Intraoral nerve sheath myxoma: Case report and systematic review of the literature

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1 CASE REPORT Jonathan Irish, MD, FRCSC, Section Editor Intraoral nerve sheath myxoma: Case report and systematic review of the literature Rafaela Elvira Rozza-de-Menezes, MSc, 1 Raquel Machado Andrade, DDS, 2 M^onica Sim~oes Israel, PhD, 3 Karin Soares Gonc alves Cunha, PhD, 4* 1 Postgraduate Program in Pathology, School of Medicine, Universidade Federal Fluminense, Niteroi, Rio de Janeiro, Brazil, 2 Postgraduate Program in Pathology, School of Medicine, Universidade Federal Fluminense, Niteroi, Rio de Janeiro, Brazil, 3 Department of Oral Medicine and Surgery, School of Dentistry, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil, 4 Postgraduate Program in Pathology, School of Medicine, Universidade Federal Fluminense, Niteroi, Rio de Janeiro, Brazil. Accepted 10 April 2013 Published online 30 July 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed /hed ABSTRACT: Background. Oral nerve sheath myxoma (NSM) is an uncommon benign neoplasm with Schwann-cell origin, which is frequently mistaken for neurothekeoma. We report a case of NSM on the buccal mucosa in a 42-year-old woman. This case is compared with previously reported cases and a systematic review is performed. Methods and Results. We conducted a case report and systematic review of oral cases considered true NSMs. A literature search was performed using PubMed, Lilacs, Scielo, Cochrane, SciVerse Scopus, Web of Science, and Embase electronic database. Twenty-five cases of oral NSM were included in the systematic review. Conclusion. Oral NSM is rare and may represent a diagnostic challenge for pathologists. To confirm the diagnosis of NSM, the evaluation of S-100 protein expression or other neural marker is essential. The use of the terms NSM and neurothekeoma as synonymous or as variants of the same tumor should be avoided, because they are clearly distinct lesions. VC 2013 Wiley Periodicals, Inc. Head Neck 35: E397 E404, 2013 KEY WORDS: peripheral nerve sheath neoplasms, neurothekeoma, mouth neoplasms, immunohistochemistry, diagnosis INTRODUCTION Nerve sheath myxoma (NSM) is an uncommon benign peripheral nerve sheath neoplasm first described in 1969 by Harkin and Reed 1 and Scheithauer et al. 2 This neoplasm arises most commonly within the dermis and subcutaneous tissues on the face and upper extremities and is extremely rare in the intraoral region. 3 5 Intraoral NSM was first reported in 1974 by Mincer and Spears 6 and few cases in the oral mucosa were reported so far in the medical literature In 1980, Gallager and Helwig 9 introduced the term neurothekeoma in the literature to designate a benign cutaneous tumor, regarded as having a neural origin, which shared many clinical and histological similarities to NSM. Since then, many authors have considered NSM and neurothekeoma as variants of the same tumor, being the NSM, the myxoid, or hypocellular variant and the neurothekeoma the cellular variant ,18,22,27,29,32 Although currently, it is known that they are distinct lesions with different origins and distinct morphological and immunohistochemical features, 24 the terms NSM and neurothekeoma have been erroneously used interchangeably, causing great confusion. One of the differences between these 2 lesions is the expression of S- *Corresponding author: K. S. Gonc alves Cunha, Hospital Universitario Ant^onio Pedro, Rua Marqu^es do Parana, o andar, sala 01, Centro - Niteroi, Rio de Janeiro, Brazil, CEP karingcunha@gmail.com 100 protein, which is observed only in NSM, supporting that it is a peripheral nerve sheath tumor, with immunophenotype of Schwann cells. To try to differentiate these 2 types of tumors and avoid confusion, some authors refer to neurothekeoma as cellular neurothekeoma. 4,5,20,26,28 The purpose of this article was to report a rare case of an NSM on the buccal mucosa and to do a systematic review of oral NSM and discuss its clinical and histological aspects, as well as its histological differential diagnoses. CASE REPORT A 42-year-old white woman was referred to our Oral Diagnosis Clinic complaining of an asymptomatic nodule on the right buccal mucosa on the occlusion line. The lesion was first noticed by the patient about 1 year before, and she presented with a slowly growing nodule. The patient had the habit of chronically biting the lesion. Her medical history did not show any relevant information. No alterations were observed on extraoral examination. Intraoral examination demonstrated a sessile nodule, normochromic, intact mucosa with fine vascular network, elastic, measuring 1.5 cm cm (Figure 1A). The clinical hypotheses were traumatic fibroma and fibrolipoma. An excisional biopsy was performed and the microscopic analysis showed a tumor in the connective tissue subjacent of the intact surface epithelium. It was composed of multiple myxoid lobules surrounded by HEAD & NECK DOI /HED DECEMBER 2013 E397

