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Type, paste, and edit text Clinical Presentation A 48-year-old female was referred to the Dental School of the Autonomous University of Coahuila, México, for the evaluation of a lesion located on the anterior left buccal mucosa. Clinical examination revealed a normal-colored exophytic nodule, which was firm on palpation; the nodule measured approximately 5 x 5 x 9 mm in size and was covered by an intact smooth mucosa (Figure 1). The patient did not remember when she first noted the lesion, and it was asymptomatic. Her medical history was non-contributory. Differential Diagnosis The clinical presentation was clearly that of a benign process. Our differential diagnosis included reactive lesions and benign submucosal neoplasms that might affect the buccal mucosa. Our primary clinical consideration was a fibrous hyperplasia (traumatic/irritation fibroma). Despite the absence of a history of trauma or biting, the location of the nodule precisely in the space of the absent premolars suggested trauma by suction of the buccal mucosa. Fibrous hyperplasia is the most common benign hyperplastic intraoral lesion, and the buccal mucosa is its preferred site of occurrence. Fibrous hyperplasia often appears as solitary pink nodules near the level of the occlusal plane.1 Pyogenic granulomas are often red to violaceous easily bleeding masses, often ulcerated. However, they can theoretically re-epithelize and appear as pink smooth nodules, and the extensive fibrosis in the stroma confer a firmer consistency. The most affected site is the gingiva, followed by the lips, tongue, and buccal mucosa. Finally, among the reactive lesions, we also consider a mucocele, a common lesion of the oral mucosa. This entity usually appears as a translucent or bluish fluctuant nodule on the lower labial mucosa; in a large review of patients with oral mucocele, it was found to affect the buccal mucosa in only 4.8% of the cases. In the present case, the lesion probably was a long-standing one that became fibrotic and appeared firmer.3 When dealing with oral exophytic nodular lesions, mesenchymal neoplasms originating from the adipose tissue should be considered. Lipoma is rare in the oral region; however, it can present as a smooth nodule, and the buccal mucosa is the most common site. Its color may vary from yellow to pink if the adipose tissue is deeper.4 Neural tumors are clinically indistinguishable from mesenchymal tumors. The most common tumors affecting the oral region are neurofibroma, traumatic neuroma, and granular cell tumor (GCT), while schwannoma, perineurioma, and palisaded encapsulated neuroma rarely affect this region. All these tumors can present as solitary smooth surface nodules affecting the tongue, labial mucosa, palate, and less commonly the buccal mucosa. Neurofibroma is the most common peripheral nerve sheath neoplasm, commonly diagnosed in children and young adults, and affecting the tongue and buccal mucosa. Traumatic neuroma presents as smooth, non-ulcerated nodules, that most commonly affect the mucosa overlying the mental foramen and lower labial mucosa. GCT presents as a firm solitary nodule beneath an intact mucosa and it commonly presents in the dorsal tongue, followed by the buccal mucosa.5 In conclusion, a reactive lesion was favored, but the entities cited here as differential diagnoses could not be ruled out clinically; therefore, histopathological features are considered for the final diagnosis. Diagnosis and management Considering the benign nature and size of the lesion, an excisional biopsy was performed. Histopathological analysis with hematoxylin and eosin (H&E) staining revealed a well circumscribed, non-encapsulated hypocellular proliferation of thick collagen fibers, even sclerotic, showing nests of pale-stained epithelioid cells with indistinct cytoplasmic borders and oval nuclei, interspersed between the collagen bundles and in focal areas around the nodule, resembling a pseudo-capsule (Figure 2, A-D). Scattered small blood vessels were seen within the dense collagen. Small normal appearing nerve bundles were identified in the stroma outside the tumor. This suggested a neural neoplasm. The patient recovered well, and follow-up showed no recurrence. Immunohistochemical analysis was performed to characterize the cellular population through a panel of antibodies directed to neural structures, including glucose transporter 1 (Glut-1), epithelial membrane antigen (EMA), Claudin-1, S-100 