Introduction

Schwannomas, also known as neurilemomas are neuroectodermal derived lesions. The cell of origin is Schwann cell, which is responsible for maintaining the myelin coating of neurons.¹ Schwann cells are glial cells that provide insulation for both the motor and the sensory neural signal in the peripheral nervous system. They have predilection for sensory nerves with the eighth nerve being most frequently affected.²

Schwannomas are usually isolated, solitary, slow-growing and well encapsulated lesions. In some cases, they are associated with neurofibromatosis syndrome and patients develop multiple Schwannomas, known as Schwannomatosis.¹

Aims of the present study are to analyse the spectrum of demographic and clinical presentations of Schwannoma with special emphasis on occurrence at unusual sites, to discuss the histopathological features of this lesion at these unusual locations and analyse with the available literature.

Materials and Methods

A 3-year retrospective cross-sectional observational study was done on 18 diagnosed cases of Schwannoma located at unusual sites after procuring Institutional Ethical Committee Clearance (IEC:15/23). The clinical, radiological and pathological details were retrieved from the hospital records and the pathology database. Parameters described in Table 1 were analysed.

Results

Age and Gender

Of the 18 cases studied, the age ranged from 20- 82 years with a mean age being 45.5 years. Sex ratio was equal.

Site and Size

Head and neck region, and the lower limb were the most common sites, consisting for 28% cases each, followed by 22% cases in abdomen/retroperitoneum region, 16 % cases in thorax, and 6% of cases in the upper limb (Figure 1).

Figure 1: Topographical distribution of the lesion

Clinical presentation

Majority of cases (38 %) presented with painless swelling. Other symptoms included backache (11%), abdominal pain (11%), limb pain (5%). Symptoms like blurring of vision (5%) and reduced hearing (5%) were noted in patients who presented with retro maxillary lesion. The duration of symptoms ranged from 5 days to 6 years.

Preoperative radiology

Imaging was done in 10 cases. Majority of cases underwent magnetic resonance imaging (MRI) (50%) followed by computed tomography (30%), ultrasonography (10%) and radiography (X-ray) (10%). The radiology in all 10 cases were suggestive of benign lesion (Figure 2).

Figure 2: Axial view of CT showing ill-defined heterogenous soft tissue density lesion in right infratemporal fossa (arrow)

Clinical diagnosis

Schwannoma was diagnosed clinically in 7/18 cases. Other suggested clinical diagnosis were paraganglioma, sebaceous cyst and retro-maxillary tumour in one case each. No clinical diagnosis was mentioned in 8 cases. The clinico-histopathological correlation was 70%.

All patients underwent complete surgical excision through relevant approaches.

Pathological Analysis

Frozen was done in 2 cases and were reported as spindle cell neoplasm. Grossly, the lesions ranged 0.5- 15 cm in greatest dimension. Mean size was 4 cm (Figure 3).

Figure 3: Gross - well encapsulated lesion with cystic changes

The microscopic examination of all cases revealed the classic findings of Schwannoma with 33% cases associated with secondary changes like microcytic change, hemosiderin-laden macrophages, foam cells, myxoid change, edema, bizarre nuclei and verocay body formation. In 5/18 cases confirmatory immunohistochemistry S100 was done and found to be positive (Figure 4).

Figure 4: Microscopy - Hypocellular and hypercellular areas H and E (X200), Inset S100 positive(X200)

Discussion

Schwannomas, also known as neurinomas of Verocay, are slow growing peripheral nerve sheath tumours composed almost entirely of Schwann cells. Other tumours classified as peripheral nerve sheath tumours include neurofibroma, perineuroma, traumatic neuroma and malignant peripheral nerve sheath tumour.^1,3–7Neurinomas were first described in 1910, as a group of neurogenic tumours. Later on in 1935, these neurogenic tumours were renamed as 'Neurilemmomas' as it was proposed that they arise from nerve sheath elements.³ Lusk et al stated that highly differentiated perineural cells, the Schwann cell, gives rise to Schwannomas while perineural fibrocytes give rise to more invasive neurofibroma.⁸ Eventually it was found that the Schwann cell is the common precursor for most nerve sheath tumours, hence named as Schwannoma.^3,6

Schwannoma, most commonly occur in patients between age group of 20 - 50 years and only about 12% are seen in the paediatric or adolescent population.⁹ In our study also, most of the cases were between 3^rd – 5^th decade. This was also noted in studies done by Gupta et al and Adani et al. ^9,10

