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 Table of Contents  
Year : 2020  |  Volume : 10  |  Issue : 3  |  Page : 181-183

Orbital hybrid peripheral nerve sheath tumors

Department of Ophthalmology, Tung Wah Eastern Hosptial, Causewaybay, Hong Kong

Date of Submission10-Feb-2020
Date of Acceptance28-Apr-2020
Date of Web Publication27-Jul-2020

Correspondence Address:
Dr. Kai Ching Peter Leung
Department Of Ophthalmology, Tung Wah Eastern Hospital, Causewaybay
Hong Kong
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjo.tjo_28_20

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Hybrid peripheral nerve sheath tumors (HPNST) are recently classified tumors from the World Health Organization Classification of soft tissue tumors that display combined features of more than one peripheral nerve sheath tumor. Acknowledgment is important because of its association with the development of neurofibromatosis type 1, type 2, and schwannomatosis. Orbital involvement is rare and only six cases of HPNST have been documented on literature. This article serves to review the pathophysiology, clinical manifestation, diagnosis, treatment, and prognosis of this infrequent but important orbital tumor.

Keywords: Hybrid peripheral nerve sheath tumor; neurofibroma-schwannoma; neurofibroma-perineurioma; orbital; orbital tumor

How to cite this article:
Leung KC, Ko TC. Orbital hybrid peripheral nerve sheath tumors. Taiwan J Ophthalmol 2020;10:181-3

How to cite this URL:
Leung KC, Ko TC. Orbital hybrid peripheral nerve sheath tumors. Taiwan J Ophthalmol [serial online] 2020 [cited 2021 Jun 18];10:181-3. Available from: https://www.e-tjo.org/text.asp?2020/10/3/181/290873

  Introduction Top

Hybrid peripheral nerve sheath tumor (HPNST) is a unique pathological entity that contained mixed components of neurofibroma, perineurioma, and schwannoma. Three subtypes of HPNST have been identified: neurofibroma-schwannoma, schwannoma-perineurioma and neurofibroma-perineurioma in decreasing level of incidence. Significance of hybrid tumor is important because of its potential risk of associated neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis.[1] Orbital involvement of HPNST is rare, but reports are growing with five new cases described in between 2017 and 2019.[2],[3],[4],[5],[6] Clinical manifestation and prognosis within the orbit remained largely unknown due to its paucity. This article reviews the pathophysiology, clinical manifestation, diagnosis, treatment, and prognosis of this infrequent but important orbital tumor.

  Pathophysiology Top

HPNST are rare tumors categorized under the World Health Organization Classification of soft tissue tumors that display features of more than one peripheral nerve sheath tumor.[7] The development of neurocutaneous tumors (NF1, NF2, and schwannomatosis) and HPNST are highly linked to somatic and biallelic mutations of NF1 gene (17q11.2) and NF2 gene (22q12.2). Specifically, functional loss of neurofibromin protein in NF1 gene mutation causes neurofibroma and subsequent NF1, where loss of NF2 gene function contributed to development perineurioma and NF2.[8],[9],[10] Similarly, biallelic inactivation NF2 gene mutation related merlin loss is associated with schwannoma and schwannomatosis development, which also includ mutations of the switch-sucrose nonfermentable chromatin remodeling subunit SMARCB1/INI1 (22q11.23).[11],[12]

In hybrid neurofibroma-schwannoma, the plexiform type of neurofibroma is most commonly seen and is pathognomonic for NF1.[13] Surprisingly, hybrid neurofibroma-schwannoma has been observed to be associated with the development of NF2, schwannomatosis, and NF1 in decreasing frequency.[11],[14] A further study on this HPNST has also discovered that 44% of tested tumors harbor monosomy of chromosome 22 and linked to the development of NF2.[12] The reason why NF1 are less encountered remained unexplained. Preliminary studies have reported a possible precursor role for perineurial proliferation in NF1 in hybrid neurofibroma-perineurioma.[1],[15] Little is known about the connection between hybrid schwannoma-perineurioma and neurocutaneous syndromes, which development appeared sporadic.