protein, and CD34. Glut-1 showed strong cytoplasmic and membranous positivity in the aggregates of epithelioid pale-stained cells intermixed in the sclerotic collagen, and in focal areas surrounding the nodule. Positivity in the basal and spinous layers of the superficial epithelium, as well as in the perineurium of the nerve bundles in the surrounding stroma served as internal controls. Claudin-1 and EMA showed membranous positivity in the same cells (Figure 3, A-D). On the basis of the histopathologic and immunohistochemical findings, the final diagnosis was soft tissue perineurioma of sclerosing type. Discussion Perineuriomas are benign neoplasms originating solely through proliferation of the perineurial cells. Two types have been reported; soft tissue or extraneural and intraneural. The sclerosing subtype is an uncommon variant of the extraneural perineurioma that has a predilection for the fingers of young adults7 but is infrequently encountered in the oral cavity. A review of oral extraneural perineurioma reported in the English literature over a period of 34 years revealed that 73% were of the conventional subtype and only 9% were of the sclerosing subtype. The conventional extraneural perineurioma mainly affects the subcutis of the limbs and intraorally the mandible, tongue, and buccal mucosa as a non- encapsulated loosely arranged spindle cell proliferation that is positive for EMA, Glut-1, and Claudin-1.6,8 To date, only two intraoral cases of sclerosing perineurioma have been reported, both in 2010; both the patients were males in their second and third decades of life, with the lesion affecting the buccal mucosa and the lower lip. These cases presented as submucosal painless nodules covered by a smooth normal-colored surface. Clinical diagnoses were mucocele and benign mesenchymal tumor. The main histopathological features included a well-circumscribed, densely collagenized, sclerotic stroma with nests of epithelioid cells with indistinct cytoplasm.9,10 The histopathologic features of the present case are similar to these two cases and to typical sclerosing perineuriomas described in the hands of two females.11,12 Regarding immunohistochemistry, the neoplastic cells of sclerosing perineurioma are strongly reactive to Glut-1, EMA, Claudin-1, and collagen type IV, while vimentin reacts in a diffuse pattern throughout the tissue. Glut-1 has been recognized as the preferred marker to identify perineurial origin. Positivity has also been seen with CD10, CD99, β- catenin, and focally for laminin.7,9,10,13-15 Other markers documented with variable positivity in sclerosing perineurioma of the hands are the cytokeratin cocktail (AE1, AE3, and CK1), CAM 5.2, muscle-specific actin, and α-smooth muscle actin (SMA). The latter appeared to be positive in cells different from cells immunoreactive for EMA, Claudin-1, and Glut-1.7,16 In classic soft tissue perineurioma, variable immunoreactivity has been identified for CD34 and SMA.6 S-100 protein is usually negative, and this finding is very important to exclude neurofibroma, traumatic neuroma, schwannoma, and palisaded encapsulated neuroma.9,10 Neurofibroma should be positive for S-100, CD34, and neurofilament protein.17 Intraneural perineurioma is rare in the oral region. It usually affects adolescents and young adults and presents with enlargement of a neural branch; it is composed almost entirely of spindle-shaped cells arranged in a whorled pattern or in ill-defined fascicles. Further, perineurial cells proliferate around Schwann cells in an onion bulb-like pattern. These cells are positive for EMA, Glut-1, and Claudin-1.8,18 While not necessary for diagnosis, clonal cytogenetic aberrations have been documented in cases of sclerosing perineurioma, including rearrangements and/or deletions of chromosome 10q, translocations in 2p and 9q involving the ABL1 gene, and mutations on chromosome 22, specifically in the region of the NF2 gene. The latter has also been detected in soft tissue and intraneural perineurioma. Additionally, the loss of chromosome 13 was identified in a soft tissue perineurioma of the thigh.19-22 When diagnosing neural lesions, immunohistochemistry is a useful diagnostic aid to identify and characterize the nature of the neoplastic cells. In fact, when a pathologist believes that a lesion is neural but the S-100 protein is negative, perineurioma should be considered as a differential diagnosis. To the best of our knowledge, this is the third case of oral sclerosing perineurioma.