Intramuscular Hybrid Nerve Sheath Tumor of the Thigh: Case Report and Literature Review

Abstract

Background/Aim

Hybrid nerve sheath tumor (HNST) is a benign peripheral nerve sheath tumor with combined features of more than one histological type, such as schwannoma, neurofibroma, and perineurioma. It remains under-recognized in routine clinical practice. Herein, we describe an unusual case of intramuscular HNST of the thigh.

Case Report

The patient was a 41-year-old man with no history of trauma who presented with a 3-month history of a palpable mass in the right thigh. Physical examination revealed a 4-cm, elastic hard, mobile, nontender mass. Magnetic resonance imaging exhibited a well-circumscribed intramuscular mass with low-to-intermediate signal intensity on T1-weighted sequences and higher signal intensity peripherally and lower signal intensity centrally, representing a target sign, on T2-weighted sequences. Complete surgical excision of the tumor was carried out. Microscopically, the tumor showed dual histological components of both schwannoma and neurofibroma. Immunohistochemically, the schwannomatous component was strongly and diffusely positive for S-100 protein and negative for CD34, while the neurofibromatous component contained CD34-positive fibroblasts and S-100 protein-positive Schwann cells. Epithelial membrane antigen was negative for both components. These findings were consistent with a diagnosis of HNST (hybrid schwannoma/neurofibroma). The patient had no evidence of local recurrence and no neurological deficit at the final follow-up.

Conclusion

Although extremely rare, HNST should be included in the extended differential diagnosis of a well-circumscribed, intramuscular soft-tissue mass in the extremities, particularly in young and early middle-aged adults.

Hybrid nerve sheath tumor (HNST) is a recently recognized soft-tissue tumor with combined features of more than one type of conventional benign peripheral nerve sheath tumors. It usually presents as a painless, subcutaneous/dermal mass and often affects young adults, with no sex predilection (1). Pain or neurological deficit is uncommon unless the tumor reaches a certain size. The most common example is hybrid schwannoma/perineurioma, followed by hybrid schwannoma/ neurofibroma. Hybrid neurofibroma/perineurioma is rare (1). HNST has a benign clinical course with a low probability of recurrence after surgical excision (2-4). Malignant transformation of HNST is exceptionally rare (5). Herein, we report an unusual case of intramuscular HNST (hybrid schwannoma/neurofibroma) of the thigh in an early middle-aged man. We also provide a literature review about the clinicopathological, imaging, and genetic features of HNST. Written informed consent was obtained from the patient to publish this case report and accompanying images.

Case Report

A 41-year-old man presented with a 3-month history of a slow-growing, painless mass in the anterolateral aspect of the right thigh. Physical examination showed a 4-cm, elastic hard, mobile, nontender mass. Neurovascular examinations, including Tinel sign, were normal. Laboratory data were within normal limits. The patient’s past medical history was unremarkable. Magnetic resonance imaging (MRI) demonstrated a well-circumscribed intramuscular mass with low-to-intermediate signal intensity on T1-weighted sequences (Figure 1A) and higher signal intensity peripherally and lower signal intensity centrally, representing a target sign, on T2-weighted sequences (Figure 1B). Our preoperative diagnosis was an intramuscular schwannoma.

Figure 1. Axial magnetic resonance images of an intramuscular lesion in the right thigh. The lesion shows low-to-intermediate signal intensity on T1-weighted sequence (A) and higher signal intensity peripherally and lower signal intensity centrally, representing a target sign, on T2-weighted sequence (B).

Surgery was performed using a pneumatic tourniquet. A longitudinal skin incision was made over the mass. The mass was easily seen under the vastus lateralis muscle and was completely excised. The nerve related to the origin of the tumor could not be identified. Grossly, the tumor was well circumscribed, with a yellowish-white cut surface (Figure 2). Microscopically, the tumor was composed of schwannomatous nodules (Figure 3A) within an otherwise typical neurofibroma (Figure 3B). Mitotic activity and nuclear atypia were not present. Immunohistochemically, the schwannomatous component was strongly and diffusely positive for S-100 protein (Figure 4A) and negative for CD34, whereas the neurofibromatous component contained S-100 protein-positive Schwann cells (Figure 4A) and CD34-positive fibroblasts (Figure 4B). Staining for epithelial membrane antigen (EMA), smooth-muscle actin (SMA), and desmin was negative in both components. Based on these findings, the tumor was diagnosed as a HNST (hybrid schwannoma/neurofibroma).

Figure 2. Gross appearance of hybrid schwannoma/neurofibroma with a yellowish-white cut surface.

Figure 3. Histological findings of hybrid schwannoma/neurofibroma. (A) The schwannomatous component shows proliferating spindle-shaped cells arranged in fascicles with focal nuclear palisading (hematoxylin and eosin staining, original magnification ×100). (B) The neurofibromatous component consists of bland spindle cells with thin, wavy nuclei in a collagenous stroma (hematoxylin and eosin staining, original magnification ×100).