2 ROZZA DE MENEZES ET AL. FIGURE 1. (A) Clinical aspect of the lesion: sessile nodule, covered by intact and normal mucosa with located on the right buccal mucosa. (B) Tumor composed by multiple myxoid lobules surrounded by loose fibrous tissue (hematoxylin-eosin stain; original magnification 34). (C) Scattered spindle and stellate cells, as well as some mast cells, arranged in a disorganized form in a myxoid stroma (hematoxylin-eosin stain; original magnification 320). (D) Myxoid intralobular substance positive by Alcian blue staining ph 2.5 (original magnification 310). (E) Spindle and stellate tumor cells expressing S-100 (immunohistochemical; original magnification 320). (F) Spindle and stellate tumor cells expressing neuron-specific enolase (NSE) (immunohistochemical; original magnification 320). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] loose fibrous tissue (Figure 1B). Inside of these lobules, there were scattered spindle and stellate cells with ovoid vesicular nuclei, as well as some mast cells. Tumor cells were arranged in a disorganized form in a myxoid stroma with sparse collagen fibers (Figure 2C). A few lobules were more cellular. Mitoses and necrosis were not seen. Peripheral nerves, skeletal muscle fibers, blood vessels, and adipocytes were seen in the vicinity of the tumor mass in the deeper areas of the specimen. The myxoid intralobular substance was positive by Alcian blue staining (ph 2.5; Figure 1D). Immunohistochemical analysis using a polymer-conjugated protocol was performed with the antibodies: anti-s-100, anti neuron-specific enolase (NSE), and anti-epithelial membrane antigen (EMA). The spindle and stellate tumor cells expressed S-100 (Figure 1E) and NSE (Figure 1F). EMA expression was not observed. After histopathological and histochemical/immunohistochemical analysis, the final diagnosis was oral NSM. The patient returned 1 month later, without any complaint, but later she was lost to follow-up. DISCUSSION Literature search A literature search was performed by 2 authors independently (R.E.R.M. and R.M.A.) using PubMed, Lilacs, Scielo, Cochrane, SciVerse Scopus, Web of Science, and Embase electronic database, without year and language restriction, with the terms: (1) nerve sheath myxoma and human; (2) neurothekeoma and human; (3) nerve sheath myxoma and oral; and (4) neurothekeoma and oral. The last literature search of those databases was updated in August An article was initially considered eligible for inclusion in the systematic review if it included a case report or a study with at least 1 under the name NSM or E398 HEAD & NECK DOI /HED DECEMBER 2013

3 INTRAORAL NERVE SHEATH MYXOMA FIGURE 2. Flowchart of articles for our literature search from initial identification through final selection for review. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] neurothekeoma located on oral mucosa. First, all abstracts of the retrieved articles were reviewed by 2 authors (R.E.R.M. and R.M.A.). Full texts of the articles considered eligible for inclusion were accessed for further evaluation and selection. All articles that did not include oral cases were excluded. All the references of the selected articles were reviewed to identify relevant studies not found by initial search. Cases that were not investigated for expression of S- 100 protein or did not show S-100 expression were excluded. Relevant data were obtained from full texts of all selected articles by 2 authors (R.E.R.M. and K.S.G.C): age at diagnosis, sex, tumor location, duration, clinical features, clinical size, clinical diagnosis, tumor duration, histochemical and immunohistochemical results (Alcian blue staining, S-100, NSE, EMA, and other neural markers ), duration of follow-up, and outcome. Results The flowchart for selection of articles for systematic review is presented in Figure 2. A total of 25 cases of NSM (including the current case) from 14 articles were included in this systematic review. The majority of articles found were case reports and were dated from 1988 to Systematic review of reported