Significantly Elevated FDG Activity in Neurothekeoma.

ABSTRACT: Neurothekeoma is a very rare cutaneous lesion affecting mainly young patients. The lesion is generally benign. We report here that intense FDG activity on PET/CT was noted at the site of primary neurothekeoma of the right shoulder in a 16-year-old boy. Abnormal FDG activity was also seen in the metastatic neurothekeoma in the lung in the same patient 2 years later.

Neurothekeoma With PI3K w552*, ALK P1469S, SMO G461S, and ERBB3 L77M Genetic Alterations.

ABSTRACT: Neurothekeoma, a lesion of possible fibrohistiocytic origin, is a rare, benign, superficial soft tissue tumor, histologically subclassified in 3 types: myxoid, cellular, or mixed. It clinically presents as a solitary, pink to brown nodule, ranging from 0.3 to 2.0 cm. Four point mutations (PI3K w552*, ALK P1469S, SMO G461S, and ERBB3 L77M) were identified by next-generation sequencing of a neurothekeoma presenting in the left inner thigh of a 53-year-old man. We highlight novel genetic alterations (SMO G461S and ERBB3 L77M) and previously known mutations (PI3KCA w552* and ALK P1469S) that play a role in other pathogenic pathways, but to the best of our knowledge, these have not yet been reported in neurothekeoma.

PRAME expression in cellular neurothekeoma: A study of 11 cases.

BACKGROUND: Preferentially expressed antigen in melanoma (PRAME) has been widely investigated in the skin, mainly in melanocytic tumors, and constitutes an aid in differentiating benign from malignant lesions. Very few studies have been performed on non-melanocytic tumors. MATERIALS: We investigated the immunohistochemical expression of PRAME on a series of 11 neurothekeomas (NTKs), together with 3 cases of nerve sheath myxoma (NSM) and 1 case of plexiform fibrohistiocytic tumor (PFT), in order to evaluate the presence and usefulness of this marker in their differential diagnosis. RESULTS: PRAME was variably expressed in all cases of NTK, with moderate intensity in three cases and faint in the remaining cases; on the contrary, cases of NSM and PFT were negative. CONCLUSIONS: This study expands the entities of cutaneous non-melanocytic tumors expressing PRAME, and confirms that this marker is not restricted to malignant tumors. Expression of PRAME in NTK does not seem to be related to distinctive histopathologic features.

Multiple myxoid cellular neurothekeomas in a patient with systemic lupus erythematosus.

Cellular neurothekeoma is a cutaneous tumor with a distinctive histopathologic appearance characterized by a dermal-based multinodular proliferation of epithelioid to spindled cells. Although the tumor may show varying amounts of myxoid stroma, extensive myxoid change is uncommon. The tumor typically presents as a solitary nodule with a predilection for the head and neck and upper limbs; examples of multiple cellular neurothekeomas are decidedly rare. The present report describes a unique case of multiple myxoid cellular neurothekeomas arising in a 60-year-old female with systemic lupus erythematosus. Two papular lesions were identified involving the skin inferior to the umbilicus and the left inguinal crease. Both lesions were histopathologically similar, forming a nodular mass composed of epithelioid cells in a prominent myxoid stroma. By immunohistochemistry the lesional cells expressed NKI/C3, microphthalmia transcription factor (MiTF), and CD68, with focal staining for PGP9.5, factor XIIIa, and CD10 also observed. The tumors were negative for S-100, SOX-10, epithelial membrane antigen, desmin, smooth muscle actin, glial fibrillary acid protein, and CD34. The present case confirms that cellular neurothekeoma can present clinically as multiple lesions and can have a predominantly myxoid appearance, potentially mimicking other cutaneous myxoid lesions.

Pediatric cellular neurothekeoma: Seven cases and systematic review of the literature.

