Hybrid nerve sheath tumor of the spinal canal and neurofibromatosis-2, where the twain shall meet—a case report and review of literature

Abstract

Background

A hybrid nerve sheath tumor is a biphasic, benign neoplasm of peripheral nerve sheaths, consisting of combinations of neurofibroma, schwannoma, or perineurioma. These tumors were recognized only recently, in 2013; they commonly occur sporadically but rarely with syndromic associations, such as neurofibromatosis syndrome, Carney complex, and schwannomatosis. With an occurrence of 1 in every 33,000 individuals, neurofibromatosis type 2 is a rare autosomal dominant condition characterized by bilateral vestibular schwannomas. Herein we report a serendipitous occurrence of a hybrid nerve sheath tumor with neurofibromatosis type 2 syndrome, with an emphasis on its diagnostic mimics.

Case report

A 35-year-old Indian male patient presented to the clinic with balance dysfunction, left-sided hearing loss, and spastic weakness in all four limbs during the past 6 months. Neurological examination revealed increased motor tone in all four limbs, bilateral 4/5 limb strength, a right grip strength of 80%, and a left grip strength of 90%. Romberg’s sign, Babinski sign (extensor), and Hoffman’s sign were positive. No cerebellar signs were elicited. A cranial nerve examination revealed bilateral hearing impairment, with hearing of the left being greater than that of the right.

Magnetic resonance imaging revealed, an ependymoma at C1–2, a hyperintensive T2 lesion (likely a meningioma), a neurofibroma at C2, and bilateral vestibular schwannomas at the cerebellopontine angle. The patient underwent tumor excision surgery under somatosensory evoked potential/motor evoked potential monitoring. The tumor at the C2 level showed a nodular arrangement with typical schwannian nodules (SOX-10 strongly positive and epithelial membrane antigen negative); these nodules were encased by a hypocellular neurofibroma component (CD34⁺), forming a lattice around the former. No necrosis or increased proliferation index was noted.

Conclusion

Neurofibromatosis type 2 syndrome is a rare condition, associated with mutations in both alleles of the NF2 (Merlin) gene, and is associated with meningiomas and ependymomas, as seen in this patient. Its occurrence alongside a spinal hybrid nerve sheath tumor is rare and can often lead to an erroneous diagnosis of other nerve sheath tumors or, rarely, a malignant nerve sheath tumor. This case highlights this rare confluence and its mimickers.

Introduction

In medicine you will encounter unique and atypical presentations; however, it is the nature of pathology that you will find the secrets behind them. This case serves as the union of two rare diseases/lesions with an atypical presentation and underlying unusual pathological findings.

A hybrid nerve sheath tumor (HNST) is a biphasic, benign neoplasm of peripheral nerve sheaths that displays combinations of neurofibroma, schwannoma, or perineurium. Typically, this tumor is present in the dermis or subcutaneous tissues of the extremities and trunk and rarely poses any immediate health risk. HNSTs were recognized only recently, in 2013, by the World Health Organization (WHO). These tumors commonly occur sporadically and rarely with syndromic associations, such as neurofibromatosis syndrome, Carney complex, and schwannomatosis [1]. These unique neoplasms pose a diagnostic challenge because of their diverse morphology and other common mimics.

With an occurrence of 1 in every 25,000–40,000 individuals, neurofibromatosis type 2 syndrome (NF2) is a rare autosomal dominant condition characterized by bilateral vestibular schwannomas and meningiomas [2]. However, a paraspinal HNST uncovering an NF2 is less common. Herein we report a serendipitous occurrence of an HNST with NF2 syndrome, with an emphasis on diagnostic mimics.

Case presentation

Presentation and imaging

A 35-year-old Indian male patient presented to the clinic with an imbalance while walking, bilateral tinnitus, and left-sided hearing loss for the past 6 months, which worsened in the past 5 days. In addition, the patient experienced bilateral upper and lower limb tingling, numbness, and a cotton wool sensation while walking. Right-sided spastic weakness was also present. Tinnitus was continuous and increased at night. It was not associated with headache, nausea, or vomiting. The patient’s past history noted episodes of ear discharge 2 years prior, which improved with medication, and dizziness for the past 2 years, which is positional.