cases The main clinical and histochemical/immunohistochemical characteristics of oral NSM cases from the selected articles for the systematic review (including the current case) are summarized in Tables 1 and 2, respectively. The mean age at diagnosis was 35.9 years (SD, 21.5), ranging from newborn (zero) to 84 years. Oral NSMs were more commonly diagnosed in the fourth and fifth decades of age (Figure 3). There was a slight female predilection (male:female, 1:1.5). Gingiva (24%; n 5 6) was the most frequent oral location of NSM, followed by buccal mucosa (20%; n 5 5), and tongue (16%; n 5 4). Cases of NSM were also reported on the hard palate, lip mucosa, and vestibule (Figure 4). As for duration time, it varied from 3 months to 240 months (20 years), with a mean time of diagnosis of 38.2 months (SD, 61.9). For this calculation, we did not include the cases from Pe~narrocha et al 18 (2000) and Rawal et al 31 (2012) because there was no precise time for diagnosis. The size of the lesions varied from 0.6 to 5.0 cm, but 61.5% measured less than 1.0 cm. The most common clinical hypothesis (66.7%) was traumatic fibroma/fibroepithelial polyp. In any case included in this systematic review, there was a clinical suspicion of NSM. HEAD & NECK DOI /HED DECEMBER 2013 E399

4 ROZZA DE MENEZES ET AL. TABLE 1. Clinical features of nerve sheath myxomas. Reference Age/sex Site Duration, mo Clinical features Clinical diameter, largest dimension in cm Clinical diagnosis Follow-up, mo Outcome, recurrence Yamamoto and Kawana 11 elastic, painless 41/F Tongue 12 Pedunculated nodule, whitish, Terrier et al 12 35/M Upper gingiva 60 Polipod nodule, pink (lighter than the normal mucosa), covered by fine vascular network, flaccid/elastic, painless, slow growing Rodriguez Peralto 46/F Buccal mucosa 7 Nodule, bluish, painful, slow and el-naggar 13 growing Soybean-sized Fibroma 9 Absent 5.0 NA 15 Absent NA Fibroma/ mucocele 4 Absent Green et al 14 Smith et al 32 46/M Tongue NA NA NA NA NA NA Tiffee and Pulitzer 15 71/F Buccal mucosa NA Submucosal nodule 0.6 Fibroma NA NA Katsourakis et al 16 24/M Hard palate 72 Nodule, normochromic, painless, slow growing Pe~narrocha et al 18 Newborn/F Tongue Since birth Pedunculated bilobulated nodule, normochromic, elastic, painless, slow growing Makino et al 22 8/M Tongue 3 Nodule, covered by degenerative mucosa, firm elastic, painless, slow growing Prado et al 27 84/F Lower gingiva 24 Nodule, normochromic, flaccid, painless 53/M Buccal mucosa NA Sessile nodule, firm, normochromic, painless, slow growing NA Pleomorphic adenoma/ fibroma 18 Absent 3.0 NA 120 Absent 1.0 Fibroma NA Absent 1.0 Trauma-induced hyperplasia NA Lesion had been previously excised 9 mo before 4.0 Benign tumor NA NA Nishioka et al 4 2/F Buccal mucosa 9 Nodule, red, painless 0.8 Fibro-epithelial polyp NA NA 52/F Lower lip (mucosa) 36 Nodule, slow growing 0.7 Benign tumor NA NA Safadi et al 29 32/F Upper gingiva 6 Nodule, firm elastic, painless, NA Epulis 10 Absent slow growing 12/M Lower gingiva 12 Exophytic growth, NA NA normochromic, firm Vered et al 30 31/F Maxillary vestibule 4 Submucosal swelling, normochromic 1.0 Fibroma/giant cell lesion 0.7 Mucocele NA NA 35/F Upper gingiva 240 Grey swelling, firm 0.6 Fibroma NA NA E400 HEAD & NECK DOI /HED DECEMBER 2013

5 INTRAORAL NERVE SHEATH MYXOMA TABLE 1. Continued Outcome, recurrence Follow-up, mo Clinical diameter, largest dimension in cm Clinical diagnosis Reference Age/sex Site Duration, mo Clinical features NA Absent 2.5 Benign tumors and tumor-like lesions * Rawal et al 32 33/F Upper gingiva Months Pedunculated nodule, lobulated, firm, pinkish-red, painless, slow growing NA NA 1.5 Traumatic fibroma or fibrolipoma Present case 42/F Buccal mucosa 12 Sessile nodule, normochromic, covered by fine vascular network, elastic, painless, slow growing Abbreviations: NA, not available; NOS, no other specification. *Including pyogenic granuloma, peripheral giant cell granuloma, peripheral ossifying fibroma, and giant cell fibroma, peripheral odontogenic tumors, and oral focal mucinosis. For immunohistochemistry, beyond S-100 positivity, 19 cases were investigated for NSE expression and 18 (94.7%) were positive. EMA expression was investigated in 7 cases. Of these, only 1 case (14.3%) was positive. Other neural markers were also investigated in some cases (Table 1): neurofilament, glial fibrillary acidic protein (GFAP), Leu-7 (CD57), nerve growth factor receptor (NGFR), S-100b, S-100A6, and protein gene product 9.5 (PGP9.5). In the present article, we report a rare case of an oral NSM on the buccal mucosa and perform a systematic review of oral NSM reported in the literature. In general, oral NSM was more frequent in women and in adults during the fourth and fifth decades of age, but it also occurred relatively frequently during the first decade of age and there was 1 congenital case. Clinically, they usually present as a slow and painless growth. Similar clinical features are also observed in cutaneous lesions, which are more common through the third to fifth decades of age and preferentially affect women. 