In present study, equal male to female ratio was found, similar to studies done by Chikkannaiah et al, Akyildiz et al, Majumder et al and Hao et al.^11–14 However Gilmer et al and Torossian et al found a female preponderance in their respective case studies. ^15,16

The symptoms are mostly related to the tumour location, especially on the sites of weight bearing and pertaining to nerve compression. The usual presenting symptoms ranged from painless swelling to nerve compression symptoms such as tingling, burning sensation, weakness, paraesthesia.^13,14 Painless swelling was predominantly the major symptoms in majority of the studies.^4,13,14,17 Occurrence of pain and neurological deficit are ominous signs suggestive of malignancy. The unusual symptoms such as nasal obstruction, hoarseness, epiphora, hearing loss, Horner’s syndrome, dysphagia, paraesthesia, pain and respiratory symptoms were noted by few authors based on the site of lesion.^18,19The most common clinical presentation in our study was painless swelling.

The spectrum of clinical diagnosis considered by the clinicians other than Schwannoma include ganglion cyst, lipoma, Dupuytren’s contracture, fibroma, hydatid cyst, haemangioma and epidermal inclusion cyst. ¹⁴ In present study the other clinical diagnosis suggested by clinicians were epidermal inclusion cyst, retromaxillary tumour and paraganglioma.

Majority of Schwannomas are benign and can occur at a variety of anatomical location. They mostly arise at intracranial site from sensory nerve roots. The most common affected nerve is vestibular branch of the eighth nerve followed by trigeminal nerve. Other lower cranial nerves may be involved in the setting of neurofibromatosis.²⁰ The unusual sites of occurrence documented are parotid, nasopharyngeal region, posterior pharynx, skull base, chest wall, thorax, posterior mediastinum, abdomen, retroperitoneum, pelvis and penis.^{12,14,19,21–26} In our study the unusual sites reported were retro maxillary region, paraaortic region of the thorax, mediastinum, stomach, retroperitoneum and thigh.

The head and neck region account for 25–45% cases of Schwannomas and usually affect patients in their fifth decade.²⁷ The uncommon site of extracranial Schwannomas in the head and neck include parapharyngeal region, submandibular area, parotid, intraoral and paranasal sinus.²⁷ Arshad et al, in their study diagnosed 9/42 cases Schwannoma at head and neck region. There was no sex predilection and mean age of 30.7 years.¹⁸ Leu and Chang et al reviewed a series of 52 cases originating in head and neck region over a period of 8 years where 25 cases occurred in scalp, face, external ear, 9 cases were located in oral cavity/nasal cavity and 18 cases in neck. ¹⁷ Head and neck was the most common site in our study as well and constituted 5/18 cases with a mean age of 54.6 years.

In the lower extremity, the usual sites of Schwannoma include posterior tibial nerve and achilles tendon, however this site is affected in <10% of all cases.^1,5,28–30 Foot and ankle region are extremely infrequent sites. Kim et al reviewed 397 peripheral nerve sheath tumours, only 8% Schwannomas were located in the lower extremity.³¹In our study, 5/18 cases were reported in lower extremities at thigh, gluteal lesion and popliteal fossa with a mean age of 48.6 years.

Retroperitoneal location is also extremely uncommon with reported incidence ranging from 0.7 to 2.7%.²⁵ Surendrababu et al reported a rare case of retroperitoneal Schwannoma mimicking ovarian cyst. ³² In our study 4/18 cases were reported in the retroperitoneum region with a mean age of 36 years.

Neurogenic tumours represent 15-25% of mediastinal tumours, generally occurring in the posterior paravertebral area.³³ Thoracic neurogenic tumours are generally located in the mediastinum or on the chest wall. Rarely these lesions originate in the lung. Matsumoto et al. reported a 2 cm lesion on the pleura in a 19 year old female which was incidentally detected and was eventually diagnosed as Schwannoma.³⁴ In present study, only 2/18 cases were noted in the thorax region with a mean age of 32.5 years.

Occurrence in the upper extremity is not encountered often. Usually, the ulnar nerve is involved while only 7% of Schwannomas involve the median nerve. In the upper limb, they may be mistaken for ganglion cyst or carpal tunnel syndrome.¹⁴ Typically, they appear as swollen, slow-growing lesions along the nerve length. In a study by Tang et al, eight cases of upper-limb Schwannomas were studied with a mean age of 56 years.³⁵ In our study we found only one case in the upper limb region.