The patient was conscious and oriented with stable vitals during examination. On inspection of the back, no café au lait spots were found. Neurological examination revealed increased motor tone in all four limbs, bilateral 4/5 limb strength, a right grip strength of 80%, and a left grip strength of 90%. Deep tendon reflexes were all rated 3+. Bilateral Romberg’s sign, Babinski sign (extensor), and Hoffman’s sign were positive. No cerebellar signs were elicited and the abdominal reflex was absent. A cranial nerve examination revealed bilateral hearing impairment, with the hearing of the left being greater than that of the right. Ear examination revealed a right intact tympanic membrane with grade 1 retraction and healed central perforation with tympanoscleortic notch in the left ear. Tympanography revealed a type A tympanogram with minimal to moderate sensorineural hearing loss in the right ear and moderate sensorineural hearing loss in the left ear. In addition, bilateral ipsilateral and contralateral reflexes were absent until the frequency reached 4 kHz.

On completion of the clinical evaluation, on the day of presentation, magnetic resonance imaging (MRI) of the spine and brain was ordered. The MRI of the spine revealed a well-defined T2 hyperintense extramedullary lesion noted on the posterior aspect of the craniovertebral (CV) junction, causing significant compression of the cervical cord. This lesion is likely meningioma. In addition, Dumbbell-shaped intra- and extramedullary lesions at C2, along with a neurofibroma (Fig. 1A,B). MRI of the brain revealed bilateral cerebellopontine (CP) angle lesions (left larger than right), likely vestibular schwannomas, which led to the clinical diagnosis of NF2 on the basis of the 2018 diagnostic criteria (Fig. 1C). These two lesions were considered important because of their position. Additional visualized lesions included intramedullary lesions in the upper cervical cord at the C1 and C2 levels, which are likely ependymomas, and hyperintense signal changes in the lower brain stem and upper cervical cord at the C3 level, which are likely syrinxes.

Fig. 1

Magnetic resonance images of the spine and brain. (a) Median section of the spine with Dumbbell-shaped intra and extramedullary lesions at C2, neurofibroma, (b) transverse section of the spine with umbbell-shaped intra and extramedullary lesions at C2, neurofibroma, (c) cerebellopontine angle lesion of vestibular schwannoma

A computed tomography (CT) scan of the spine was done a day before surgery, and showed a well-defined axial broad-based lesion in the foramen magnum region with focal hyperdensities (likely calcification) causing spinal canal stenosis, (likely meningioma).

Treatment and posttreatment outlook

The patient was scheduled for tumor excision surgery, 1-day following CT scan of the spine. Under aseptic precautions, the surgical site was painted and draped, and the incision was made and advanced. The foramen magnum rim was drilled, and the C1 arch and partial C2 lamina were removed. The dura was opened and the flaps were retracted. A large, partly calcified meningioma was noted in the region of the foramen magnum which was was attached to the posterior and both the lateral leaflets, extending to the ventrolateral aspect of the spinal cord. The meningioma was excised in toto in piecemeal fashion and the dural attachments were coagulated. Later, myelotomy was performed at C1 and C2 and Pial sutures were placed. A brownish-red intramedullary tumor was noted; it was moderately vascular. Tumoral decompression was performed and somatosensory evoked potential (SSEP)/motor evoked potential (MEP) was monitored at regular intervals. The tumor had a good plane of dissection all around, except the super-anterior portion, which was left behind. Near-total excision of the tumor was performed. The dura was closed using 5.0 prolene sutures. MEPs and SSEPs were recorded and were found to be normal throughout the procedure. A large extradural C2 neurofibroma was noted on the left side. It was soft and firm, moderately vascular, and with a good plane of dissection. The complete tumor was excised. Hemostasis was secured. The wound was closed with Vicryl 2-0 and Ethilon sutures, over a number 12 Romavac drain.

