini DA, Pretorius DH. Diagnostic evaluation of the fetal face using 3-dimensional ultrasound. Ultrasound Q. 2008 64. Reuser TT, Cruysberg JR. Ectopic teeth in the orbit of a neonate. Br J Ophthalmol. 1995 Dec;79(12):1144-5. 65. Ramos-Perea C, Fernández-Seín A, Bonet N, et al. Congenital orbital alveolar rhabdomyosarcoma. Bol Asoc Med P R. 1983 Oct;75(10):481-3. 66. Robinson AJ, Blaser S, Toi A, et al. MRI of the fetal eyes: morphologic and biometric assessment for abnormal development with ultrasonographic and clinicopathologic correlation. Pediatr Radiol. 2008 Sep;38(9):971-81. 67. Rodriguez-Galindo C, Ramsey K, Jenkins JJ, et al. Hemangiopericytoma in

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children and infants. Cancer. 2000 Jan 1;88(1):198-204.

68. Rosati P, Guariglia L. Early transvaginal fetal orbital measurements: a screening tool for aneuploidy? J Ultrasound Med. 2003 Nov;22(11):1201-5. 69. Seider N, Gilboa M, Barishak YR, et al. Congenital combined orbito-nasal lipoblastoma: clinico-pathologic study. Orbit. 2007 Jun;26(2):125-7. 70. Sheng WQ, Hisaoka M, Okamoto S, et al. Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues. Am J Clin Pathol. 2001 Mar;115(3):348-55. 71. Shields JA, Shields CL. Orbital cysts of childhood--classification, clinical features, and management. Surv Ophthalmol. 2004 May-Jun;49(3):281-99. 72. Singh AD, Traboulsi EI, Reid J, et al. Orbital cyst: prenatal diagnosis.

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Ophthalmology. 2009 Oct;116(10):2042-42.e2. 73. Stidham DB, Burgett RA, Davis MM, Plager DA: Congenital malignant rhabdoid tumor of the orbit. J AAPOS 1999;3:318–320. 74. Stein-Wexler R. Pediatric soft tissue sarcomas. Semin Ultrasound CT MR. 2011 Oct;32(5):470-88. 75. Sukonpan K, Phupong V. A biometric study of the fetal orbit and lens in normal pregnancies. J Clin Ultrasound. 2009 Feb;37(2):69-74. 76. Tsang HH, Dolman PJ, Courtemanche DJ, et al. Prenatal Presentation of Frontoorbital Congenital Infantile Fibrosarcoma: A Clinicopathologic Report. JAMA Ophthalmol. 2013 Apr 4:1-3. 77. Tse DT, Abdulhafez M, Orozco MA, et al. Evaluation of an integrated orbital tissue expander in congenital anophthalmos: report of preliminary clinical experience. Am J Ophthalmol. 2011 Mar;151(3):470-82.e1. 78. Tuncer S, Kebudi R, Peksayar G, et al. Congenital mesenchymal chondrosarcoma of the orbit: case report and review of the literature. Ophthalmology. 2004 May;111(5):1016-22. 79. Uhl M, Altehoefer C, Kontny U, et al. MRI-diffusion imaging of neuroblastomas: first results and correlation to histology. Eur Radiol. 2002 Sep;12(9):2335-8. 80. Vazquez E, Castellote A, Mayolas N, et al. Congenital tumours involving the head, neck and central nervous system. Pediatr Radiol. 2009 Nov;39(11):115872. 81. Watanabe H, Watanabe T, Kaneko M, et al. Treatment of unresectable malignant rhabdoid tumor of the orbit with tandem high-dose chemotherapy and gammaknife radiosurgery. Pediatr Blood Cancer. 2006 Nov;47(6):846-50. 82. Wilson RD. Management of fetal tumors. Best Pract Res Clin Obstet Gynaecol. 2008 Feb;22(1):159-73. 83. Wong HS, Parker S, Tait J, et al. Antenatal diagnosis of anophthalmia by threedimensional ultrasound: a novel application of the reverse face view. Ultrasound Obstet Gynecol. 2008 Jul;32(1):103-5. 84. Yazici B, Bilge AD, Yazici Z, et al. Congenital cranio-orbital myofibroma. Ophthal Plast Reconstr Surg. 2011 Jul-Aug;27(4):e108-11. 85. Yen MT, Tse DT. Congenital orbital cyst detected and monitored by prenatal ultrasonography. Ophthal Plast Reconstr Surg. 2001 Nov;17(6):443-6. 86. Zhang N, Lin LK. Presumed primary orbital neuroblastoma in a 20-month-old female. Ophthal Plast Reconstr Surg. 2010 Sep-Oct;26(5):383-5. Legends