Ultrasonography is usually the first imaging modality, and it often reveals a solid, strongly defined, ovoid, homogenous mass. To rule out any bone involvement or anomalies, an X-ray may be taken. Schwannomas often exhibit isointense or decreased signal intensity on T1-weighted images compared to skeletal muscle and heterogeneously elevated intensity on T2-weighted imaging. The target sign, spilt fat sign, and fascicular split sign are some further characteristics of Schwannoma.³⁵ In our study, MRI was performed on majority of cases (50%).

Complete excision is recommended since incomplete resection may result in recurrence.³⁶ Grossly, the lesions are most often spheric or ovoid, firm or rubbery tumours. They range in size from 0.5-15 cm. In our study, grossly the size of the lesion size varied from 1-4 cm. Strauss et al in their study of 28 cases of benign retroperitoneal Schwannoma have reported size range from 5-23 cm and weight range between 0.5-2 kg. ³⁷

The histology of Schwannoma typically shows encapsulated lesion with areas of dense cellularity of aggregated spindle shaped cells arranged short fascicles and bundles termed as Antoni-A regions. Along with hypocellular areas with myxoid matrix termed as Antoni-B regions. Immunohistochemistry is positive for S100 in majority of the cases, vimentin, and neuron-specific enolase are positive, but negative for smooth muscle actin and CD117.^13,37,38 Other differentials like solitary fibrous tumour are S100 negative; CD34, CD99 and STAT-6 positive. Paraganglioma are S100 diffusely positive only in sustentacular cells and chromogranin is diffuse positive.^13,39,40 The distinction between Schwannoma and neurofibroma is important because the latter shows a small potential for malignant transformation.⁴¹ Neurofibromas are not encapsulated and lack the biphasic pattern of Schwannomas. They have a haphazard arrangement of nerve fibres, what is likened to “Shredded Carrot” appearance as opposed to the somewhat oriented nuclei seen in Verocay bodies, a pathognomonic feature of Schwannomas.⁴⁰

Malignant transformation of Schwannoma account for 5% of peripheral nerve sheath tumours. ^4,29,42 The histopathological diagnosis of malignant transformation requires the following criteria: 1. demonstrable areas of benign Schwannoma, 2. unequivocal malignant foci manifested by increased cellularity, numerous mitoses, anaplastic cells and invasiveness, 3. transitional areas between malignant and benign regions.⁴³

Malignant Schwannomas are rare and usually are associated with Von Recklinghausen’s disease. They act as high-grade sarcomas with a high likelihood of producing local recurrence and distant metastasis.²³ The histology of malignant component in most of the lesions is of epithelioid morphology.⁴⁴ However, in our study malignant transformation was not seen in any case during the follow up period of 3 years.

Conclusion

Schwannomas are benign lesion with very good prognosis and have minimal chance of malignant progression. They have predilection for cranial nerves and spinal nerve roots but can occur at unusual sites. These sites and misleading presentations may pose diagnostic challenge for both clinician and pathologists alike. Thus, unawareness of this benign entity can lead to unnecessary treatment. Pathologists must be aware of the occurrence of Schwannoma at unusual sites for the proper management.