The patient was admitted to the intensive care unit (ICU) and extubated 1 day postoperatively. On examination, the patient demonstrated increased spasticity and worsening posterior column signs. Physiotherapy and gait training were suggested, alongside steroid and baclofen treatment. He was stable and was discharged in stable condition. The second stage of removal of vestibular schwannomas was planned for later.

Then, 18 days after discharge, the patient started experiencing reduced sleep and appetite and cerebrospinal fluid (CSF) leaking from the site of the wound. Symptoms were not associated with fever. A diagnostic lumbar puncture revealed an increased cell count. The swab from the wound grew Staphylococcus aureus. The patient received two sutures under aseptic conditions to prevent further leakage of CSF. The patient also received acetazolamide and appropriate antibiotic treatment for meningitis. During day 3 of admission, the patient developed urinary retention and paraparesis for which an MRI of the entire spine was carried out, which did not demonstrate any compressive lesions. The patient was treated with steroids and improved clinically. The patient was discharged on day 8 of admission, with stable vitals, a healthy wound, and no new neurological complications.

Pathology findings

Histopathology of the C2 lesion revealed a biphasic tumor with cellular zones and nodules of spindle cells with hypocellular zones. Nuclear palisades and Verocay bodies were observed in the cellular zone, suggesting a schwannoma (Figs. 2 and 3). In the hypocellular zone, buckled nuclei and shredded collagen, which are signs of neurofibroma, were observed (Fig. 4). No necrosis or high proliferation index was observed.

Fig. 2

Histopathology of the hypercellular region of the biphasic C2 lesion under 100× magnification

Fig. 3

Histopathology of the hypercellular region of the C2 biphasic lesion, showing Verocay bodies under 400× magnification, indicating schwannoma

Fig. 4

Histopathology of the hypocellular region of the C2 biphasic lesion with shredded collagen under 400× magnification, indicative of neurofibroma

Immunohistochemistry (IHC) of the schwannian component revealed strong cytoplasmic and nuclear positivity for SOX-10 (Fig. 5), in addition to strong, retained nuclear expression of INI-1(Fig. 6). The nonschwannian components formed a strong CD34⁺ antibody lattice around the Schwannian nodule (Fig. 7). In addition, the epithelial membrane antigen (EMA) antibody highlighted cytoplasmic positivity in the perineurial component (Fig. 8).

Fig. 5

Immunohistochemistry of the schwannian component of the C2 lesion, positive for SOX-10

Fig. 6

Immunohistochemistry of the schwannian component of the C2 lesion with strong retained nuclear expression of INI-1

Fig. 7

Immunohistochemistry of the non-schwannian component of the C2 lesion forming a strong CD34⁺ lattice around the schwannian nodule

Fig. 8

Epithelial membrane antigen highlighting cytoplasmic positivity in the perineurial component

An intramedullary C1–2 lesion demonstrated fascicles of monomorphic neoplastic ependymal cells forming true rosettes (as indicted by arrow in Fig. 9), suggesting ependymoma (Fig. 9). Immunohistochemistry revealed that the lesion was glial fibrillary acidic protein (GFAP)-positive and had cytoplasmic positivity for EMA monoclonal antibodies (Figs. 10, 11). The lesion at the CV junction exhibited syncytial whorls of neoplastic meningothelial cells with indistinct cytoplasmic outlines, characteristic of meningioma (Fig. 12).