BACKGROUND/OBJECTIVES: Neurothekeoma is a rare, benign, cutaneous neoplasm consisting of Schwann cells and perineural cells in myxoid stroma. Cellular neurothekeoma (CNT) was previously thought to represent a morphologic variant of neurothekeoma, but recent studies have shown that CNTs are unrelated to neurothekeomas and are more likely of histiocytic lineage. METHODS: Herein, we describe seven cases of CNT in pediatric patients. A comprehensive search of PubMed was performed, and 71 cases of cellular neurothekeoma in pediatric patients were reviewed. RESULTS: The clinical differential diagnosis for these lesions included Spitz nevi, keloid, juvenile xanthogranuloma, cutaneous lymphoid hyperplasia, and lymphomatoid papulosis. All cases were treated by excision or excisional biopsy. Histopathologically, all demonstrated multilobular, primarily intradermal neoplasms composed of plump spindled or epithelioid mononuclear cells with abundant eosinophilic pale-staining cytoplasm. Immunophenotypic findings included CD68 and NKI/C3 positivity, and negative staining with cytokeratin, S-100, Melan-A, and SOX-10. CONCLUSION: Cellular neurothekeoma is distinguished from conventional neurothekeoma by increased cellularity, a lack of myxoid stroma, and a lack of neural expression with immunohistochemical stains. These uncommon neoplasms should be included in the differential diagnosis of dermal nodules in children. Accurate diagnosis of these lesions is essential, as they can be mistaken for malignancy leading to unnecessary treatment.

Cellular neurothekeoma: Report of two cases with unusual immunohistochemical features.

Cellular neurothekeoma (CNT) is a dermal lesion with still unknown histogenesis, characterized by immunohistochemical staining for NKI/C3, NSE, MiTF, CD10 and CD68, whereas S100 protein, desmin and cytokeratins are negative. Particularly, in several studies NKI/C3 has been reported as a strong marker of CNT. We describe herein the clinical, histopathological and immunohistochemical features of two cases morphologically consistent with myxoid CNT, one of which showing some atypical features, both characterized by negative immunohistochemical staining for NKI/C3. Our findings stress the importance of morphology in diagnosing CNT and underline the fact that NKI/C3 can fail to stain cases belonging to the "neurothekeoma family." In selected cases of CNT, an expanded immunohistochemical panel is mandatory to differentiate this tumor from other dermal lesions.

Multiple cellular neurothekeomas in a middle-aged woman including the lower extremity: A case report and review of the current literature.

Cellular neurothekeoma is a benign cutaneous neoplasm that typically occurs on the head, neck, and upper body of young adults with a slight female predominance. It is a rare lesion to diagnose and multiple neurothekeomas in one patient are even more uncommon finding. We present a case of multiple neurothekeomas in a middle-aged woman with lower extremity involvement and summarize the current literature on multiple neurothekeoma patients. A 46-year-old female presented with nearly one dozen skin-colored papules on the head, upper limb, and lower limb. The lesions were clinically diagnosed as dermatofibromas and a nevus. Eight lesions were biopsied and confirmed to be cellular neurothekeomas, with one initially misinterpreted on histology as a dermatofibroma. Awareness of cellular neurothekeoma as a diagnostic entity and the possibility of atypical presentations as seen in our case (eg, in multiple numbers, in older adults, and on the lower extremity) are important in allowing for accurate clinical and histological diagnosis of these lesions. The possibility of a syndromic association with multiple cellular neurothekeomas should be explored further.

Orbital nerve seath myxoma with extraocular muscle involvement: a rare case.

A 66-year-old woman with breast cancer presented with a painless mass in the left orbit. MRI revealed a well-defined intraconal mass in the temporal quadrant of the orbit. Fifteen months later, a further MRI indicated the mass had grown, displacing the left optic nerve and making contact with the lateral rectus muscle, suggesting its possible intramuscular origin. Despite the clinical and radiological characteristics of the lesion and its slow growth, a PET/CT study was developed because of the history of malignant disease. No metabolic activity of the mass or malignant lesion in other locations was observed. After surgical excision, histopathological examination revealed an abundant myxoid matrix with few spindle-shaped cells and no signs of malignancy. The cells were immunopositive for CD34, positive for S-100 protein, and negative for EMA, actin, and CD57. A diagnosis was made of a nerve sheath myxoma. The orbital location of these tumors is extremely rare.