  Clinical Manifestation Top

HPNST chiefly occurs in subcutaneous and subdermal areas, infrequently involving the orbit, facial nerve, and nasopharynx.[16],[17] Literature review has reported six cases of HPNST that arose from within the orbit.[2],[3],[4],[5],[6],[18] Orbital HPNST appears to occur in young adults without any gender (three males, three females) and laterality predilection. The most frequently occurring orbital HPNST subtype is neurofibroma-schwannoma (five cases) followed by neurofibroma-perineurioma (one case). The tumor tends to present unilaterally over the superior aspect of the orbit, which may involve the distribution of supraorbital and supratrochlear nerves. Extraconal orbital HPNST appears to present more often than intraconal involvement, which was speculated by the presence of a greater number of nerves in extraconal space relative to the intraconal area.[3]

Clinically, orbital HPNST manifest as a space-occupying lesion that causes local displacement over the course of the nerve. The onset is slow, and vision is not affected unless there is intraconal involvement. Orbital tenderness, diplopia, and hyperesthesia are infrequently described. Localized mass effect gives rise to clinical signs such as nonaxial proptosis, ptosis, and hypoglobus. All but one case was asymptomatic and was discovered as an incidental finding.

  Diagnosis Top

On histological analysis, orbital HPNST demonstrates a biphasic pattern, such as a clear transition of the different cell types or intermingling. Specifically, neurofibroma-schwannoma exhibits islands of schwannoma in a background of neurofibroma.[14] Schwannoma lobules classically display Antoni A and B areas, where Antoni A represents highly cellular spindle cells arranged in fascicles with nuclear palisading and Verocay bodies and Antoni B areas have reduced cellularity with myxoid regions. Neurofibroma demonstrates the proliferation of Schwann cells, perineural cells in a background of mucin, fibroplasia, and collagen, which nuclei showed wavy serpentine and pointed ends. Neurofibroma-perineurioma hybrid has a unique retiform appearance that has a mosaic arrangement of spindle cells that merge with background neurofibroma [Figure 1].[1]
Figure 1: Example of a hybrid neurofibroma-perineurioma that displayed retiform arrangement merging into the background neurofibroma on haematoxylin and eosin stain. Low power view

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Immunohistochemistry facilitates diagnosis with neurofibroma manifesting S-100 protein and immunostain positivity; schwannoma showing strong S-100 positivity; and perineurioma showing epithelial membrane antigen, glucose transporter protein 1 and claudin-1 positivity [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d.[19] The study of staining patterns of S-100 helps in differentiating schwannoma from neurofibroma. Expression of S-100 protein is more diffusely stained involving all of schwannoma tumor cells, contrasting to neurofibroma, where staining is only limited to about 50% of cells.[1] Nonetheless, a biopsy of normal-looking nerve fibers may aid diagnosis in ambivalent cases.
Figure 2: (a) Immunohistochemistry of neurofibroma staining positive with the S-100 protein × 200. (b) Immunohistochemistry of neurofibroma staining positive with immunostain × 200. (c) Immunohistochemistry of schwannoma staining positive with S-100 protein × 100. The staining pattern of schwannoma is characteristically much more diffuse and involves almost all tumor cells compared with neurofibroma. (d) Immunohistochemistry of perineurioma staining positive with epithelial membrane antigen × 200

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  Treatment and Prognosis Top

Surgical excision through anterior orbitotomy remains the mainstay of treatment for orbital HPNST, given its common superior extraconal presentation. For intraconal tumors excision through frontotemporal craniotomy and transconjunctival approach were reported for better surgical access. Tumors are commonly yellowish-gray, firm, well-demarcated, circumscribed, and devoid of vascularity, makingin vivo identification and retrieval of tumor possible. The postoperative course is generally satisfactory with resolution of proptosis. Reports of dysesthesia over the course of supraorbital and supratrochlear nerve were regularly described after surgical exploration (three cases). Visual acuity and diplopia improved in cases of intraconal tumors, with mild residual abducens cranial nerve palsy after craniotomy.

No cases of malignant transformation were observed after total excision despite reports in extra-orbital neurofibroma-perineurioma hybrid tumors.[1],[2] No associated cases of neurocutaneous syndromes were reported. To date, no recurrence of orbital HPNST were described after excision on 1-year follow-up, although long-term reviews are necessary to acertain the true recurrence rate given the slow and insidious nature with this tumor.

  Summary Top

HPNST is increasingly being reported to occur within the orbit. Acknowledgment is important because of its association with the development of NF1, NF2, and schwannomatosis, with possible malignant transformation. Variable clinical presentations occur and relate to extraconal and intraconal involvement. Diagnosis is achieved through detailed histological and immunopathological examinations. The mainstay of treatment involved surgical excision, which yielded acceptable outcomes. Active screening for development into neurocutaneous syndromes, malignant transformation and recurrence postoperatively is essential for this infrequent and unique group of tumors.

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Conflicts of interest

The authors declare that there are no conflicts of interests of this paper.