References

1. Jack CM, Jones G, Edwards MR, Singh SK. A case report of three peripheral Schwannomas attached to the Achilles paratenon. The Foot. 2010 Jun 1;20(2-3):78-80.
2. Ward BK, Gourin CG, Francis HW. Vestibular Schwannoma surgical volume and short-term outcomes in Maryland. Archives of Otolaryngology - Head and Neck Surgery. 2012;138(6):577–83.
3. Joshi R. Learning from eponyms: Jose Verocay and Verocay bodies, Antoni A and B areas, Nils Antoni and Schwannomas. Indian Dermatol Online J. 2012;3(3):215.
4. Albert P, Patel J, Badawy K, Weissinger W, Brenner M, Bourhill I, et al. Peripheral Nerve Schwannoma: A Review of Varying Clinical Presentations and Imaging Findings. Journal of Foot and Ankle Surgery [Internet]. 2017;56(3):632–7. Available from: http://dx.doi.org/10.1053/j.jfas.2016.12.003
5. Watanabe K, Fukuzawa T, Mitsui K. Tarsal tunnel syndrome caused by a Schwannoma of the posterior tibial nerve. Acta Med Okayama. 2018;72(1):77–80.
6. Colreavy MP, Lacy PD, Hughes J et al. Head and neck Schwannomas–a 10 year review. The Journal of Laryngology and Otology. 2000 Feb;114(2):119-24.
7. Mott RC, Dellon AL. Multiple Schwannomas of the foot: Case report and strategy for treatment. J Am Podiatr Med Assoc. 2003;93(1–6):51–7.
8. Lusk MD, Kline DG, Garcia CA. Tumors of the brachial plexus. Neurosurgery. 1987 Oct 1;21(4):439-53.
9. Malone JP, Lee WJ, Levin RJ. Clinical characteristics and treatment outcome for nonvestibular Schwannomas of the head and neck. American Journal of Otolaryngology - Head and Neck Medicine and Surgery. 2005;26(2):108–12.
10. Akyildiz EU, Yalcinkaya U. Thoracic neurogenic tumors: A clinicopathologic evaluation of 42 cases. Neurol Asia. 2015;20(1):59–63.
11. Chikkannaiah P, Boovalli MM, Nathiyal V, Venkataramappa S. Morphological spectrum of peripheral nerve sheath tumors: An insight into World Health Organization 2013 classification. J Neurosci Rural Pract. 2016;7(3):346–54.
12. Majumder A, Ahuja A, Chauhan DS, Paliwal P, Bhardwaj M. A clinicopathological study of peripheral schwannomas. Med Pharm Rep. 2021 Apr;94(2):191-196. doi: 10.15386/mpr-1708. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118219/
13. Hao X, Levine D, Yim J, Qi C, Firestone L, Beiser I, et al. Schwannoma of foot and ankle: Seven case reports and literature review. Anticancer Res. 2019;39(9):5185–94.
14. Gilmer-Hill HS, Kline DG. Neurogenic tumors of the cervical vagus nerve: Report of four cases and review of the literature. Neurosurgery. 2000;46(6):1498–503.
15. Torossian JM, Beziat JL, Abou Chebel N, Devouassoux-Shisheboran M, Fischer G. Extracranial cephalic Schwannomas: a series of 15 patients. The Journal of Craniofacial Surgery. 1999 Sep 1;10(5):389-94.
16. Leu YS, Chang KC. Extracranial head and neck Schwannomas: A review of 8 years experience. Acta Otolaryngol. 2002;122(4):435–7.
17. Zubair A, Kumar R, Jat B, Sagar P, Kairo A, Kumar R. Unusual Sites for Extracranial Head–Neck Schwannomas. Indian Journal of Otolaryngology and Head and Neck Surgery. 2020 Dec;72:416-21.
18. Samet A, Podoshin L, Fradis M, Simon J, Lazarov N, Boss H. Unusual sites of Schwannoma in the head and neck. The Journal of Laryngology and Otology. 1985 May;99(5):523-8.
19. Young ED, Ingram D, Metcalf-Doetsch W et al. Clinicopathological variables of sporadic Schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers. Journal of Neurosurgery. 2017 Sep 8;129(3):805-14.
20. Nawabi DH, Sinisi M. Schwannoma of the posterior tibial nerve. Journal of Bone and Joint Surgery - Series B. 2007;89(6):814–6.
21. Hilton DA, Hanemann CO. Schwannomas and their pathogenesis. Brain Pathology. 2014 Apr;24(3):205-20.
22. Ueda M, Okamoto Y, Ueki M. A pelvic retroperitoneal Schwannoma arising in the right paracolpium. Gynecol Oncol. 1996;60(3):480–3.
23. Li Q, Gao C, Juzi JT, Hao X. Analysis of 82 cases of retroperitoneal Schwannoma. ANZ J Surg. 2007;77(4):237–40.
24. Muneeb A, Khan MS, Iqbal H, Shafqat G. Chest Wall Schwannoma: Case Report and a Review of Imaging Findings Case Presentation. Cureus. 2018 Dec; 10(12): e3694. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390888/
    