Nerve sheath myxoma of the tongue.

Nerve sheath myxoma (NSM) of the oral mucosa is a slow-growing, benign, often asymptomatic submucosal mass. We report on a case of classical NSM of the tongue, with diagnostic and therapeutic approach to the case. Many NSM arise within the endoneurium of a peripheral nerve. It is a rare condition with no apparent differences between sexes in its prevalence. It can occur at any age.

SOX-10 and MiTF expression in cellular and 'mixed' neurothekeoma.

BACKGROUND: Neurothekeoma and nerve sheath myxoma have long been interpreted as related tumors that share nerve sheath linage. Lack of S100 expression in neurothekeoma and similarities of gene expression profiles between neurothekeoma and fibrohistiocytic tumors have created reasonable doubt about this concept. SOX-10 represents a marker for schwannian and melanocytic differentiation, and is expressed in other tumors of nerve sheath linage. Microphthalmia transcription factor (MiTF) expression has been repeatedly reported in cellular neurothekeoma in the recent literature and was proposed as a helpful marker in this entity. METHODS: We investigated 25 cases of cellular neurothekeoma, 8 cases of mixed neurothekeoma and 1 case of nerve sheath myxoma for the expression of SOX-10, MiTF, S100, NKI/C3, Melan-A and smooth muscle actin (SMA) using immunohistochemistry. RESULTS: A lack of SOX-10 expression was demonstrated in 100% of cellular and mixed neurothekeomas, but was present in the case of nerve sheath myxoma. More than two thirds of neurothekeomas showed very focal or no reactivity with MiTF. CONCLUSIONS: Our data suggest that neurothekeoma and nerve sheath myxoma are unrelated, and that cellular and mixed neurothekeoma may not be of nerve sheath lineage. In addition, MiTF should not be regarded as a useful marker in neurothekeoma.

Cellular neurothekeoma of the eyelid: a unique internal palpebral presentation.

A 50-year-old woman presented with a mass lesion of the inferolateral palpebral conjunctiva similar in appearance to a chalazion, but unusual enough in presentation that excisional biopsy was initially performed. Histopathologic analysis revealed a dermal fibrohistiocytic neoplasm consistent with cellular neurothekeoma. Neurothekeoma is a benign tumor; the cellular variant is rare and of unclear histogenesis. Completely internal eyelid location is particularly rare, with other identifiable case reports of cellular neurothekeoma palpebrae referring to external or unspecified eyelid location. This case provides an example of the chalazion as masquerader and re-emphasizes the importance of maintaining a broad differential diagnosis and high index of suspicion regarding atypically appearing chalazia.

Immunohistochemical analysis of KBA.62 in 18 neurothekeomas: a potential marker for differentiating neurothekeoma, but a marker that may lead to confusion with melanocytic tumors.

BACKGROUND: Neurothekeoma represents a neoplasm of uncertain histogenesis that often occurs on the head and neck of younger individuals. Distinguishing neurothekeoma from other tumors, particularly malignancies such as melanoma, can be difficult given the variable presence of nuclear atypia, mitoses and extension into fat or skeletal muscle. KBA.62 represents an anti-melanoma monoclonal antibody that marks approximately 93% of melanomas. This study sought to evaluate KBA.62 expression in neurothekeomas, both as means of affirming the diagnosis and as a potential confounding factor in excluding a melanocytic process. METHODS: Eighteen neurothekeomas from 17 patients were analyzed by light microscopy and immunohistochemistry. Immunohistochemistry was performed with KBA.62, S100 and CD10 antibodies. The diagnosis of neurothekeoma was confirmed by at least two dermatopathologists. RESULTS: All cases showed similar light microscopic and immunohistochemical features. With the exception of two cases, cells expressed CD10 and exhibited morphologic features consistent with neurothekeoma. All 18 cases were S100 immunonegative. The epithelioid cells of all neurothekeomas were KBA.62 immunopositive, including both of two neurothekeomas occurring in the same patient. CONCLUSIONS: In this study 100% of neurothekeomas tested were KBA.62 positive, admittedly to varying degrees, suggesting the utility of this reagent as being supportive of the diagnosis of neurothekeoma.

A benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma.

There are several recent reports describing hybrid peripheral nerve sheath tumors showing a biphasic component of neoplastic cells. These combinations include a mixture of neurofibroma and schwannoma, schwannoma and perineurioma, neurofibroma and perineurioma, and perineurioma and granular cell tumor. A case of a triphasic combination of neurofibroma, schwannoma, and perineurioma has also been described. We describe the clinicopathologic and immunohistochemical characteristics of 9 cases of a benign cutaneous plexiform nerve sheath tumor located on the lips and exhibiting hybrid features of perineurioma and cellular neurothekeoma. Clinically, lesions were solitary dome-shaped papules located on the lips. Histopathologically, the neoplasms consisted of well-circumscribed but uncapsulated dermal nodules with a plexiform pattern. They were composed of nests or rounded aggregations of neoplastic cells embedded in a slightly myxoid stroma. Within the aggregates, cells were distributed in a storiform and lamellar pattern. Immunohistochemically, most neoplastic cells expressed strong immunoreactivity for S100A6, MiTF, NKI/C3, PGP9.5, EMA, and NSE, whereas variable, focal, and weaker positivity for CD34, claudin-1, and Glut-1 was seen in some cases. On the basis of these findings, we believe that this neoplasm is a distinctive benign cutaneous plexiform nerve sheath tumor with histopathologic and immunohistochemical hybrid features of perineurioma and cellular neurothekeoma.

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

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.

Expression of MiTF may be helpful in differentiating cellular neurothekeoma from plexiform fibrohistiocytic tumor (histiocytoid predominant) in a partial biopsy specimen.

BACKGROUND: Overlapping histopathologic features of cellular neurothekeoma (CNT) and plexiform fibrohistiocytic tumor (PFHT), when both are predominantly composed of histiocytoid cells, make distinction between these entities challenging. Some have suggested that CNT and PFHT are related entities. No prior study has demonstrated a reliable immunohistochemical panel to differentiate these entities. METHODS: Skin biopsies diagnosed as CNT and PFHT, from 2004 to 2010 were retrieved with accompanying pathology reports. Each case was reviewed by at least 2 dermatopathologists and 2 soft tissue pathologists for confirmation of diagnosis. All cases were then evaluated for immunohistochemical expression of PAX2, NKIC3, CD10, and microphthalmia transcription factor (MiTF). RESULTS: Histopathologically, the histiocytoid areas of each tumor shared similar architecture, demonstrating nests and fascicles of histiocytoid to spindled cells, with some separation of nests by collagen bands. Both CNT and PFHT were uniformly positive for NKIC3 and CD10, and both were frequently PAX2 positive. MiTF was strongly and diffusely positive in CNT and was consistently negative in the PFHT. CONCLUSIONS: CNT and PFHT share many histopathologic features and immunohistochemical staining patterns. Of the stains we evaluated, we found that expression of MiTF may be a reliable marker for distinguishing CNT from histiocytoid-predominant PFHT, especially in instances where only a small part of the tumor is sampled for evaluation.

Cellular neurothekeoma with fascicular growth features mimicking cellular dermatofibroma.