  References Top

Michal M, Kazakov DV, Michal M. Hybrid peripheral nerve sheath tumors: A review. Cesk Patol 2017;53:81-8.  Back to cited text no. 1
Taubenslag KJ, Nickols HH, Chelnis JG, Mawn LA. Hybrid neurofibroma/schwannoma of the supraorbital nerve: Clinicopathologic correlation of a rare tumor. Ophthalmic Plast Reconstr Surg 2017;33:S104-6.  Back to cited text no. 2
Stevenson LJ, McElnea EM, McKelvie PA, Hardy TG. Hybrid neurofibroma/schwannoma of the orbit. Ophthalmic Plast Reconstr Surg 2019;35:e49-52.  Back to cited text no. 3
Hong S, Hara T. Hybrid nerve sheath tumor in the orbit: A case report and review of literature. Surg Neurol Int 2019;10:250.  Back to cited text no. 4
Verhelst E, Lauwers N, Siozopoulou V, de Keizer RW, de Groot V. Intraconal hybrid neurofibroma – Schwannoma of the orbit. Acta Ophthalmol 2017;95. [doi: 10.1111/j. 1755-3768.2017.01190].  Back to cited text no. 5
Leung KC, Chan E, Ng HY, Ko TC. Novel case of hybrid perineurioma-neurofibroma of the orbit. Can J Ophthalmol 2019;54:e283-5.  Back to cited text no. 6
Jo VY, Fletcher CD. WHO classification of soft tissue tumours: An update based on the 2013 (4th) edition. Pathology 2014;46:95-104.  Back to cited text no. 7
Lasota J, Fetsch JF, Wozniak A, Wasag B, Sciot R, Miettinen M. The neurofibromatosis type 2 gene is mutated in perineurial cell tumors: A molecular genetic study of eight cases. Am J Pathol 2001;158:1223-9.  Back to cited text no. 8
Giannini C, Scheithauer BW, Jenkins RB, Erlandson RA, Perry A, Borell TJ, et al. Soft-tissue perineurioma. Evidence for an abnormality of chromosome 22, criteria for diagnosis, and review of the literature. Am J Surg Pathol 1997;21:164-73.  Back to cited text no. 9
Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers 2017;3:17004.  Back to cited text no. 10
Harder A, Wesemann M, Hagel C, Schittenhelm J, Fischer S, Tatagiba M, et al. Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients. Am J Surg Pathol 2012;36:702-9.  Back to cited text no. 11
Stahn V, Nagel I, Fischer-Huchzermeyer S, Oyen F, Schneppenheim R, Gesk S, et al. Molecular analysis of hybrid neurofibroma/schwannoma identifies common monosomy 22 and α-T-catenin/CTNNA3 as a novel candidate tumor suppressor. Am J Pathol 2016;186:3285-96.  Back to cited text no. 12
McCarron KF, Goldblum JR. Plexiform neurofibroma with and without associated malignant peripheral nerve sheath tumor: A clinicopathologic and immunohistochemical analysis of 54 cases. Mod Pathol 1998;11:612-7.  Back to cited text no. 13
Feany MB, Anthony DC, Fletcher CD. Nerve sheath tumours with hybrid features of neurofibroma and schwannoma: A conceptual challenge. Histopathology 1998;32:405-10.  Back to cited text no. 14
Agaimy A. Microscopic intraneural perineurial cell proliferations in patients with neurofibromatosis type 1. Ann Diagn Pathol 2014;18:95-8.  Back to cited text no. 15
Kuroda N, Kazakov DV, Hes O, Michal M, Goda M, Miyazaki K, et al. Hybrid peripheral nerve sheath tumor of the nasal cavity showing schwannomatous, neurofibromatous, and perineuriomatous areas. Med Mol Morphol 2010;43:82-5.  Back to cited text no. 16
Murray S, Bullock MJ, Taylor SM. A case of multiple neurofibroma/schwannoma hybrid tumors of the facial nerve. Otolaryngol Head Neck Surg 2015;152:569-70.  Back to cited text no. 17
Youens KE, Woodward J, Wallace D, Cummings TJ. Hybrid neurofibroma-schwannoma of the orbit. Orbit 2008;27:223-5.  Back to cited text no. 18
Hirose T, Tani T, Shimada T, Ishizawa K, Shimada S, Sano T. Immunohistochemical demonstration of EMA/Glut1-positive perineurial cells and CD34-positive fibroblastic cells in peripheral nerve sheath tumors. Mod Pathol 2003;16:293-8.  Back to cited text no. 19


  [Figure 1], [Figure 2]


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