2 Similar to what occurs in the skin, 2 the majority of oral NSM presented as an elastic nodule with normal color. Two cases in this systematic review had a multilobulated appearance. 18,31 Fetsch et al 24 (2005) suggested that local trauma might play a role in the etiology of NSM. In fact, many oral NSMs included in this systematic review, including the present case, were located in areas subjected trauma. Clinically, NSM resembles other more frequent oral lesions, such as non-neoplastic reactive lesions (ie, traumatic fibroma), benign salivary lesions (ie, mucocele), and other benign mesenchymal neoplasms (ie, lipoma, fibrolipoma, schwannoma, and neurofibroma). This explains the complete discordance between the clinical and histological diagnosis in all the cases included in the systematic review. Local excision is the treatment of choice for NSM and, in general, recurrences are reported as uncommon. 2 Nevertheless, in a study with 57 NSMs (56 cutaneous lesions and 1 intraoral lesion), high local recurrence rate was observed. 24 In the skin, recurrences have been attributed to incomplete resection of the tumor. 35,36 In our review, there was 1 case, which was a recurrence of a lesion removed 9 months earlier, but there was no information about the surgical margins. 27 One of the main histological differential diagnoses of NSM is neurothekeoma. 2,24,30 Both lesions present similar clinical characteristics and biological behavior. The overall histological appearance of NSM is a well-circumscribed, but nonencapsulated lesion, characteristically showing proliferation of spindle, stellate, and occasionally epithelioid-shaped cells. 2,22,25,27 The stroma usually presents an abundant myxoid background/matrix of mucopolysaccharide, composed by hyaluronic acid. 7 The arrangement is multinodulated with several lobules separated by connective tissue septa. 4,22,27 Mast cells are frequently seen in these tumors. NSM is histopathologically differentiated from neurothekeoma by its less cellularity and larger degree of myxomatous change. 2 Moreover, neurothekeoma tumor cells frequently present hyperchromatic nuclei and high mitotic counts (as high as 10 per 10 high-power fields). 2 Multinucleated cells are also commonly seen in neurothekeoma. 2 In both NSM and neurothekeoma, mucin HEAD & NECK DOI /HED DECEMBER 2013 E401

6 ROZZA DE MENEZES ET AL. TABLE 2. Histochemical and immunohistochemical features of nerve sheath myxomas. Reference Alcian blue (ph 2.5) S-100 NSE EMA Other neural markers Yamamoto and Kawana 11 (1) (1) (1) NP NF (-) Terrier et al 12 (1) (1) NP NP NP Rodriguez Peralto and el-naggar 13 NP (1) NP (-) NP NP (1) (1) NP NF (1) NP (1) (1) NP NF (-) NP (1) (1) NP NF (-) Green et al 14 NP (1) (1) NP NF (-) NP (1) (1) NP NF (-) NP (1) (1) NP NF (-) NP (1) (-) NP NF (-) Smith et al 32 NP (1) NP NP Leu-7 (-) GFAP (-) Tiffee and Pulitzer 15 NP (1) NP NP Katsourakis et al 16 (1) (1) NP (-) GFAP (1) Pe~narrocha et al 18 (1) (1) (1) NP NP Makino et al 22 (1) (1) (1) (-) S-100b (1) Prado et al 22 NP (1) NP NP NP NP (1) (1) (-) NGFR (-) Nishioka et al 4 NP (1) (1) (-) NGFR (-) NP (1) (1) (1) NGFR (-) Safadi et al 29 NP (1) (1) NP GFAP (-) NP (1) (1) NP S-100-A6 (1) PGP9.5 (1) Vered et al 30 NP (1) (1) NP S-100-A6 (1) PGP9.5 (1) NP (1) (1) NP S-100-A6 (1) PGP9.5 (1) Rawal et al 31 NP (1) NP NP NP Present case (1) (1) (1) (-) NP Abbreviations: NSE, neuron-specific enolase; EMA, epithelial membrane antigen; (1), positive; NP, not performed; NF, neurofilament; (-), negative; GFAP, glial fibrillary acidic protein; NGFR, nerve growth factor receptor; PGP9.5, protein gene product 9.5. within the tumor lobules shows strong positivity for Alcian blue In 2005, Fetsch et al 24 based a study of 57 cases, concluded that NSM is a distinct peripheral nerve sheath tumor with immunoreactivity features of Schwann cell differentiation. It was noticed that NSM consistently express S-100 protein, GFAP, and NSE. 24 In opposition, neurothekeoma is reported to be negative for S-100 and FIGURE 3. Distribution of cases of nerve sheath myxoma according to age group. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] E402 HEAD & NECK DOI /HED DECEMBER 2013