25. Song YJ, Seol SH, Kim S, Kim DK, Kim KH, Kim DI, Kang DK, Kim JY. Benign posterior mediastinal schwannoma-Multiple diagnostic imaging modalities. Clin Case Rep. 2019 Oct 31;7(12):2585-2587. doi: 10.1002/ccr3.2274.
26. Yusoff AA, Khair SZ, Abdullah WS, Abd Radzak SM, Abdullah JM. Somatic mitochondrial DNA D-loop mutations in meningioma discovered: a preliminary data. Journal of cancer Research and Therapeutics. 2020 Oct 1;16(6):1517-21.
27. Jha AJ, Basetty CR, Viner GC, Tedder C, Shah A. Posterior Tibial Nerve Schwannoma Presenting as Tarsal Tunnel Syndrome. Cureus. 2019;11(8):1–10.
28. Knight DMA, Birch R, Pringle J. Benign solitary Schwannomas: A review of 234 cases. Journal of Bone and Joint Surgery - Series B. 2007;89(3):382–7.
29. Kim DH, Murovic JA, Tiel RL, Moes G, Kline DG. A series of 397 peripheral neural sheath tumors: 30-year experience at Louisiana State University Health Sciences Center. Journal of Neurosurgery. 2005 Feb 1;102(2):246-55.
30. Surendrababu NRS, Cherian SR, Janakiraman R, Walter N. Large retroperitoneal Schwannoma mimicking a cystic ovarian mass in a patient with Hansen’s disease. Journal of Clinical Ultrasound. 2008;36(5):318–20.
31. Woo OH, Yong HS, Shin BK, Oh YW, Kim HK, Kang EY. Wide spectrum of thoracic neurogenic tumours: A pictorial review of CT and pathological findings. British Journal of Radiology. 2008;81(968):668–76.
32. Galukande M, Khingi A. Chest wall Schwannoma presenting as a solitary malignant lesion: a case report. Springerplus. 2016 Dec;5(1):1-3.
33. Yuk Kwan Tang C, Fung B, Fok M, Zhu J. Schwannoma in the upper limbs. BioMed Research International. 2013;2013.
34. Murphey MD, Smith WS, Smith SE, Kransdorf MJ, Temple HT. From the archives of the AFIP: Imaging of musculoskeletal neurogenic tumors: Radiologic-pathologic correlation. Radiographics. 1999;19(5):1253–80.
35. White W, Shiu MH, Rosenblum MK, Erlandson RA, Woodruff JM. Cellular Schwannoma. 1990;1266–75.
36. Strauss DC, Qureshi YA, Hayes AJ, Thomas JM. Management of benign retroperitoneal Schwannomas: a single-center experience. The American Journal of Surgery. 2011 Aug 1;202(2):194-8.
37. Martins MD, Anunciato De Jesus L, Fernandes KPS, Bussadori SK, Taghloubi SA, Martins MAT. Intra-oral Schwannoma: Case report and literature review. Indian Journal of Dental Research. 2009;20(1):121–5.
38. Grosu-Bularda A, Teodoreanu RN, Liţă FF, Hodea FV, Lăzărescu AL, Enache V, et al. Clinical and pathological features of upper limb nerve tumors – four years retrospective study. Romanian Journal of Morphology and Embryology. 2021;62(3):733–42.
39. Sawas FA, Lababede O, Meziane MA, Arrossi AV. A 54-year-old woman with incidentally discovered mass on a chest radiograph. Chest. 2009 Jun 1;135(6):1673-8.
40. Nascimento AF, Fletcher CDM. The controversial nosology of benign nerve sheath tumors: Neurofilament protein staining demonstrates intratumoral axons in many sporadic Schwannomas. American Journal of Surgical Pathology. 2007;31(9):1363–70.
41. Gupta TKD, Brasfield RD, Strong EW, Hajdu SI. Benign solitary Schwannomas (neurilemomas). Cancer. 1969;24(2):355–66.
42. Woodruff JM, Selig AM, Crowley K, others. Schwannoma (neurilemmoma) with malignant transformation. Am J Surg Pathol. 1994;18:882–95.
43. Kransdorf MJ. Malignant soft-tissue tumors in a large referral population: distribution of diagnoses by age, sex, and location. AJR Am J Roentgenol. 1995 Jan;164(1):129-34. doi: 10.2214/ajr.164.1.7998525.
44. Hallahan K, Vinokur J, Demski S, Faulkner-Jones B, Giurini J. Tarsal tunnel syndrome secondary to Schwannoma of the posterior tibial nerve. The Journal of Foot and Ankle Surgery. 2014 Jan 1;53(1):79-82.