Fig. 9

Intramedullary C1–2 lesion (ependymoma) with fascicles of monomorphic neoplastic ependymal cells forming true rosettes (as indicated by arrow) using hematoxylin and eosin under 5 mm magnification

Fig. 10

Immunohistochemistry with glial fibrillary acidic protein positivity of the C1–2 intramedullary lesion under 5 mm magnification

Fig. 11

Immunohistochemistry with cytoplasmic epithelial membrane antigen monoclonal antibody positivity of the C1–2 intramedullary lesion under 5 mm magnification

Fig. 12

Syncytial whorls of neoplastic meningothelial cells with indistinct cytoplasmic outlines using hematoxylin and eosin under 5 mm magnification, characteristic of meningioma

Discussion and conclusion

History

A hybrid nerve sheath tumor is a benign neoplasm with combined features of greater than one nerve sheath tumor, most commonly presenting in the dermis or subcutaneous tissue. They were first described in 1998 by Feany and colleagues, who described seven cases of HNST in adult patients, all of which involved a schwannoma/neurofibroma combination. The following decade saw sporadic and few case series describing this novel entity. Hornick et al. [3] published a large series of 42 hybrids consisting of schwannoma/perineurium in 2009, which focused on more facets of this entity [4]. In 2013, the WHO working group substantiated the existence of HNSTs and expanded on the different composite components and their associations with syndromes [1].

Diagnostic challenge and mimics

In the current case, the patient presented with a C2 neural HNST in the spinal canal with a CP angle schwannoma, without a café au lait spot. This is atypical for NF1. Currently, diagnostic reconsideration is imperative. This union of two atypical presentations and occurrences opens the window for discussion of the etiological correlation between the two lesions. NF2 is a more appropriate explanation of the presentation at hand. It may also be associated with ependymomas, meningiomas, and ocular abnormalities but rarely with HNSTs, with a frequency quotient of 10–15%.

To explore the rarity and diagnostic challenge of this case, the HNST in the patient was a combination of schwannoma and neurofibroma. This is not only a rare occurrence but also a challenging diagnosis owing to its ability to radiologically mimic a basic schwannoma. A more common occurrence is a combination of neurofibroma and perineurioma. The use of IHC for complex pathologies can be highly effective, as indicated by the following IHCs: SOX-10, which stains schwannomas and neurofibromas but is negative in perineurioma; EMA, which stains perineurial cells but is negative in schwannomas and neurofibromas; CD34, which stains the fibroblasts in neurofibromas; and INI-1, which stains malignant peripheral nerve sheath tumor (MPNST) tissue lacking nuclear expression (70%), which is retained in other nerve tumors.

Clinical presentations similar to the one at hand (HNST of the spinal canal) may yield an erroneous diagnosis of neurofibromatosis type 1 (NF1). These findings suggest that IHC is a useful tool for eliminating differentials and reaching a definitive diagnosis. NF2 may be associated with diagnostic mimics of HNSTs present in the spinal canal. The IHC findings were (1) meningioma: positive EMA antibody, negative SOX-10 stain, and positive CD34 antibody; (2) schwannomas: biphasic morphology, positive SOX-10 stain, negative EMA antibody, and negative CD34 antibody; (3) MPNSTs: patchy and focal positivity for SOX-10 stain, loss of INI-1 stain nuclear expression, and high mitosis and nuclear atypia positivity; and (4) ependymomas: positive SOX-10 stain, dot-like positive EMA antibody, negative CD34 antibody.

Reported cases of spinal HNST

An extensive literature review found that the occurrence of spinal hybrid nerve sheath tumors is extremely rare, especially if these tumors present with syndromic associations (Table 1). This is a summary of the only three reported cases of spinal HNST, described in individual reports, none of which presented with syndromic associations. What is unique about these cases are the different clinical presentations and tumor locations found in all three, as well as the different diagnostic modalities used, such as claudin and GLUT-1.