Figure 1. Sagittal (A) and coronal (B) T1-weighted MRI, demonstrating a right retrobulbar mass causing profound proptosis in a 1-day-old neonate. The mass occupies nearly the entire right orbit and deforms the ipsilateral globe. Note the irregular postcontrast enhancement pattern originally thought to be consistent with cavernous hemangioma. Figure 2. Clinical appearance of the same neonate on the second day of life, with gross right-sided proptosis, severe exposure and retracted eyelids (A,B). Light reflex was

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absent in the right eye, and a brisk APD was observed. Vascularized oral (C, closed arrow) and subcutaneous nodules (D) were identified during a comprehensive examination of the cutaneous and mucosal surfaces.

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Figure 3. (A) Intraoperative appearance on day 3 demonstrating the relationship between the orbital mass and proptotic eye. Meticulous dissection permitted globesparing surgery with tumor-free margins. (B) Postoperative appearance at 1 month demonstrating significant improvement in eyelid position. (C) Hematoxylin and eosin stain demonstrating basophilic cells in a vascularized connective tissue matrix with areas of extensive necrosis (10x magnification). (D) Homer-Wright rosettes (20x magnification). This histopathologic appearance is consistent with metastatic neuroblastoma.

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Figure 4. (A) Prenatal ultrasound at 23 weeks of gestation demonstrating a large left orbital cyst surrounding the globe and optic nerve (open arrow) and measuring 3.3 x 3.9 x 3.0 cm. This mass remained stable in size on subsequent fetal imaging studies. (B) Oneday-old neonate with extreme left sided proptosis, corneal opacification, and marked prolapse of a transilluminating orbital cyst.

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Figure 5. Coronal (A) and axial (B) T1-weighted MRI scans demonstrating a large left orbital cyst without dural connections. Significant globe displacement and attenuation of the ipsilateral optic nerve (open arrow) is visible on the axial image. (C) Intraoperative image demonstrating a cleavage plane within the orbital cyst. Its identification permitted full surgical excision without rupture. Histopathology demonstrated a simple epithelial cyst lined by stratified squamous and cuboidal epithelium. (D) Direct visualization of the severely attenuated left optic nerve (closed arrow).

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Figure 6. The globe was successfully preserved, but the patient subsequently developed a large angle sensory exotropia. She pictured here at the 15-month postoperative visit after fitting of a cosmetic scleral shell (A). At age 15, she demonstrates symmetric craniofacial development with absence of forehead flattening, brow depression or cheek hypoplasia (B).

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Figure 7. (A) Profound proptosis of the right globe in a 7-day-old neonate with corneal epithelial defect, chemosis and superotemporal conjunctival erosion. Focal protrusion of the underlying mass is readily apparent, suggesting aggressive clinical behavior. (B) Respected specimen demonstrating gross infiltration of the eye. Globe sparing surgery could not safely be performed. (C) Retraction of the stretched eyelids reveals the exenterated orbit. The apex was positive for residual infantile fibrosarcoma, prompting the initiation of chemotherapy. (D) Appearance of the child 4 years following chemotherapy. She is wearing a prosthesis over an inflated orbital tissue expander. Note the absence of forehead flattening, brow depression or cheek hypoplasia.

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