Figure 4. Immunohistochemical findings of hybrid schwannoma/neurofibroma. (A) S-100 protein is strongly and diffusely positive in the schwannomatous areas and focally positive in the neurofibromatous areas (asterisk) (original magnification ×100). (B) CD34 is focally positive in the neurofibromatous areas (asterisk) and negative in the schwannomatous areas (original magnification ×100).

There was no immediate neurological deficit following surgery. At three months of follow-up, the patient had no evidence of recurrence and no neurological deficit.

Discussion

Hybrid schwannoma/neurofibroma, first properly described by Feany et al. in 1998 (2), is strongly associated with neurofibromatosis (NF) and schwannomatosis (6,7). In the present case, there were no stigmata or family history of NF or schwannomatosis. Although HNST shows a wide anatomical distribution in somatic soft-tissue, skeletal muscle involvement is exceedingly rare (3). To the best of our knowledge, this is the first description of hybrid schwannoma/neurofibroma in an intramuscular location.

There is scant literature on the radiological appearance of HNST (7-10). The gold standard imaging modality for evaluating HNST is MRI. Using MRI, the majority of lesions reveal low-to-intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images, as seen in our case. Post-contrast images display a significant enhancement (7). In addition, several MRI findings have been described in intramuscular schwannoma or neurofibroma, including split-fat sign, fascicular sign, target sign, thin hyperintense rim, and entering and exiting nerve (11-15). Post-contrast images may demonstrate a marked central or heterogeneous enhancement (11,12). In the present case, it was not possible to distinguish intramuscular HNST from intramuscular conventional schwannoma based on preoperative imaging findings alone.

The definitive diagnosis of HNST is made after surgical excision and histopathological analysis. Histologically, hybrid schwannoma/neurofibroma is usually composed of hypercellular, schwannomatous nodules within an otherwise typical neurofibroma (1). The schwannomatous component consists of spindle-shaped cells with normochromatic elongated nuclei and modest eosinophilic cytoplasm and may exhibit Verocay body formation. In the neurofibromatous component, the tumor cells show thin, wavy nuclei in a variably loose myxoid stroma with abundant collagen fibers. Mitotic activity is scarce or absent (16). Due to the morphological overlap with pure peripheral nerve sheath tumors, the diagnosis usually requires immunohistochemistry. By immunohistochemistry, the schwannomatous areas are strongly and diffusely positive for S-100 protein and SOX10 but negative for CD34 or EMA, and the neurofibromatous areas show a mixed population of cells including CD34-positive fibroblasts and S-100 protein and SOX10-positive wavy Schwann cells (1). EMA, claudin-1, and GLUT-1-positive perineurial cells may be seen in the neurofibromatous areas (1). SMA and desmin are typically negative. Based on the histological and immunohistochemical findings, we confirmed the proliferation of neoplastic Schwann cells with S-100 protein positivity and CD34-positive fibroblastic cells in the present case.

There are several molecular genetic studies of HNST (17-20). In 2016, Stahn et al. reported that monosomy of chromosome 22 was found in 7 of 16 (44%) cases of hybrid schwannoma/neurofibroma (17). In addition, the authors detected focal deletion of the catenin alpha 3 (CTNNA3) gene in a single case. In 2020, Ronellenfitsch et al. reported that erb-b2 receptor tyrosine kinase 2 (ERBB2) mutations were identified in 3 of 7 (43%) cases of schwannomatosis-associated hybrid schwannoma/neurofibroma, whereas no ERBB2 mutations were found in NF2-associated or sporadic hybrid schwannoma/neurofibroma cases (18). In 2021, vestigial like family member 3 (VGLL3) rearrangements were detected in 14 of 18 (77.8%) cases of hybrid schwannoma/perineurioma (19). In that study, several VGLL3 fusion partners were discovered in hybrid schwannoma/perineurioma, including chromodomain helicase DNA binding protein 7 (CHD7), chromodomain helicase DNA binding protein 9 (CHD9), and mastermind like domain containing 1 (MAMLD1). Moreover, dystonin (DST)-B-Raf proto-oncogene, serine/threonine kinase (BRAF), sequestosome 1 (SQSTM1)-caudal type homeobox 1 (CDX1), or CDH9-zinc finger homeobox 3 (ZFHX3) gene fusions have been identified in hybrid schwannoma/perineurioma (19,20). However, VGLL3 fusions were not found in any hybrid schwannoma/neurofibroma cases examined (20). Further studies with a large number of cases are needed to understand the correlation between HNST and certain gene fusions.

In conclusion, we described an extremely rare case of intramuscular HNST (hybrid schwannoma/neurofibroma) of the thigh. HNST should be included in the differential diagnosis of a well-circumscribed, intramuscular soft-tissue mass in the extremities, particularly in young and early middle-aged adults.

Conflicts of Interest

The Authors declare no conflicts of interest associated with this study.

Authors’ Contributions

YC searched the literature, collected the data, and reviewed the article. JS provided direct patient care. KO performed the histopathological evaluations. JN performed the operation and drafted the article. All Authors read and approved the final article.

Acknowledgements

This study was supported in part by the Japan Society for the Promotion of Science KAKENHI (21K09336).