Table 1 Summary of published cases of spinal hybrid nerve sheath tumors

Review of neurofibromatosis types 1 and 2

Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder characterized by skin pigmentation/macules called café au lait spots and the development of neurofibromas. This disease is also known as von Recklinghausen disease. Neurofibromatosis type 1 is associated with a mutation of the NF1 gene on the long arm of chromosome 17 [8]. The type of mutation may differ from stop mutations, (1;17) and (17;22) translocations, or point mutations 17q11.2 [9,10,11,12]. This mutation is associated with a defect in the synthesis of Neurofibrin-1, a tumor suppressor protein secreted by Schwann cells and oligodendrocytes. It functions by downregulating the Ras signaling pathway by promoting hydrolysis of the active form of Ras (GTP-bound Ras) to inactive GDP-bound Ras [12]. This leads to benign tumor cell proliferation, usually on or just below the skin. Tumors may develop in any part of the body, including the brain, and some may rarely develop malignant potential (particularly tumors that grow along the nerve sheath), leading to malignant hybrid nerve sheath tumors [13]. In a seminal paper by Woodruff, where he reviewed malignant peripheral nerve sheath tumor (MPNST) in patients with NF1, he concluded that neurofibroma was the precursor lesion, and it was either plexiform neurofibroma or a localized intraneural neurofibroma involving a large or medium-sized nerve or nerve plexus [14]. Patients with NF1 may also be prone to developing conditions, such as optic glioma, leukemia, Cowden syndrome, hamartoma neoplastic syndrome, and tuberous sclerosis, among other syndromic associations [8, 15]. In addition to the café au lait spots, children with NF1 may develop Lisch nodules in the iris (which usually do not interfere with vision). It may also be associated with hypertension or irritable bowel syndrome and constipation (in children) [16, 17].

In addition, neurofibromatosis type 2 is an autosomal dominant syndrome, but it is associated with the development of multiple CNS tumors, including schwannomas, meningiomas, and ependymomas [18]. It can be differentiated from NF1 by the absence of café au lait spots. This disease is caused by a mutation in the NF2 gene on chromosome 22, leading to the production of an abnormally shortened version of the NF2 protein, known as the “Merlin protein.” The Merlin protein is a tumor suppressor gene that serves as an upstream regulator of the Hippo signaling pathway. Merlin is associated with the ERM family of membrane cytoskeleton proteins. Its absence/mutation can lead to the inability to form proper cell-to-cell junctions and insensitivity to normal growth arrest signals generated by cell-to-cell contact. It is involved in the activation of the MST-1 protein, MST-2 protein, and Lats protein, while inactivating the YAP protein, which is a transcriptional coactivator. This leads to the prevention of tumorigenesis. The Merlin protein also serves a suppressor function in the Ras/Rac pathway and facilitates the binding of the ECM receptor proteins CD44, integrins, and actin. Sometimes, schwannomatosis is itself linked to somatic mutations in the NF2 gene or loss of heterozygosity (which is associated with Merlin protein inhibition), which may account for the syndromic association of HNST with neurofibromatosis type 2 [7, 19, 20]. NF2 is most commonly associated with acoustic schwannomatosis of the vestibulocochlear nerve, which leads to symptoms, such as balance dysfunction, hearing symptoms, and tinnitus, similar to those of the patient at the time of presentation. Less commonly, it may also be associated with facial weakness or paralysis [21]. Complications include diminished vision, fluid accumulation in the brain, and limb numbness or weakness [22]. Sometimes it may be associated with cataracts in one or both eyes in children [23]. It may be differentiated from NF1 by the absence of café au lait spots.

Neurofibromatosis type 2 syndrome is a rare autosomal dominant disease associated with mutations in both alleles of the NF2 gene. Its occurrence with an HNST of the spine in this patient mimics the presentation of NF1 and discounts the cerebellar element of balance dysfunction by presumed but absent spinocerebellar tract involvement. This highlights the importance of using IHC concurrently with MRI in making important definitive diagnoses of unusual presentations. In addition, the use of IHC could help differentiate HNSTs from other lesions, such as primary schwannomatosis or neurofibromatosis, in the spinal segment. Thus, the two, albeit rare and less known, links HNST and NF2. This case highlights this rare confluence and the potential risks of misdiagnosis.