7 INTRAORAL NERVE SHEATH MYXOMA FIGURE 4. Distribution of cases of nerve sheath myxoma according to location. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] GFAP. 24 They concluded that NSM is a distinct clinicopathologic entity of nerve sheath derivation and that it is, most probably, not a subtype of neurothekeoma. 24 For this reason, in this systematic review, we included only lesions immunopositive for S-100, which is an important finding that clearly differentiates them from neurothekeoma. Therefore, we believe that only true NSMs were included in our study. 4,11 16,18,22,27,29 32 Beyond S-100 expression, the majority of oral NSMs, including the current case, expressed NSE. 4,11,14,18,22,29,30 Few cases (n 5 3) in this systematic review were evaluated for GFAP immunoexpression. 4,16,32 In 3 cases, 1 was positive. In general, NSMs typically show a very limited EMA expression, which is often confined to perineural cells located on the periphery of the tumor lobules. 24 In the present case, we did not observe any positivity for EMA, which was a feature also observed in the majority of oral NSMs included in this systematic review. Interestingly, the only case positive for EMA expression 4 showed a great expression within the lobules of the tumors, suggesting a mixed Schwann cell and perineural cell origin. Recently, Sheth et al (2011), 37 in a microarray-based gene expression profile study, confirmed that NSMs are of peripheral nerve sheath origin, with have very similar molecular genetic signatures to schwannomas, and suggested that neurothekeomas, on the other hand, may actually be a variant of fibrous histiocytomas. Although it is clear that NSMs and neurothekeomas are distinct lesions, many articles, even recent published ones, use these 2 terms as synonymous, or still consider them as variants of the same tumor ,18,22,27,29,32 Moreover, many cases of oral lesions reported under the name NSM did not present immunohistochemical features compatible with this entity, being S-100 negative. In other cases, any investigation of the S-100 expression was performed. The histological differential diagnosis of NSM includes other types of peripheral nervous sheath tumors, such as plexiform neurofibroma and plexiform schwannoma with myxoid change, 2 because they also present a multilobulated architecture, fusiform tumor cells, and usually a mucoid matrix. 4,30 Plexiform neurofibromas may be difficult to differentiate from NSMs in hematoxylin-eosin stained sections. Mucoid matrix is abundant in plexiform neurofibromas and reacts strongly in Alcian blue, similar to NSMs. 2 Nevertheless, in plexiform neurofibromas, the mucoid matrix, as well as the tumor cells and the mast cells, are present in both lobules (fascicles) and interlobulated area, and are not confined within the lobules as shown in NSM. 2 Unlike NSM, plexiform schwannomas present a collagenous capsule and often show clearly Antoni A areas. 2 Nevertheless, some cases of NSM may show focal nuclear palisading and/or Verocay body-like formations. 24 This feature was not observed in any oral NSM included in this systematic review. Non-neural entities may also be included in the histological differential diagnosis (ie, focal mucinosis, fibrous lesions with myxomatous pattern, and peripheral odontogenic myxomas). Differently from NSM, these not have mast cells, do not express neural markers, 4,22,24,27 and do not present a lobulated pattern. 2 Moreover, odontogenic myxomas are usually intraosseous lesions, but peripheral (gingival) lesions may occur. Therefore, only in cases of gingival NSM, peripheral odontogenic myxoma may be included in the differential diagnosis. In conclusion, oral NSM is rare, clinically similar to other more common alterations, such as non-neoplastic reaction lesions, and may represent a diagnostic challenge for pathologists. Other lesions of myxomatous nature should be included in the microscopical differential diagnosis, mainly the neurothekeoma. To confirm the diagnosis of NSM, the evaluation of S-100 protein expression or other neural marker is essential. The use of the terms NSM and neurothekeoma as synonymous or as variants of the same tumor should be avoided, because they are clearly distinct lesions. 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