BACKGROUND: Cellular neurothekeoma (CNT) is a benign cutaneous mesenchymal neoplasm. Most demonstrate a lobulated to micronodular architecture. Rarely, CNT demonstrates a predominantly fascicular growth pattern, without prominent sclerosis and thus can mimic cellular dermatofibroma (DF). METHODS: Three CNT with a predominantly fascicular pattern were obtained. The clinicopathologic features and accompanying immunohistochemical stains were evaluated. RESULTS: All cases demonstrated a moderately cellular proliferation of epithelioid to spindle cells with pale to eosinophilic slightly granular cytoplasm, vesicular nuclei, and a single nucleolus arranged in a fascicular pattern with thick collagen bundles at the periphery (collagen trapping). One case had prominent epidermal hyperplasia. The neoplastic cells expressed NKI-C3, CD10, and micropthalmia transcription factor and lacked expression of factor XIIIa, S-100, epithelial membrane antigen, and CD34. CONCLUSIONS: Our cases showed an unusual pattern of CNT with a predominantly fascicular growth pattern, thickened collagen bundles at the periphery, and occasionally epidermal hyperplasia. The overlap with cellular DF is striking. The presence of plump to epithelioid cytomorphology with abundant cytoplasm, with focally prominent nucleoli; the presence of focal lobulated to micronodular growth pattern along with micropthalmia transcription factor positivity; and lack of factor XIIIa expression are helpful in distinguishing fascicular CNT from cellular DFs.

Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis.

Neurothekeomas and dermal nerve sheath myxomas have previously been considered related cutaneous neoplasms of peripheral nerve sheath origin based on light microscopic similarities. However, recent immunohistochemical and ultrastructural data indicate nerve sheath myxomas exhibit true nerve sheath differentiation, whereas no such compelling evidence exists for neurothekeomas. Although neurothekeomas lack a specific immunohistochemical profile, similar antigen expression and histopathologic patterns suggest neurothekeomas may be categorized as fibrohistiocytic tumors. To date, no known molecular studies have examined the histogenetic relationship of these tumors. We report the first microarray-based gene expression profile study of these entities on formalin-fixed paraffin-embedded tissues. Cases of dermal schwannomas, dermal nerve sheath myxomas, myxoid/mixed/cellular neurothekeomas, and cellular fibrous histiocytomas diagnosed in the past 3 years were identified in our database. Archival formalin-fixed paraffin-embedded tissue from 28 patients was selected for microarray analysis (seven schwannomas, five nerve sheath myxomas, nine myxoid/mixed/cellular neurothekeomas and seven cellular fibrous histiocytomas). Following tumor RNA isolation, amplification and labeling using commercially available kits, labeled targets were hybridized to the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array (Santa Clara, CA, USA). Acquisition of array images and data analyses was performed using appropriate software. Hierarchical clustering and principal component analysis demonstrated discrete groups, which correlated with histopathologically identified diagnoses. Dermal nerve sheath myxomas demonstrate very similar molecular genetic signatures to dermal schwannomas, whereas neurothekeomas of all subtypes more closely resemble cellular fibrous histiocytomas. We are the first to report distinct gene expression profiles for nerve sheath myxomas and neurothekeomas, which further substantiates the argument that these are separate entities. Our molecular data confirms that dermal nerve sheath myxomas are of peripheral nerve sheath origin, and suggests that neurothekeomas may actually be a variant of fibrous histiocytomas.

Fibrohistiocytic tumors containing zebra body-like inclusions and fibripositors.

Plexiform fibrohistiocytic tumor (PFH) and cellular neurothekeoma (CN) are dermal neoplasms that present many histological and immunophenotype similarities as well as unknown histogenesis. Recently, the ultrastructural detection of zebra body-like inclusions in lesional histiocytes has been considered crucial to favor the diagnosis of PFH over that of CN. Here we report two examples of dermal tumors that were diagnosed as CN. Electron microscopy revealed cytoplasmic collections of myelin and zebra body-like inclusions in tumor cells; these inclusions focally merged together or with multivesicular bodies; tumor cells also showed collagen secretion granules and fibripositors, i.e., channels containing single, double or multiple copies of collagen fibrils. These observations support the view that PFH and CN have a common histogenesis and consists of cells sharing phagocityc and fibrillogenic abilities.